Journal articles on the topic 'BRCA2'
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1
Friedlander, Michael, Kathleen N. Moore, Nicoletta Colombo, Giovanni Scambia, Byoung-Gie Kim, Ana Oaknin, Alla Sergeevna Lisyanskaya, et al. "Efficacy of maintenance olaparib for newly diagnosed, advanced ovarian cancer patients (pts) by BRCA1 or BRCA2 mutation in the phase III SOLO1 trial." Journal of Clinical Oncology 37, no. 15_suppl (May 20, 2019): 5551. http://dx.doi.org/10.1200/jco.2019.37.15_suppl.5551.
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5551 Background: In SOLO1 (NCT01844986), maintenance olaparib resulted in a significant improvement in progression-free survival (PFS) for newly diagnosed, BRCA1- and/or BRCA2-mutated, advanced ovarian cancer pts compared with placebo (HR 0.30, 95% CI 0.23–0.41; median not reached vs 13.8 months; Moore et al. N Engl J Med 2018). We investigated PFS in SOLO1 for the subgroups of pts with BRCA1 mutations ( BRCA1m) or BRCA2 mutations ( BRCA2m). Methods: All pts were in clinical complete or partial response to platinum-based chemotherapy and were randomized to maintenance olaparib (300 mg twice daily; tablets) or placebo. After 2 years, pts with no evidence of disease discontinued study treatment, but pts with evidence of disease could continue study treatment. PFS by BRCAm was a predefined analysis. BRCAm were identified by central germline (Myriad or BGI) or local testing; Foundation Medicine testing confirmed tumor BRCAm. Results: Median follow-up for PFS was ~41 months in the olaparib and placebo arms. Of 391 randomized pts, 282 had BRCA1m (72%), 106 had BRCA2m (27%) and three (1%) had both (Table). Two pts in the olaparib arm had somatic BRCAm (one BRCA1m, one BRCA2m); all others had germline BRCAm. At the primary data cut-off, 155 pts in the BRCA1-mutated group (55%), 43 in the BRCA2-mutated group (41%) and none in the BRCA1/2 -mutated group had disease progression. The percentage of BRCA1-mutated pts who received olaparib and were progression-free at 1, 2 and 3 years was 86%, 69% and 53% (vs 52%, 36% and 26% receiving placebo) and for BRCA2-mutated pts was 92%, 85% and 80% (vs 50%, 32% and 29%, respectively). Conclusions: Significant PFS benefit with olaparib versus placebo was demonstrated for all pts, regardless of whether they had BRCA1m or BRCA2m. Statistical tests were not used to compare BRCA1- and BRCA2-mutated pts, but those with BRCA2m appeared to receive greater benefit from maintenance olaparib than those with BRCA1m. Clinical trial information: NCT01844986. [Table: see text]
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Zhang, Yinuo. "BRCA1, BRCA2 and primary ovarian insufficiency." E3S Web of Conferences 165 (2020): 05009. http://dx.doi.org/10.1051/e3sconf/202016505009.
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BRCA1 and BRCA2 genes belong to the family of ataxia-telangiectasia-mutated (ATM)-mediated DNA DSB repair genes that play a critical role in the DNA double-strand break (DSB) repair. Mutations in BRCA genes significantly increase the lifetime risk of breast, ovarian, fallopian tube and primary peritoneal cancers. In addition to the increased risk for multiple malignancies, recent literature suggest that mutations in BRCA genes could lead to decreased ovarian reserve and subsequent ovarian aging. In this review, we will focus on role of BRCA1 and BRCA2 in ovarian function, particularly ovarian aging and primary ovarian insufficiency. Serum AMH values are generally lower in BRCA1 mutation carriers but not in BRCA2 mutation carriers. BRCA2 carriers were more likely to have chemotherapy-induced amenorrhea DNA not stable, linking with ovarian aging. The mechanism by which BRCAs mutation in the pathogenesis of POI is the inpaired function of repairing DNA breaks. Future studies investigating the knockout models to elucidate the role of the BRCAs genes in ovarian development and oocyte maturation will be interesting.
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Wang, Aifen, Robert W. Holloway, Lijuan Cui, Yan Sun, and Zihan Zhao. "Association betweenBRCA1 and BRCA2 mutations and prognosis in women with endometrial carcinoma." Journal of Clinical Oncology 37, no. 15_suppl (May 20, 2019): e17115-e17115. http://dx.doi.org/10.1200/jco.2019.37.15_suppl.e17115.
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e17115 Background: To evaluate the prognosis of BRCA mutation carriers compared to non-carriers and to demonstrate whether BRCA1 and BRCA2 mutation carriers present similar survival patterns among endometrial carcinomas. Methods: This data was from NCI Cancer Genome Atlas endometrial cancer database (TCGA) with pathogenic mutations in BRCA1 (58) or BRCA2 (77) or BRCA1and BRCA2 coexisted mutation (40) and non-mutation (461). We compared clinicopathologic features and prognosis of patients with BRCA1 or BRCA2 or BRCA1and BRCA2 coexisted mutation. Survival time was analyzed for the combined data using Cox proportional hazard models with BRCA1and BRCA2 as time-varying covariates. Results: We found histologic types of patients with BRCA1 or BRCA2 mutation presented more progressive than non-carriers ( p = 0.029, p= 0.029, respectively). BRCA1 or BRCA2 mutations were detected to be associated with younger patients at diagnosis ( p = 0.036, p = 0.001, respectively). BRCA2 mutation carrier was identified more advanced stage than BRCA non-carriers. Compared to patients with BRCA1 mutation, the body mass index is higher in non-carriers. Before around 100 months survival, BRCA2 mutation carriers had the most favorable overall survival (OS). OS rate of all patients with BRCA1 or BRCA2 mutation was higher than non-carriers. BRCA1 and BRCA2 mutation carriers had similar OS. Around 100 months later, BRCA1 carriers had more favorable OS than patients with BRCA2 mutation, BRCA1 / BRCA2 coexisted mutation and non-carriers ( p < 0.001). Patients with BRCA2 mutation had the most favorable progression-free survival (PFS), following by BRCA1 and BRCA2 coexisted mutation and BRCA2 alteration carriers ( p= 0.011). BRCA non-carriers had the worst PFS and OS all the time. Conclusions: BRCA1 or BRCA2 mutation carriers have favorable overall survival and progression-free survival among patients with endometrial carcinoma. [Table: see text]
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Ponce, Jordi, Sergi Fernandez-Gonzalez, Iris Calvo, Maite Climent, Judith Peñafiel, Lidia Feliubadaló, Alex Teulé, et al. "Assessment of ovarian reserve and reproductive outcomes in BRCA1 or BRCA2 mutation carriers." International Journal of Gynecologic Cancer 30, no. 1 (November 27, 2019): 83–88. http://dx.doi.org/10.1136/ijgc-2019-000626.
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IntroductionThe clinical impact on fertility in carriers of BRCA1 and BRCA2 mutations remains unclear. The aim of this study was to assess ovarian reserve as measured by anti-mullerian hormone levels in BRCA1 or BRCA2 mutation carriers, as well as to investigate the impact of anti-mullerian hormone levels on reproductive outcomes.MethodsThe study involved a cohort of women who tested positive for BRCA1 and BRCA2 screening or were tested for a BRCA1 or BRCA2 family mutation. Blood samples were collected for anti-mullerian hormone analysis and the reproductive outcomes were analyzed after a mean follow-up of 9 years. Participants were classified into BRCA mutation-positive versus BRCA mutation-negative. Controls were healthy relatives who tested negative for the family mutation. All patients were contacted by telephone to collect data on reproductive outcomes. Linear regression was used to predict anti-mullerian hormone levels by BRCA status adjusted for a polynomial form of age.ResultsResults of anti-mullerian hormone analysis and reproductive outcomes were available for 135 women (BRCA mutation-negative, n=66; BRCA1 mutation-positive, n=32; BRCA2 mutation-positive, n=37). Anti-mullerian hormone curves according to BRCA status and adjusted by age showed that BRCA2 mutation-positive patients have lower levels of anti-mullerian hormone as compared with BRCA-negative and BRCA1 mutation-positive. Among the women who tried to conceive, infertility was observed in 18.7% of BRCA mutation-negative women, in 22.2% of BRCA1 mutation-positive women, and in 30.8% of BRCA2 mutation-positive women (p=0.499). In the multivariable analysis, there were no factors independently associated with infertility.DiscussionBRCA2 mutation-positive carriers showed more diminished anti-mullerian hormone levels than BRCA1 mutation-positive and BRCA mutation-negative women. However, these differences do not appear to have a negative impact on reproductive outcome. This is important to consider at the time of reproductive counseling in women with BRCA1 or BRCA2 mutations.
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Labidi-Galy, Sana Intidhar, Manuel Rodrigues, Jose L. Sandoval, Jean Emmanuel Kurtz, Florian Heitz, Anna Maria Mosconi, Ignacio Romero, et al. "Efficacy of maintenance olaparib plus bevacizumab in patients with newly diagnosed advanced ovarian cancer according to BRCA mutation genotype in the phase III PAOLA-1/ENGOT-ov25 trial." Journal of Clinical Oncology 40, no. 16_suppl (June 1, 2022): 5571. http://dx.doi.org/10.1200/jco.2022.40.16_suppl.5571.
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5571 Background: In the Phase III PAOLA-1/ENGOT-ov25 trial, the addition of maintenance olaparib (ola) to bevacizumab (bev) in patients (pts) with newly diagnosed advanced high-grade ovarian cancer (HGOC) resulted in prolonged progression-free survival (PFS), particularly for pts with HRD-positive tumors including a BRCA1/ BRCA2 mutation (BRCAm; Ray-Coquard et al. NEJM 2019). Preclinical data suggest that pts with mutations (mut) in the RING domain of BRCA1 are less sensitive to ola. The magnitude of benefit from ola + bev, according to the location of mut in the functional domains (FD) of BRCA , remains to be explored. Methods: Pts with newly diagnosed advanced HGOC in response after platinum-based chemotherapy + bev received maintenance bev (15 mg/kg q3w for 15 months [mo]) + either ola (300 mg bid for 24 mo) or placebo (pbo). In this post hoc exploratory analysis, PFS was analyzed in pts with BRCAm according to mut location in the FDs of BRCA1 (RING, DNA-binding domain [DNA-BD], or BRCA1 C terminus [BRCT]) and BRCA2 (RAD51-BD; DNA-BD). Results: Among the 806 randomized pts, 235 (29.2%) harbored a BRCAm: 160 (19.9%) with a BRCA1 mut and 76 (9.4%) with a BRCA2 mut. BRCA1 mut in FDs of RING, DNA-BD and BRCT were detected in 19 (11.8%), 41 (25.6%) and 34 (21.2%) pts, respectively. BRCA2 mut were detected in FDs of RAD51-BD and DNA-BD in 37 (48.7%) and 14 (18.4%) pts, respectively. With a median follow-up of 25.5 mo, 24-mo PFS rates and hazard ratios (HRs) according to mut locations are reported in the Table. In pts with a BRCA1 DNA-BD mut, 24-mo PFS was 89% and 14% (ola + bev vs pbo + bev; HR 0.08, 95% confidence interval [CI] 0.02–0.26) compared with 64% and 24% for pts with mut in RING + BRCT + other domains (HR 0.33, 95% CI 0.19–0.57). In pts with BRCA2 mut, 24-mo PFS for pts with mut in the DNA-BD was 91% vs 100% (ola + bev vs pbo + bev) compared with 82% and 44% for pts with mut in RAD51-BD + other domains (HR 0.21, 95% CI 0.08–0.54). Conclusions: In this exploratory analysis, pts with newly diagnosed advanced HGOC and a BRCAm had a PFS benefit from maintenance ola + bev regardless of mut locations in BRCA1/BRCA2. Sensitivity to ola + bev maintenance was particularly high for pts with mut in the DNA-BD of BRCA1. Pts with a mut in the DNA-BD of BRCA2 commonly had excellent outcomes. Clinical trial information: NCT02477644. [Table: see text]
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Labidi-Galy, Sana Intidhar, Manuel Rodrigues, Jose L. Sandoval, Jean Emmanuel Kurtz, Florian Heitz, Anna Maria Mosconi, Ignacio Romero, et al. "Efficacy of maintenance olaparib plus bevacizumab in patients with newly diagnosed advanced ovarian cancer according to BRCA mutation genotype in the phase III PAOLA-1/ENGOT-ov25 trial." Journal of Clinical Oncology 40, no. 16_suppl (June 1, 2022): 5571. http://dx.doi.org/10.1200/jco.2022.40.16_suppl.5571.
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5571 Background: In the Phase III PAOLA-1/ENGOT-ov25 trial, the addition of maintenance olaparib (ola) to bevacizumab (bev) in patients (pts) with newly diagnosed advanced high-grade ovarian cancer (HGOC) resulted in prolonged progression-free survival (PFS), particularly for pts with HRD-positive tumors including a BRCA1/ BRCA2 mutation (BRCAm; Ray-Coquard et al. NEJM 2019). Preclinical data suggest that pts with mutations (mut) in the RING domain of BRCA1 are less sensitive to ola. The magnitude of benefit from ola + bev, according to the location of mut in the functional domains (FD) of BRCA , remains to be explored. Methods: Pts with newly diagnosed advanced HGOC in response after platinum-based chemotherapy + bev received maintenance bev (15 mg/kg q3w for 15 months [mo]) + either ola (300 mg bid for 24 mo) or placebo (pbo). In this post hoc exploratory analysis, PFS was analyzed in pts with BRCAm according to mut location in the FDs of BRCA1 (RING, DNA-binding domain [DNA-BD], or BRCA1 C terminus [BRCT]) and BRCA2 (RAD51-BD; DNA-BD). Results: Among the 806 randomized pts, 235 (29.2%) harbored a BRCAm: 160 (19.9%) with a BRCA1 mut and 76 (9.4%) with a BRCA2 mut. BRCA1 mut in FDs of RING, DNA-BD and BRCT were detected in 19 (11.8%), 41 (25.6%) and 34 (21.2%) pts, respectively. BRCA2 mut were detected in FDs of RAD51-BD and DNA-BD in 37 (48.7%) and 14 (18.4%) pts, respectively. With a median follow-up of 25.5 mo, 24-mo PFS rates and hazard ratios (HRs) according to mut locations are reported in the Table. In pts with a BRCA1 DNA-BD mut, 24-mo PFS was 89% and 14% (ola + bev vs pbo + bev; HR 0.08, 95% confidence interval [CI] 0.02–0.26) compared with 64% and 24% for pts with mut in RING + BRCT + other domains (HR 0.33, 95% CI 0.19–0.57). In pts with BRCA2 mut, 24-mo PFS for pts with mut in the DNA-BD was 91% vs 100% (ola + bev vs pbo + bev) compared with 82% and 44% for pts with mut in RAD51-BD + other domains (HR 0.21, 95% CI 0.08–0.54). Conclusions: In this exploratory analysis, pts with newly diagnosed advanced HGOC and a BRCAm had a PFS benefit from maintenance ola + bev regardless of mut locations in BRCA1/BRCA2. Sensitivity to ola + bev maintenance was particularly high for pts with mut in the DNA-BD of BRCA1. Pts with a mut in the DNA-BD of BRCA2 commonly had excellent outcomes. Clinical trial information: NCT02477644. [Table: see text]
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Richters, Lisa Katharina, Philip C. Schouten, Stefan Kommoss, Jan Hauke, Alexander Burges, Dimo Dietrich, Ahmed El-Balat, et al. "BRCA-like classification in ovarian cancer: Results from the AGO-TR1-trial." Journal of Clinical Oncology 35, no. 15_suppl (May 20, 2017): 5546. http://dx.doi.org/10.1200/jco.2017.35.15_suppl.5546.
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5546 Background: BRCA associated cancers show a distinct pattern of genomic gains and losses that is associated with impaired repair of DNA double-strand breaks via homologous recombination (HR). We investigated whether BRCA1- and BRCA2-like classifiers could predict BRCA1 and BRCA2 mutation status in ovarian cancer. In addition, we explored whether promoter hypermethylation or mutations in other genes involved in DNA repair associate with a BRCA-like profile in ovarian cancer. Methods: The AGO-TR1 cohort study (NCT02222883 ) enrolled 525 consecutive patients with primary (PR) and platinum sensitive relapsed (RE) ovarian cancer to perform paired mutational analysis of germline and tumor tissue. We performed mutation panel sequencing, BRCA1 promoter hypermethylation and low-coverage whole genome sequencing to classify samples as BRCA1-like or BRCA2-like in 298 ovarian cancer samples (PR: n = 159, RE: n = 139). Results: A BRCA-like profile was observed in 58.1% of the samples without germline or somatic mutation in BRCA1/2 (n = 179; BRCA1-like: n = 26, BRCA2-like: n = 23, BRCA1- and 2-like: n = 55). There was no significant difference between PR- and RE-cases (54.5% vs 61.3%). 64 of 70 BRCA1 germline mutation carriers could be identified by the BRCA1-like classifier (sensitivity: 0.91). The BRCA2-like classifier identified BRCA2 germline mutation carrier with a sensitivity of 0.71 (17 of 24). The complementary use of both classifiers led to the detection of 22 of 25 somatic mutations in BRCA1 (16/16) or - 2 (6/9). Remarkably, 12 of 13 tumor samples from germline RAD51C mutation carriers were recognized by the BRCA1-like classifier (sensitivity: 0.92). No correlation of PALB2 mutation status (n = 7) with BRCA-like profile was observed. Of 28 tumor samples with a BRCA1 promoter hypermethylation 26 had a BRCA1-like profile (sensitivity: 0.93). Conclusions: A high number of ovarian cancer cases display a BRCA-like profile. Mutations (germline and somatic) in BRCA1, BRCA2, RAD51C as well as BRCA1 hypermethylation strongly associate with a BRCA-like profile and can explain 146 of 212 cases. Future studies will investigate whether the classifiers identify patients who benefit from HR-deficiency directed approaches beyond the BRCA mutation status. Clinical trial information: NCT02222883.
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Arun, Banu, Angelica Gutierrez Barrera, Rachel M. Layman, Stephen K. Gruschkus, Isabelle Bedrosian, Constance T. Albarracin, Carlos Hernando Barcenas, Vicente Valero, Jennifer Keating Litton, and Debu Tripathy. "Outcome of patients with breast cancer and a germline BRCA mutation in a prospective cohort." Journal of Clinical Oncology 38, no. 15_suppl (May 20, 2020): 1544. http://dx.doi.org/10.1200/jco.2020.38.15_suppl.1544.
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1544 Background: There are limited large prospective single institution studies on outcome of breast cancer in patients with germline BRCA1 and BRCA2 mutation. The primary aim of this study was to determine the effect of a germline BRCA1 or BRCA2 mutation on recurrence-free survival (RFS) and overall survival (OS) in patients with breast cancer. Methods: This is a prospective cohort study of patients with invasive breast cancer recruited from the UT MD Anderson Cancer Center Breast Medical Oncology and Clinical Cancer Genetics Center. For the purpose of this analysis, newly diagnosed breast cancer patients who have had germline BRCA1 and BRCA2 testing within 12 months were included. Clinical and pathological data, and data regarding outcomes were collected in this prospective cohort. The Kaplan-Meier method and corresponding log-rank test were used to estimate OS and RFS and to compare survival by mutation status. Results: Between 1996 and 2015, 3026 patients were recruited. Median age at diagnosis was 45 (19-87) years. A germline BRCA mutation was detected in 361 (11.9%) patients (207 with BRCA1, 154 with BRCA2). After a median follow-up time of 5.3 (0.04-20.7) years, 437 (14.4%) patients recurred and 340 (11.2%) were deceased. At median follow-up time 5 years, 79.3% of BRCA1, 91.4% of BRCA2 and 89.6% of BRCA negative patients were disease free; this difference was significant (p = 0.0001). Difference in OS between BRCA1/2-positive and BRCA-negative patients was also significant (p = 0.0001), with 81.2% of BRCA1, 93.4% of BRCA2 and 90% of BRCA negative patients being alive at 5 years. Amongst 600 patients with triple negative breast cancer (TNBC) patients, DFS and OS were not significantly different between the 3 groups. Of those patients diagnosed under 40 years (n = 937), RFS and OS was significantly different between 3 groups at 5 years (0.001 for RFS and OS); 75% BRCA1, 92% BRCA2 and 86% BRCA negative patients were disease free and 77% BRCA1, 94% BRCA2 and 88% BRCA negative patients were alive. Conclusions: Patients with BRCA1 or BRCA2 mutations have different survival outcomes. The prognosis of the first cancer needs to be taken into consideration when deciding for preventive surgeries to prevent second primary breast cancers in these patients. Furthermore, for BRCA1 mutation carriers more effective therapy strategies need to be evaluated to improve outcome.
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Sy, Shirley M. H., Michael S. Y. Huen, and Junjie Chen. "PALB2 is an integral component of the BRCA complex required for homologous recombination repair." Proceedings of the National Academy of Sciences 106, no. 17 (April 15, 2009): 7155–60. http://dx.doi.org/10.1073/pnas.0811159106.
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Mutations in breast cancer susceptibility gene 1 and 2 (BRCA1 and BRCA2) predispose individuals to breast and ovarian cancer development. We previously reported an in vivo interaction between BRCA1 and BRCA2. However, the biological significance of their association is thus far undefined. Here, we report that PALB2, the partner and localizer of BRCA2, binds directly to BRCA1, and serves as the molecular scaffold in the formation of the BRCA1-PALB2-BRCA2 complex. The association between BRCA1 and PALB2 is primarily mediated via apolar bonding between their respective coiled-coil domains. More importantly, BRCA1 mutations identified in cancer patients disrupted the specific interaction between BRCA1 and PALB2. Consistent with the converging functions of the BRCA proteins in DNA repair, cells harboring mutations with abrogated BRCA1-PALB2 interaction resulted in defective homologous recombination (HR) repair. We propose that, via its direct interaction with PALB2, BRCA1 fine-tunes recombinational repair partly through its modulatory role in the PALB2-dependent loading of BRCA2-RAD51 repair machinery at DNA breaks. Our findings uncover PALB2 as the molecular adaptor between the BRCA proteins, and suggest that impaired HR repair is one of the fundamental causes for genomic instability and tumorigenesis observed in patients carrying BRCA1, BRCA2, or PALB2 mutations.
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Shatavi, Seerin Viviane, Lindsay Dohany, Mohammad Muhsin Chisti, Ishmael A. Jaiyesimi, and Dana Zakalik. "Unique genetic characteristics of BRCA mutation carriers in a cohort of Arab American women." Journal of Clinical Oncology 31, no. 15_suppl (May 20, 2013): 1541. http://dx.doi.org/10.1200/jco.2013.31.15_suppl.1541.
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1541 Background: Worldwide ethnic variations in the distribution of BRCA1 and BRCA2 mutations of breast cancer patients have been recently recognized. This has led to investigations of the epidemiology, genetics and clinical characteristics of BRCA positive individuals within specific populations. This study aims to describe the findings of BRCA genetic testing in a cohort of Arab American women. Methods: A total of 73 women of Arab ancestry were evaluated in the Beaumont Cancer Genetics Program from Jan 2008 to Jan 2013. Criteria for genetic testing included a personal or family history suggestive of Hereditary Breast and Ovarian Cancer Syndrome (HBOC). Patients underwent comprehensive genetic counseling, followed by full sequence analysis for germline mutations in BRCA1 and BRCA2. Results: 63 women of Arab ancestry underwent genetic testing for BRCA1 and BRCA2. 13 (21%) patients were found to be mutation carriers, of whom 10 (16%) of the 63 had deleterious mutations (7 in BRCA2, and 3 in BRCA1), and 3 (5%) had variants of undetermined significance (VUS) in BRCA2. Of the 10 patients with deleterious mutations, 4 (40%) unrelated individuals had the same mutation, 5804del4, in exon 11 of BRCA2. The remaining patients had deleterious mutations in exon 2, exon 20, and exon 13 of BRCA2; one patient had a BRCA1 and BRCA2 mutation (exon 18). 7 of 10 patients with deleterious mutations had a cancer diagnosis, of which 5 had breast cancer, 1 had ovarian cancer, 1 had pancreatic cancer, and 3 were unaffected. Conclusions: This study demonstrates that BRCA mutations (predominantly in BRCA2) were seen in a significant proportion of Arab American women undergoing genetic testing for HBOC. A mutation in BRCA2, 5804del4, was seen in nearly half (4/10) of the carriers of deleterious mutations. This mutation, in exon 11, has not previously been associated with Arab ethnicity and may represent a founder mutation. Knowledge of the genetic spectrum, frequency, and clinical characteristics of BRCA mutation carriers will lead to greater understanding of hereditary cancer in Arab American women.
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Keung, Yi-Kong, Adriana Hu, Annie Yeung, Amy Chan, and Eddie Hu. "Higher prevalence of BRCA2 mutations among Chinese breast cancer patients in a community oncology clinic." Journal of Clinical Oncology 30, no. 15_suppl (May 20, 2012): e12017-e12017. http://dx.doi.org/10.1200/jco.2012.30.15_suppl.e12017.
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e12017 Background: According to a large US population-based study, BRCA1 and 2 mutations occur in about 6 and 4% breast cancer cases age <45. Asians have the lowest prevalence of BRCA1 mutation among five US racial groups. The prevalence of BRCA1 and BRCA2 mutations was reported as 8.1% and 2.7% among pts with family history in Shanghai, compared to 4.9% and 7.5% respectively in Hong Kong. We would like to explore the BRCA mutations in a clinic located in an Asian-majority community in California. Methods: Consecutive female breast cancer pts selected for BRCA testing according to NCCN guidelines are retrospectively studied from 10/2009 to 10/2011. Sequencing of all translated exons and immediately adjacent intronic regions of the BRCA1 and BRCA2 was performed on the peripheral blood (Myriad, Utah). Results: Twenty-six pts were included in this study. Six pts have bilateral breast cancers; 2 synchronous and 4 metachronous with intervals of 11-13 years. Nine pts (34.6%) had BRCA2 germline mutations, of which 5 were considered deleterious and 4 of uncertain significance. Eleven pts (42.3%) had no BRCA mutation. BRCA results were unavailable in six pts because they were either not yet done or denied by health insurance. Conclusions: 1. High prevalence of BRCA2 mutation is seen in our pts selected according to NCCN guidelines. The presence of BRCA2 but not BRCA1 mutation in our study is intriguing. 2. Triple negative breast cancer is not more prevalent in BRCA2 mutation carriers. 3. Similar frequency of family history of breast/ovarian cancer is noted among pts with or without BRCA2 mutation, deleterious or of uncertain significance. The role of the BRCA2 mutation of uncertain significance needs to be further elucidated. 4. Due to the small sample size, further study is required to confirm our findings. [Table: see text]
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Kauff, Noah D., Susan M. Domchek, Tara M. Friebel, Mark E. Robson, Johanna Lee, Judy E. Garber, Claudine Isaacs, et al. "Risk-Reducing Salpingo-Oophorectomy for the Prevention of BRCA1- and BRCA2-Associated Breast and Gynecologic Cancer: A Multicenter, Prospective Study." Journal of Clinical Oncology 26, no. 8 (March 10, 2008): 1331–37. http://dx.doi.org/10.1200/jco.2007.13.9626.
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Purpose Risk-reducing salpingo-oophorectomy (RRSO) has been widely adopted as a key component of breast and gynecologic cancer risk-reduction for women with BRCA1 and BRCA2 mutations. Despite 17% to 39% of all BRCA mutation carriers having a mutation in BRCA2, no prospective study to date has evaluated the efficacy of RRSO for the prevention of breast and BRCA-associated gynecologic (ovarian, fallopian tube or primary peritoneal) cancer when BRCA2 mutation carriers are analyzed separately from BRCA1 mutation carriers. Patients and Methods A total of 1,079 women 30 years of age and older with ovaries in situ and a deleterious BRCA1 or BRCA2 mutation were enrolled onto prospective follow-up studies at one of 11 centers from November 1, 1994 to December 1, 2004. Women self-selected RRSO or observation. Follow-up information through November 30, 2005, was collected by questionnaire and medical record review. The effect of RRSO on time to diagnosis of breast or BRCA-associated gynecologic cancer was analyzed using a Cox proportional-hazards model. Results During 3-year follow-up, RRSO was associated with an 85% reduction in BRCA1-associated gynecologic cancer risk (hazard ratio [HR] = 0.15; 95% CI, 0.04 to 0.56) and a 72% reduction in BRCA2-associated breast cancer risk (HR = 0.28; 95% CI, 0.08 to 0.92). While protection against BRCA1-associated breast cancer (HR = 0.61; 95% CI, 0.30 to 1.22) and BRCA2-associated gynecologic cancer (HR = 0.00; 95% CI, not estimable) was suggested, neither effect reached statistical significance. Conclusion The protection conferred by RRSO against breast and gynecologic cancers may differ between carriers of BRCA1 and BRCA2 mutations. Further studies evaluating the efficacy of risk-reduction strategies in BRCA mutation carriers should stratify by the specific gene mutated.
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Panda, Anshuman, Mark N. Stein, Gregory Riedlinger, Gyan Bhanot, and Shridar Ganesan. "Role for immune checkpoint blockade in BRCA2-mutant prostate cancer." Journal of Clinical Oncology 37, no. 8_suppl (March 10, 2019): 59. http://dx.doi.org/10.1200/jco.2019.37.8_suppl.59.
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59 Background: Except for rare cases with microsatellite instability, prostate cancer has low mutation burden and low response rate to immune checkpoint blockade (ICB). Genomic correlates of response to ICB in microsatellite stable (MSS) prostate cancer are currently unknown. Here we describe an exceptional response to ICB in BRCA2-mutant prostate cancer and explore immunologic features of BRCA-mutant tumors. Methods: A patient with BRCA2-mutant MSS prostate cancer who progressed on PARP inhibitor therapy was treated with pembrolizumab. Another 8 cases of BRCA2-mutant prostate cancer were evaluated for lymphocyte infiltration and PD-L1 expression by a pathologist. The Cancer Genome Atlas (TCGA) dataset was used to evaluate BRCA-mutant tumors from multiple histology. Presence of putative pathogenic mutations in BRCA1/2 were tested for association with mRNA levels of CD8+ T cell marker ( CD8A), immune checkpoint genes (in PD-1, CTLA-4 pathways), and expression of endogenous retroviruses (ERV). Markers of homologous recombination (HR) defects, namely number of Signature 3 mutations and large ( > 3bp) indels, were also analyzed. Results: Initial patient with BRCA2-mutant MSS prostate cancer had a rapid and ongoing response to pembrolizumab. Analysis of local cohort will be presented. In the TCGA prostate cancer dataset, BRCA2-mutant tumors showed significant overexpression of CD8A, PD-1 and CTLA-4 pathway genes, and ERV3-2. Similar results were observed in BRCA1-mutant (but not BRCA2-mutant) ER+ HER2− breast cancer, but not in BRCA-mutant triple-negative breast and ovarian cancer. Analyses of HR defect markers corroborated these observations. Conclusions: BRCA-mutation accompanied by ERV3-2 overexpression, observed in BRCA2-mutant prostate and BRCA1-mutant ER+ HER2− breast cancer, is associated with CD8+ T cell infiltration and checkpoint pathway upregulation. The effect of BRCA1/2 mutation on immunogenicity may be very tissue and/or cell-of-origin specific, with different cancer types having different levels of immune activation. The association between ERV expression and BRCA2-mutation in prostate cancer requires further investigation. BRCA2-mutant prostate cancers are a class of MSS tumors that may be sensitive to ICB.
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Bracci, Ciarapica, Zabaleta, Tartaglione, Pirozzi, Giuliani, Piva, et al. "BRCA1 and BRCA2 Gene Expression: Diurnal Variability and Influence of Shift Work." Cancers 11, no. 8 (August 9, 2019): 1146. http://dx.doi.org/10.3390/cancers11081146.
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BRCA1 and BRCA2 genes are involved in DNA double-strand break repair and related to breast cancer. Shift work is associated with biological clock alterations and with a higher risk of breast cancer. The aim of this study was to investigate the variability of expression of BRCA genes through the day in healthy subjects and to measure BRCA expression levels in shift workers. The study was approached in two ways. First, we examined diurnal variation of BRCA1 and BRCA2 genes in lymphocytes of 15 volunteers over a 24-hour period. Second, we measured the expression of these genes in lymphocytes from a group of shift and daytime workers. The change in 24-hour expression levels of BRCA1 and BRCA2 genes was statistically significant, decreasing from the peak at midday to the lowest level at midnight. Lower levels for both genes were found in shift workers compared to daytime workers. Diurnal variability of BRCA1 and BRCA2 expression suggests a relation of DNA double-strand break repair system with biological clock. Lower levels of BRCA1 and BRCA2 found in shift workers may be one of the potential factors related to the higher risk of breast cancer.
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Chahla, Elie, Antonio Cheesman, Suzanne M. Mahon, Robert W. Garrett, Ben P. Bradenham, Theresa L. Schwartz, Louay Omran, Jason R. Taylor, and Samer Alkaade. "Frequency and Significance of Abnormal Pancreatic Imaging in Patients with BRCA1 and BRCA2 Genetic Mutations." Scientifica 2016 (2016): 1–6. http://dx.doi.org/10.1155/2016/5619358.
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Objective.Pancreatic adenocarcinoma is typically diagnosed in advanced stages resulting in a significant reduction in the number of patients who are candidates for surgical resection. Although the majority of cases are believed to occur sporadically, about 10% show familial clustering and studies have identified an increased frequency of BRCA germline mutations. The role of screening for pancreatic adenocarcinoma in these populations is unclear. Our study aims to identify the abnormal pancreatic imaging findings in BRCA1 and BRCA2 mutation carriers.Methods.A retrospective review of patient medical records with known BRCA1 and BRCA2 mutations was conducted. Data was collected and all available abdominal imaging studies were reviewed.Results.A total of 66 patients were identified, 36 with BRCA1 and 30 with BRCA2 mutations. Only 20/66 (30%) had abdominal imaging (14 BRCA1 and 6 BRCA2 patients). Of those patients with abdominal imaging, abnormal pancreatic imaging findings were detected in 7/20 (35%) cases.Conclusion.Our study shows a high incidence of abnormal pancreatic imaging findings in patients with BRCA genetic mutations (35%). Larger studies are needed to further define the role of pancreatic cancer screening and the significance of abnormal imaging findings in BRCA1 and BRCA2 mutation carriers.
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Ferrone, Cristina R., Douglas A. Levine, Laura H. Tang, Peter J. Allen, William Jarnagin, Murray F. Brennan, Kenneth Offit, and Mark E. Robson. "BRCA Germline Mutations in Jewish Patients With Pancreatic Adenocarcinoma." Journal of Clinical Oncology 27, no. 3 (January 20, 2009): 433–38. http://dx.doi.org/10.1200/jco.2008.18.5546.
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Purpose The prognostic significance of germline BRCA1 and BRCA2 mutations in Jewish patients with pancreatic adenocarcinoma (PAC) is unknown. Our objective was to define the prevalence of BRCA1 and BRCA2 in an unselected group of Jewish patients and to compare the clinical characteristics and overall survival (OS) of patients with resected BRCA mutation-associated PAC to PAC patients without mutations. Patients and Methods Jewish patients with PAC resected between January 1986 and January 2004 were identified. DNA was extracted from the archived material, anonymized, and genotyped for founder mutations in BRCA1 (185delAG, 5382insC) and BRCA2 (6174delT). Standard two-sided statistical tests were utilized. Results Of the 187 Jewish patients who underwent resection for PAC, tissue was available for 145 patients. Eight subjects (5.5%) had a BRCA founder mutation (two with BRCA1 [1.3%], six with BRCA2 [4.1%]). The BRCA2 founder mutation was identified in 4.1% of patients with pancreatic adenocarcinoma compared with only 1.1% of cancer-free Washington, DC,–area controls (4.1% v 1.1%; P = .007; odds ratio, 3.85; 95% CI, 2.1 to 10.8). Patients with and without BRCA1 or BRCA2 mutations did not differ in age (mean, 66 v 73 years; P = .6) or other clinicopathologic features. OS was not significantly different (median, 6 v 16 months; P = .35). A previous cancer was reported by 24% (35 of 145) of patients with the most common sites being breast cancer (9 of 35; 74%) and prostate cancer (8 of 35; 23%). Conclusion Founder mutations for BRCA1 and BRCA2 were identified in 5.5% of Ashkenazi patients operated on for PAC. BRCA2 mutations were more prevalent than documented by population studies. Consistent with previous reports, BRCA2 mutations are associated with an increased risk of PAC.
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Reisinger, Raquel, Sergiusz Wesolowski, Umang Swami, Pedro C. Barata, Edgar Javier Hernandez, Roberto Nussenzveig, Gordon Lemmon, et al. "Differences in the genomic landscape of advanced prostate cancer (aPC) patients (pts) with BRCA1 versus BRCA2 mutations as detected by machine learning analysis of the comprehensive genomic profile (CGP) of cell-free DNA (cfDNA)." Journal of Clinical Oncology 39, no. 6_suppl (February 20, 2021): 162. http://dx.doi.org/10.1200/jco.2021.39.6_suppl.162.
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162 Background: PARP inhibitors (PARPi) provide significant clinical benefit for men with aPC with BRCA 1 and BRCA 2 mutations. However, in clinical trials, pts with BRCA1 mutations appeared to derive less benefit than pts with BRCA2 (De Bono et al., 2020). Probabilistic Graphical Models (PGMs) are artificial intelligence (AI) algorithms that capture multivariate, multi-level dependencies in complex patterns in large datasets while retaining human interpretability. We hypothesize that PGMs can reveal variants in BRCA1 and 2 that co-segregate with other known pathogenic variants and may explain the difference in response to PARPi therapy. Methods: Multilevel gene interdependencies between BRCA1 or BRCA2 were assessed using a Bayesian Network (BN) machine learning approach and Fisher’s exact test. CGP was performed by a validated cfDNA NGS panel that sequenced 74 clinically relevant cancer genes (Guardant360, Redwood City, CA). Only variants of known significance and those of unknown significance with a pathogenic REVEL score were included in the analysis. Results: Of 4671 men with aPC undergoing cfDNA CGP, 1248 men with somatic mutations in BRCA1, BRCA2, ATM, or combinations of the three were included in the analysis. The Bayesian network analysis demonstrated positive interdependencies between pathogenic variants in BRCA1 and 7 other genes. A positive interdependency between BRCA2 and 2 genes was present (table). ATM displayed negative interdependency with both BRCA 1 and 2. Conclusions: Our results demonstrate a decreased association of BRCA2 versus BRCA1 with known or predicted pathogenic variants at other loci. This may explain increased sensitivity of aPC with BRCA2 mutations to PARPi due to fewer concurrent resistance pathways. For example, alteration of ERBB2, which segregates strongly with BRCA1, is known to induce tumor progression and invasion in aPC and is associated with castration-resistance. These hypothesis-generating data reveal differential genomic signatures associated with BRCA1 as compared to BRCA2 and may inform development of future combinatorial treatment regimens for these pts. [Table: see text]
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Faermann, Renata, Eitan Friedman, Orit Kaidar-Person, Jonathan Weidenfeld, Malka Brodsky, Anat Shalmon, Osnat Halshtok Neiman, et al. "Ductal Carcinoma In Situ (DCIS) Diagnosed by MRI-Guided Biopsy among BRCA1/BRCA2 Mutation Carriers." Breast Journal 2022 (October 27, 2022): 1–7. http://dx.doi.org/10.1155/2022/4317693.
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Background. While BRCA1/BRCA2 pathogenic sequence variants (PSVs) clearly confer an increased risk for invasive breast cancer, the extent to which these mutant alleles increase DCIS risk is less clear. Objective. To assess the rate of detection over a 5-year period, and MRI imaging features of pure noncalcified DCIS in a cohort of Israeli BRCA1/BRCA2 PSV carriers attending a high-risk clinic from 2015 to 2020. Materials and Methods. All female BRCA1/BRCA2 PSV-carriers followed at the Meirav High-risk clinic from 2015 to 2020 were eligible if they underwent semiannual breast imaging (MRI/mammography) and MRI-guided biopsy-proven pure DCIS. Clinical data, pathology information, and imaging characteristics were retrieved from the computerized archiving system. Results. 18/121 (15.2%) participating BRCA1 PSV carriers and 8/81 (10.1%) BRCA2 PSV-carriers who underwent MRI-guided biopsy were diagnosed with DCIS. The median age of BRCA1 carriers and BRCA2 carriers was 49.8 years and 60.6 years, respectively ( p = 0.55 ). Negative estrogen-receptor tumors were diagnosed in 13/18 (72%) BRCA1 and 2/8 (25%) BRCA2 PSV carriers ( p < 0.05 ). Thirteen (13/18–72%) BRCA1 carriers had intermediate to high-grade or high-grade DCIS compared with 4/8 (50%) of BRCA2 carriers ( p = 0.03 ). Over the 5-year study period, 29/1100 (2.6%) BRCA1/BRCA2 PSV carriers were diagnosed with DCIS seen on MRI only. Conclusion. MRI-detected noncalcified DCIS is more frequent in BRCA1 PSV carriers compared with BRCA2 carriers, unlike the BRCA2 predominance in mammography-detected calcified DCIS. BRCA1-related DCIS is diagnosed earlier, more likely to be estrogen receptor-negative and of higher grade compared with BRCA2-related DCIS. Future prospective studies should validate these results and assess the actual impact they might have on clinical management of BRCA PSV carriers.
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Foglietta, Jennifer, Vienna Ludovini, Fortunato Bianconi, Lorenza Pistola, Maria Sole Reda, Antonella Al-Refaie, Francesca Romana Tofanetti, et al. "Prevalence and Spectrum of BRCA Germline Variants in Central Italian High Risk or Familial Breast/Ovarian Cancer Patients: A Monocentric Study." Genes 11, no. 8 (August 12, 2020): 925. http://dx.doi.org/10.3390/genes11080925.
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Hereditary breast and ovarian cancers are mainly linked to variants in BRCA1/2 genes. Recently, data has shown that identification of BRCA variants has an immediate impact not only in cancer prevention but also in targeted therapeutic approaches. This prospective observational study characterized the overall germline BRCA variant and variant of uncertain significance (VUS) frequency and spectrum in individuals affected by breast (BC) or ovarian cancer (OC) and in healthy individuals at risk by sequencing the entire BRCA genes. Of the 363 probands analyzed, 50 (13.8%) were BRCA1/2 mutated, 28 (7.7%) at BRCA1 and 23 (6.3%) at BRCA2 gene. The variant c.5266dupC p.(Gln1756Profs) was the most frequent alteration, representing 21.4% of the BRCA1 variants and 12.0% of all variants identified. The variant c.6313delA p.(Ile2105Tyrfs) of BRCA2 was the most frequent alteration observed in 6 patients. Interestingly, two new variants were identified in BRCA2. In addition, 25 different VUS were identified; two were reported for the first time in BRCA1 and two in BRCA2. The number of triple-negative BCs was significantly higher in patients with the pathogenic BRCA1/2-variant (36.4%) than in BRCA1/2 VUS (16.0%) and BRCA1/2 wild-type patients (10.7%) (p < 0.001). Our study reveals that the overall frequency of BRCA germline variants in the selected high-risk Italian population is about 13.8%. We believe that our results could have significant implications for preventive strategies for unaffected BRCA-carriers and effective targeted treatments such as PARP inhibitors for patients with BC or OC.
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Bisgin, Atil, Ibrahim Boga, Ozge Sonmezler, Cem Mujde, Abdullah Hanta, and Sevcan Tug Bozdogan. "Meta-analysis and single-center experience on the comprehensive genomic characterization and landscape of BRCA1 and BRCA2 in Turkey." Journal of Clinical Oncology 38, no. 15_suppl (May 20, 2020): e13611-e13611. http://dx.doi.org/10.1200/jco.2020.38.15_suppl.e13611.
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e13611 Background: The detection of BRCA1 and BRCA2 mutations both somatic and germ-line became essential for the clinical management strategies of different cancers. Aiming at the identification of common and recurrent mutations that answer the questions about the association between a variant and phenotype, we collected the data of 1126 probands with pathogenic, likely pathogenic variants and variants of uncertain significance (VUS) distributed across 22 Turkish cities. Methods: Peripheral blood samples from 1126 individuals were collected and sequenced via the GeneReader (Qiagen, Hilden, Germany) and MiSeq (Illumina, San Diego, USA) NGS systems for BRCA1/ BRCA2 genes. QCI-Analyze and QCI-Interpret bioinformatics tools were used for bioinformatics analyses. Results: Total of 68 and 108 distinct variants were identified in BRCA1 and BRCA2 genes, respectively. Twenty novel variants were identified in both genes, while BRCA2 had higher heterogeneity. However, there had been no any recurrent mutations identified in any certain geographic region. Among all distinct mutations identified 11.9% were novel, corresponding to 12.8% of all carriers and 28.4% were VUS, corresponding to 32.1% of all carriers. Conclusions: This study presented with three important outcomes. First, a significant molecular heterogeneity in BRCAs among Turkish carriers were confirmed with 15.63% positivity rate. Most notably as the second, this is the first study showing the profiles of recurrent and common mutations that might be unique to Turkish landscape. In conclusion, it is critical to identify all the genetic variants, to aid in diagnosis, prevention, prognosis and treatment. Third and the last, the identification of novel mutations in BRCAs is a vital information that should be shared with mutation databases, in order to use for further clinical interpretation of Turkish population. Key words: Landscape of BRCA1/2, genetic testing, BRCA profiling, population data.
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Kiechle, M. "Hereditäres Mammakarzinom: BRCA1, BRCA2 und BRCA3." Senologie - Zeitschrift für Mammadiagnostik und -therapie 8, no. 02 (June 2011): 103. http://dx.doi.org/10.1055/s-0031-1271518.
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Kwong, A., L. Wong, C. Wong, F. Law, E. Tang, W. Chan, E. S. Ma, J. M. Ford, and D. W. West. "Clinical and pathological characteristics of Chinese patients with BRCA related breast cancer." Journal of Clinical Oncology 27, no. 15_suppl (May 20, 2009): e22226-e22226. http://dx.doi.org/10.1200/jco.2009.27.15_suppl.e22226.
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e22226 Background: Breast cancers due to underlying germline BRCA1 and BRCA2 mutations are associated with particular pathological features that may differ from sporadic breast cancers. We report clinical and pathologic characteristics of breast cancer in a clinical cohort of high risk Chinese women with BRCA mutations and those without mutations. Methods: 202 high risk women based on their age and family history were recruited from March 2007 to November 2008. Medical information was prospectively collected from the patients and medical records. BRCA1 and BRCA2 mutations were detected using full gene sequencing and multiplex ligation-dependent probe amplification (MLPA). Results: Of the 202 female probands tested, 25 (12.3 %) were BRCA mutation carriers of which 11 (44%) were BRCA1 and 14 (56%) were BRCA2 mutations. Breast cancer risk factors, other than family history, did not differ between carriers and non-carriers. Mutation carriers were more likely to have a familial history of breast cancer (p=0.07) and personal and family history of ovarian cancer (p=0.005; p=0.007). Other cancers found in carriers families included pancreatic, gastric, colon, lung, liver, and nasopharyngeal. 23% of women diagnosed with DCIS had BRCA mutations compared with 11.4% of those with invasive cancers. BRCA related tumors were more likely to be ER, PR and Her-2 negative (Triple negative, TN) (p= 0.006). Overall 9.6% of non-BRCA cancers were TN whereas 25.9% of BRCA cancers were TN. Prevalence of TN in BRCA1 carriers is 71% compared with 13.4% in BRCA2 carriers. BRCA1 mutation related cancers were significantly more likely to be ER negative than BRCA2 and this is only significant in those who are under 40 years of age (p=0.070). Conclusions: We have a high BRCA2 mutation rate in our cohort. BRCA related breast cancer is associated with families with increasing number of first degree relatives with breast and/or ovarian cancers and were higher for DCIS cancers. Prevalence of TN breast cancers was high compared to Caucasian cohorts. BRCA mutations were associated with pathologically, poor prognostic features (TN and high grade) especially in younger women. No significant financial relationships to disclose.
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Zajchowski, Deborah A., Hugh Salamon, and Ken D. Yamaguchi. "Proliferation pathway aberration frequencies in BRCA1- and BRCA2-mutated ovarian cancers." Journal of Clinical Oncology 30, no. 15_suppl (May 20, 2012): 5074. http://dx.doi.org/10.1200/jco.2012.30.15_suppl.5074.
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5074 Background: Large-scale genomic analyses of high-grade, advanced-stage serous ovarian cancers by The Cancer Genome Atlas (TCGA) project revealed aberrations in genes comprising key proliferation and survival pathways (RB-E2F, RAS, PI3K) in the majority of tumors. Patients with germline BRCA1/2-mutations have more favorable prognoses than non-BRCA carriers, and recent work suggests that BRCA2 carriers do better than BRCA1. We hypothesized that concurrent proliferation pathway aberrations and BRCA1/2 mutations in tumors might play a role in patient outcome. Methods: Mutation, copy number, and clinical data for 309 TCGA-profiled serous ovarian tumors were downloaded from the MSKCC cBIO web portal. Each tumor was scored as aberrant for a pathway if any gene (RB: RB1, CDKN2A, CCND1, CCND2, E2F3, CCNE1; PI3K: PIK3CA, PTEN, AKT1, AKT2; RAS: KRAS, BRAF, NF1) in that pathway was mutated, amplified, or deleted. Results: 205 of 309 tumors had an aberration in at least one of these pathways. The frequency of pathway alteration differed significantly in BRCA1 (82%, 28/34), BRCA2 (52%, 17/33) and BRCA1/2 WT (66%, 160/242) tumors (BRCA1 vs. BRCA2: Fisher’s p= 0.0096). BRCA1 tumors more frequently contained alterations in multiple pathways than BRCA2 or WT tumors (41% vs. 24% or 25%, respectively). RB-E2F pathway alteration frequency was significantly different (BRCA1: 56%, BRCA2: 18%, WT: 43%, p=0.0043), but no significant differences in PI3K and RAS pathway aberration frequencies (BRCA1%: 41, 38; BRCA2%: 36, 27; WT% 28, 27), respectively, were observed. In agreement with the previous report, BRCA2 patients had significantly better overall survival (OS) than either BRCA1 or WT patients (median OS months for BRCA1: 35.9, BRCA2 45.4, BRCA1/2 WT 27.8; p=0.001). Presence of pathway alterations was not significantly associated with OS in BRCA1, BRCA2, or WT patients in this cohort. Conclusions: These results show a negative association between BRCA2 mutations and aberrations in key proliferation and survival pathways. Beyond BRCA1 and BRCA2 genetic mutations, the elevated frequency of pathway alteration in BRCA1 vs. BRCA2 tumors highlights differences that may be important for patient prognosis as well as therapy responses.
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Li, Jiaheng, Bojin Zhao, Teng Huang, Zixin Qin, and San Ming Wang. "Human BRCA pathogenic variants were originated during recent human history." Life Science Alliance 5, no. 5 (February 14, 2022): e202101263. http://dx.doi.org/10.26508/lsa.202101263.
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BRCA1 and BRCA2 (BRCA) play essential roles in maintaining genome stability. BRCA germline pathogenic variants increase cancer risk. However, the evolutionary origin of human BRCA pathogenic variants remains largely elusive. We tested the 2,972 human BRCA1 and 3,652 human BRCA2 pathogenic variants from ClinVar database in 100 vertebrates across eight clades, but failed to find evidence to show cross-species evolution conservation as the origin; we searched the variants in 2,792 ancient human genome data, and identified 28 BRCA1 and 22 BRCA2 pathogenic variants in 44 cases dated from 45,000 to 300 yr ago; we analyzed the haplotype-dated human BRCA pathogenic founder variants, and observed that they were mostly arisen within the past 3,000 yr; we traced ethnic distribution of human BRCA pathogenic variants, and found that the majority were present in single or a few ethnic populations. Based on the data, we propose that human BRCA pathogenic variants were highly likely arisen in recent human history after the latest out-of-Africa migration, and the expansion of modern human population could largely increase the variation spectrum.
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Tun, N. M., G. M. Villani, and K. Ong. "Risk of having BRCA mutations in women with triple-negative breast cancer: A systematic review and meta-analysis." Journal of Clinical Oncology 29, no. 27_suppl (September 20, 2011): 160. http://dx.doi.org/10.1200/jco.2011.29.27_suppl.160.
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160 Background: Increased prevalence of BRCA1 mutations (BRCA1) has been associated with the occurrence of triple-negative breast cancer (TNBC) (estrogen receptor [ER]- and progesterone receptor [PR]-negative, HER2-negative) in independent clinical studies. However, BRCA2 mutation (BRCA2) has not been found to overrepresent in women with TNBC. We have performed a meta-analysis of these studies to provide further statistical evidence of the association between BRCA positivity and TNBC. Methods: A Medline search of the MeSH terms “BRCA”, “triple”, and “negative” yielded 37 articles. A search of ASCO abstracts yielded 18 relevant articles. Random effects model was used for analysis due to heterogeneity among the proportions of included studies (Cochran’s Q = 18.52 and 15.18, tau2 = 0.61 and 1.29, I2 = 73% and 80% for BRCA1 and BRCA2 respectively). Mantel-Haenszel method was applied to calculate the pooled event-based odds ratio (OR) with 95% confidence interval (CI). Results: 6 studies including 1,602 BC patients were eligible for analysis of BRCA1 and 4 studies including 1297 BC patients for BRCA2. 172 patients with BRCA1 mutations and 79 patients with BRCA2 mutations were analyzed. Among these 6 studies, 1 included Ashkenazi Jewish women exclusively and 1 included only women of Chinese descent. The overall prevalence of BRCA1 was 10.05% (172 out of 1,602), and for TNBC patients 21.94% (95 out of 433) with an odds ratio of 5.90 (CI: 2.75, 12.66, p < 0.00001). TNBC was not a risk for BRCA2 (OR = 0.67, CI: 0.19, 2.39, p = 0.53). Chinese women with TNBC did not have an elevated risk of BRCA1 (OR = 0.94, CI: 0.24, 3.66) in contrast to Jewish women with TNBC who had the highest risk of BRCA1 among the populations studied (OR = 21.79, CI: 9.03, 52.55). Conclusions: Women with TNBC carry a significantly high risk of having BRCA1 but not BRCA2 mutations. We recommend genetic testing for BRCA1 mutations in women with TNBC especially in Ashkenazi Jewish population. Further studies on Chinese population are needed to further establish the relationship between TNBC and BRCA1 mutations in this cohort.
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Novikova, EI, EA Kudinova, VK Bozhenko, and VA Solodkiy. "Characteristics of BRCA-associated breast cancer in the population of the Russian Federation." Features of HIV and SARS-CoV-2 coinfection in a pandemic, no. 2021(1) (February 2021): 24–29. http://dx.doi.org/10.24075/brsmu.2021.006.
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"Standard" diagnostic panels allow identification of only a few of BRCA1 and BRCA2 gene mutations most common in a population. Therefore, tests relying on such panels may return false negative results, since the coding regions of these genes may have other defects. For breast cancer (BC) patients, false negative test results may translate into selection of inadequate therapy by their doctors. This study aimed to identify the features of BRCA-associated breast cancer in the population of the Russian Federation. The study included breast cancer patients (n = 4440). At the first stage, all patients were screened for the eight most common BRCA1 and BRCA2 genes mutations with the help of real-time PCR. Next, patients that exhibited clinical signs of a hereditary disease (CSHD) in the absence of common mutations (n = 290) had the entire coding regions of BRCA1 and BRCA2 genes studied with next generation sequencing (NGS). "Standard" mutations in the BRCA1 and BRCA2 genes were identified in 169 (3.8%) cases. In the CSHD group, such mutations were revealed in 15.4% of cases. NGS uncovered 33 rare pathogenic BRCA1 and BRCA2 gene mutations in 40 out of 290 breast cancer patients (13.8%). It was concluded that among the residents of the Russian Federation, the range of pathogenic variants of BRCA-associated breast cancer is wide, and it stretches beyond the mutations considered by the "standard" diagnostic panels. Analysis of the entire coding regions of BRCA1 and BRCA2 genes allows increasing efficiency of detection of germline mutations in breast cancer patients at least twofold.
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Wen, Lu, Xiuxiu Li, Junping Shi, Shuo Zhang, Rui Wang, Ming Yao, and Jun Guo. "Allele-specific expression mediates primary resistance to poly (ADP-ribose) polymerase inhibitor therapy in a case of BRCA1/2 double-germline mutant gastric cancer." Journal of International Medical Research 48, no. 3 (November 27, 2019): 030006051988622. http://dx.doi.org/10.1177/0300060519886226.
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Breast cancer gene 1 and 2 ( BRCA1 and BRCA2) are human tumor suppressor genes. BRCA mutations increase the risk for breast, ovarian, and gastric cancer. However, double heterozygosity for BRCA1 and BRCA2 mutations in gastric cancer have not been reported and their clinical significance is unclear. In this study, a 52-year-old Chinese male patient with gastric cancer was chosen for analysis. A tumor tissue biopsy and blood sample were collected, and next-generation sequencing-based deep panel sequencing was performed on the IlluminaNextSeq-500 platform. Comprehensive genomic alterations of 450 cancer-related genes and 47 tumor susceptibility genes were analyzed. Here, we report for the first time a case of gastric cancer that carried both BRCA1 S1841Vfs*2 and BRCA2 Q1886* heterozygous mutations. Unfortunately, the patient was resistant to olaparib treatment. Further RNA analysis revealed that only the wild-type alleles of BRCA1 and BRCA2 were expressed, although genetic BRCA1 and BRCA2 mutations were present in the patient. This genetic finding may explain the mechanism for primary resistance to olaparib observed in the BRCA1/2-mutated patient.
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Rhiem, K., C. Fischer, K. Bosse, B. Wappenschmidt, and R. K. Schmutzler. "Increased risk of cervical cancer in high-risk families with and without mutations in the BRCA1 and BRCA2 genes." Journal of Clinical Oncology 25, no. 18_suppl (June 20, 2007): 5588. http://dx.doi.org/10.1200/jco.2007.25.18_suppl.5588.
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5588 Background: In BRCA germline mutation carriers increased risks for cancer at other sites than breast and ovary have been reported. Methods: To evaluate the risk of BRCA-associated cancers, we conducted a cross-section analysis in 4405 individuals from 409 families with BRCA1 (n=86) or BRCA2 mutations (n=53) and 270 high risk BRCA1/2 negative families ascertained by the Familial Breast and Ovarian Cancer Center Cologne. We considered proven mutation carriers, individuals affected by breast and ovarian cancer and their first degree relatives and identified 921 individuals from BRCA1 (604 female; 317 male), 571 from BRCA2 (365 female; 206 male) and 2913 from BRCA1/2 negative (1938 female; 975 male) families that suffered from 677 cancers other than breast and ovarian cancers. Relative risks (RR) of the study group compared to the general population were evaluated by the standardized incidence ratio (SIR), using data from two German Cancer Registries. Results: The risk for cervical cancer is significantly increased in women from BRCA1 and BRCA2 positive (RR=4.59, 95% CI=2.20 to 8.44, and RR=3.69, 95% CI=1.20 to 8.61; p=<0.001) and from BRCA1/2 negative families (RR=2.97, 95% CI=1.88 to 4.45). Moreover, the risk for pancreatic cancer in women from BRCA2 positive and BRCA1/2 negative families as well as the risk for prostate cancer in men from BRCA2 positive families is increased (RR=5.10, 95% CI=1.65 to 11.90; RR=1.98, 95% CI=1.02 to 3.46; RR=2.09; 95% CI=1.00 to 3.84). Conclusions: We here report an increased risk of cervical cancer for women from BRCA1 and BRCA2 positive and from BRCA1/2 negative high risk families, respectively. These results are in line with other studies in BRCA1 and 2 positive individuals and should be considered in the clinical risk management of these individuals. No significant financial relationships to disclose.
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McNevin, Ciara S., Karen Cadoo, Anne-Marie Baird, Pierre Murchan, Orla Sheils, Ray McDermott, and Stephen Finn. "Pathogenic BRCA Variants as Biomarkers for Risk in Prostate Cancer." Cancers 13, no. 22 (November 14, 2021): 5697. http://dx.doi.org/10.3390/cancers13225697.
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Studies have demonstrated that men with Prostate Cancer (PCa) harboring BRCA2/BRCA1 genetic aberrations, are more likely to have worse disease and a poorer prognosis. A mutation in BRCA2 is known to confer the highest risk of PCa for men (8.6 fold in men ≤65 years) making BRCA genes a conceivable genomic biomarker for risk in PCa. These genes have attracted a lot of research attention however their role in the clinical assessment and treatment of PCa remains complex. Multiple studies have been published examining the relationship between prostate cancer and BRCA mutations. Here BRCA mutations are explored specifically as a biomarker for risk in PCa. It is in this context, we examined the prognostic, clinical and therapeutic role of BRCA2/BRCA1 mutations across the evolution of PCa. The impact of the inclusion of BRCA genes on genetic screening will also be outlined.
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Choi, Doo Ho, Min Hyuk Lee, Allen E. Bale, Darryl Carter, and Bruce G. Haffty. "Incidence of BRCA1 and BRCA2 Mutations in Young Korean Breast Cancer Patients." Journal of Clinical Oncology 22, no. 9 (May 1, 2004): 1638–45. http://dx.doi.org/10.1200/jco.2004.04.179.
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Purpose The prevalence of BRCA-associated breast carcinoma in the Korean population has not been evaluated extensively. Methods Sixty Korean women who developed breast cancer by age 40 years were studied. Lymphocyte specimens from peripheral blood were processed for BRCA1 and BRCA2 by complete sequencing. Family history through three generations was obtained. Available paraffin-embedded tissue blocks were processed for immunohistochemical staining. Results In the cohort of 60 patients, nine patients with 11 deleterious mutations (six in BRCA1 and five in BRCA2) and seven missense mutations of unknown significance were found. Two patients had deleterious mutations in both BRCA1 and BRCA2 (double mutant). One half of the mutations were novel, and no founder mutations were observed in this cohort. Most of the BRCA-associated patients had no family history of breast and/or ovarian cancer. The expression of HER-2/neu, cyclin D1, and hormone receptors was less common, and p53 overexpression was more common in BRCA-associated tumors. Conclusion The prevalence of BRCA1 and BRCA2 mutations in Korean women with breast cancer at a young age was high. However, the penetrance, as evidenced by the low frequency of breast and ovarian cancers in family members, appears to be low. These data suggest that there may be different genetic and etiologic factors affecting transmission and penetrance of the BRCA genes in Korean patients with breast cancer diagnosed at a young age.
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Castro, Elena, David Olmos, Chee Leng Goh, Ed Saunders, Daniel Leongamornlert, Malgorzata Tymrakiewicz, Elizabeth Bancroft, et al. "Effect of germ-line BRCA mutations in biochemical relapse and survival after treatment for localized prostate cancer." Journal of Clinical Oncology 31, no. 6_suppl (February 20, 2013): 29. http://dx.doi.org/10.1200/jco.2013.31.6_suppl.29.
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29 Background: Biochemical relapse after local treatment for prostate cancer (PCa) indicates recurrent disease and is associated with shorter cause-specific survival (CSS). Germline BRCA mutations are associated with worse PrCa outcomes. In this study, we analyzed biochemical-progression free survival (bPFS) after conventional treatments for localized PCa in a cohort of BRCA patients from the UK. Currently, BRCA1/2 carriers are treated with the same protocols used for non-carriers. Methods: In this retrospective case-control study, each BRCA carrier (10 BRCA1 and 34 BRCA2) treated with radical prostatectomy (RP) or external beam radiotherapy (RT) was matched with 3 non-carriers (NC) by: age at diagnosis (±5 yrs), TNM stage, Gleason score, presenting PSA, local treatment (RT or RP), androgen-deprivation therapy (ADT) and year of treatment (±5yrs). All NC were screened for BRCA1 and BRCA2 mutations. Biochemical failure was reviewed according to ASTRO and NCCN criteria. The Kaplan-Meier method and a multivariate Cox regression model adjusted by matching factors were employed. Results: 176 patients (pts) were included. Median follow-up was 97 months (ms). Median age at diagnosis was 58.5 yrs (43-75). 80 pts received RT (16 BRCA2, 4 BRCA1, 60 NC) and 85% also received ADT≥6 ms. 96pts underwent RP (18 BRCA2, 6 BRCA1 and 72 NC). Following RT treatment, 5yrs-CSS was 96% in NC and 47% in BRCA carriers (p=2x10-5), whilst no difference was seen after RP (5yrs-CSS was 98.5% in NC vs 93.3% in BRCA). Five-years bFPFS after RT was 74% in NC and 24% in BRCA (p=0.002). No difference was observed in 5yrs-bPFS between BRCA carriers and NC treated with RP (52% vs 66% , p=0.346). The adjusted MVA (including tumour stage, local treatment, ADT and BRCA status) confirmed the independent prognostic value of BRCA status for bPFS and CSS. Among BRCA carriers, the independent risk was greater when the analysis was limited to BRCA2 pts . Conclusions: Our results suggest that BRCA carriers have worse local disease control than NC when conventionally treated with RT. No differences in bPFS were observed in pts treated with RP after >8 yrs median follow-up. These results may have implications for tailoring clinical management in these patients.
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Joó, József Gábor, Szabolcs Ládi, B. Zsolt Nagy, and Zoltán Langmár. "Management of hereditary ovarian cancer." Orvosi Hetilap 152, no. 40 (October 2011): 1596–608. http://dx.doi.org/10.1556/oh.2011.29218.
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Mutations in BRCA1 and BRCA2 genes account for the majority of hereditary breast and ovarian cancers. Approximately 10% of cases of ovarian cancer are due to germline mutations in BRCA1 and BRCA2. Ovarian cancer associated with BRCA1 and BRCA2 mutations has a distinct histological phenotype. This type of cancer is predominantly of serous or endometrioid histology and is high grade. Patients with BRCA1 or BRCA2 mutations should be offered risk-reducing salpingo-oophorectomy by age 40 years, or when childbearing is complete. Nowadays there are no differences between the treatments provided for sporadic and hereditary ovarian cancer, although there are indications that targeted therapy is effective in women with BRCA1/BRCA2-associated tumors. Retrospective studies reveal a high level of sensitivity to platinum agents in BRCA-associated tumors and initial trials show good efficacy and tolerability for polyADP-ribose polymerase inhibitors in mutation carriers with advanced ovarian cancers. These agents might also potentially be used in chemoprevention. Authors review the current management of hereditary ovarian cancer. Orv. Hetil., 2011, 152, 1596–1608.
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Pal, Tuya, Deborah Cragun, Xuefeng Wang, Sean J. Yoder, Tania MESA, Marilin Rosa, Ann Tezak, Anne Weidner, Susan Thomas Vadaparampil, and Catherine Phelan. "Characterization of germline and tumor genomic profile in unselected young black breast cancer patients." Journal of Clinical Oncology 35, no. 15_suppl (May 20, 2017): e13090-e13090. http://dx.doi.org/10.1200/jco.2017.35.15_suppl.e13090.
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e13090 Background: Young black women bear a disproportionate burden of breast cancer (BC), yet there is limited characterization of these cancers based on BRCA1 and BRCA2 ( BRCA) status and tumor genomics. In this pilot study, we characterized: tumor and clinical characteristics based on BRCA carrier status and overlap of basal-like (BL) and triple negative (TN) BC. Methods: A population-based sample of 481 black women diagnosed with invasive BC < age 50 were recruited through the Florida Cancer Registry (FCR). BRCA status was determined based on germline testing. TN status was determined based on pathology reports and FCR data. Among a subset of 90 participants, gene expression profiling (GEP) was conducted on tumor samples through PAM50 analyses to classify intrinsic subtypes and risk of recurrence (ROR) scores. Results: Mean age at BC diagnosis was 41.9 (range: 25-50) and mean ROR score was 49.6 (range: 8.7-80.7). Participants included 7 BRCA1 carriers, 5 BRCA2 carriers, 67 non-carriers (NC), and 11 with no confirmed testing. Of 46 BL tumors, 33 were TN (71.7%) constituting 94.3% of TN tumors (the remaining 5.7% were Luminal A). All BRCA1 carriers had BL tumors, of which 5 were TN. Sensitivity, positive predictive value, and negative predictive value in identifying BRCA1 carrier was higher based on BL compared to TN status (Table 1). BRCA2-associated tumors included 3 Luminal A, 1 Luminal B, and 1 BL. Mean ROR score was highest among BRCA1 carriers (57.7), followed by NC (50.5) and BRCA2 carriers (41.5). Conclusions: Study findings suggest BL status predicted BRCA1 positivity better than TN status. BRCA2- (compared to BRCA1-) associated tumors were more heterogeneous with over half being Luminal A, which may explain the lower ROR among BRCA2 carriers. Additional follow-up and expansion of this cohort with collection of clinical outcomes will be useful in assessing the predictive utility of ROR scores among young black women with BC. [Table: see text]
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Vidra, Radu, Tudor Eliade Ciuleanu, Adina Nemeș, Oana Pascu, Ana Maria Heroiu, Nicoleta Antone, Andreea Iulia Vidrean, et al. "Spectrum of BRCA1/2 Mutations in Romanian Breast and Ovarian Cancer Patients." International Journal of Environmental Research and Public Health 19, no. 7 (April 4, 2022): 4314. http://dx.doi.org/10.3390/ijerph19074314.
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Background: About 10,000 women are diagnosed with breast cancer and about 2000 women are diagnosed with ovarian cancer each year in Romania. There is an insufficient number of genetic studies in the Romanian population to identify patients at high risk of inherited breast and ovarian cancer. Methods: We evaluated 250 women of Romanian ethnicity with BC and 240 women of Romanian ethnicity with ovarian cancer for the presence of damaging germline mutations in breast cancer genes 1 and 2 (BRCA1 and BRCA2, respectively) using Next-Generation Sequencing (NGS) technology. Results: Of the 250 breast cancer patients, 47 carried a disease-predisposing BRCA mutation (30 patients (63.83%) with a BRCA1 mutation and 17 patients (36.17%) with a BRCA2 mutation). Of the 240 ovarian cancer patients, 60 carried a BRCA mutation (43 patients (72%) with a BRCA1 mutation and 17 patients (28%) with a BRCA2 mutation). In the BRCA1 gene, we identified 18 variants (4 in both patient groups (ovarian and breast cancer patients), 1 mutation variant in the BC patient group, and 13 mutation variants in the ovarian cancer patient group). In the BRCA2 gene, we identified 17 variants (1 variant in both ovarian and breast cancer patients, 6 distinct variants in BC patients, and 10 distinct variants in ovarian cancer patients). The prevailing mutation variants identified were c.3607C>T (BRCA1) (18 cases) followed by c.5266dupC (BRCA1) (17 cases) and c.9371A>T (BRCA2) (12 cases). The most prevalent mutation, BRCA1 c.3607C>T, which is less common in the Romanian population, was mainly associated with triple-negative BC and ovarian serous adenocarcinoma. Conclusion: The results of our analysis may help to establish specific variants of BRCA mutations in the Romanian population and identify individuals at high risk of hereditary breast and ovarian cancer syndrome by genetic testing.
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Sahnane, Nora, Ileana Carnevali, Giorgio Formenti, Jvan Casarin, Sofia Facchi, Raffaella Bombelli, Eleonora Di Lauro, et al. "BRCA Methylation Testing Identifies a Subset of Ovarian Carcinomas without Germline Variants That Can Benefit from PARP Inhibitor." International Journal of Molecular Sciences 21, no. 24 (December 19, 2020): 9708. http://dx.doi.org/10.3390/ijms21249708.
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Homologous Recombination Deficiency (HRD) is a frequent feature of high-grade epithelial ovarian carcinoma (EOC), associated with sensitivity to PARP-inhibitors (PARPi). The best characterized causes of HRD in EOCs are germline or somatic mutations in BRCA1 and BRCA2 genes. Although promoter methylation is a well-known mechanism of gene transcriptional repression, few data have been published about BRCA gene methylation in EOCs. In this retrospective study, we quantitatively analyzed by pyrosequencing a selected series of 90 formalin-fixed (FFPE) primary EOCs without BRCA germline mutations. We identified 20/88 (22.7%) EOCs showing BRCA promoter methylation, including 17/88 (19.3%) in BRCA1 and 4/86 (4.6%) in BRCA2 promoters, one of which showing concomitant BRCA1 methylation. Mean methylation levels were 49.6% and 45.8% for BRCA1 and BRCA2, respectively, with methylation levels ≥50% in 10/20 methylated EOCs. Constitutive BRCA methylation was excluded by testing blood-derived DNA. In conclusion, pyrosequencing methylation analysis of BRCA genes is a robust, quantitative and sensitive assay applicable to FFPE samples. Remarkably, a considerable subset of germline BRCA-negative EOCs showed somatic methylation and, likely, HRD. A subpopulation of women with BRCA methylation, even without BRCA mutations, could potentially benefit from PARP-inhibitors; further clinical studies are needed to clarify the predictive role of somatic BRCA methylation of PARP-therapy response.
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Shao, Changxia, Michael S. Chang, Fred C. Lam, Andrew R. Marley, Huilin Tang, Yiqing Song, Chelsey Miller, et al. "A Systematic Review and Meta-Analysis on the Prognostic Value of BRCA Mutations, Homologous Recombination Gene Mutations, and Homologous Recombination Deficiencies in Cancer." Journal of Oncology 2022 (July 20, 2022): 1–12. http://dx.doi.org/10.1155/2022/5830475.
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Patients with BRCA1/2 mutations (BRCAm), loss-of-function mutations in other homologous recombination repair (HRRm) genes, or tumors that are homologous recombination deficiency positivity (HRD+) demonstrate a robust response to PARPi therapy. We conducted a systematic literature review and meta-analysis to evaluate the prognostic value of BRCAm, HRRm, and HRD+ on overall survival (OS) among those treated by chemotherapy or targeted therapy other than PARPi across tumor types. A total of 135 eligible studies were included. Breast cancer (BC) patients with BRCA1/2m had a similar overall survival (OS) to those with wild-type BRCA1/2 (BRCA1/2 wt) across 18 studies. Ovarian cancer (OC) patients with BRCA1/2m had a significantly longer OS than those with BRCA1/2 wt across 24 studies reporting BRCA1m and BRCA2m, with an HR of 0.7 (0.6–0.8). Less OS data were reported for other tumors: 6 studies for BRCA2m compared with BRCA2 wt in prostate cancer with an HR of 1.9 (1.1–3.2) and 2 studies for BRCA1/2m compared with BRCA1/2 wt in pancreatic cancer with an HR of 1.5 (0.8–3.1). Only 4 studies reported HRD+ by either BRCA m or genomic instability score (GIS) ≥ 42 and OS by HRD status. The HR was 0.67 (0.43–1.02) for OS with HRD+ vs. HRD−. A total of 15 studies reported the association between HRRm and OS of cancers in which one or more HRR genes were examined. The HR was 1.0 (0.7–1.4) comparing patients with HRRm to those with HRR wild-type across tumors. Our findings are useful in improving the precision and efficacy of treatment selection in clinical oncology.
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Lattimore, Vanessa, John Pearson, Arthur Morley-Bunker, kConFab Investigators, Amanda Spurdle, Bridget Robinson, Margaret Currie, and Logan Walker. "Quantifying BRCA1 and BRCA2 mRNA Isoform Expression Levels in Single Cells." International Journal of Molecular Sciences 20, no. 3 (February 6, 2019): 693. http://dx.doi.org/10.3390/ijms20030693.
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BRCA1 and BRCA2 spliceogenic variants are often associated with an elevated risk of breast and ovarian cancers. Analyses of BRCA1 and BRCA2 splicing patterns have traditionally used technologies that sample a population of cells but do not account for the variation that may be present between individual cells. This novel proof of concept study utilises RNA in situ hybridisation to measure the absolute expression of BRCA1 and BRCA2 mRNA splicing events in single lymphoblastoid cells containing known spliceogenic variants (BRCA1c.671-2 A>G or BRCA2c.7988 A>T). We observed a large proportion of cells (>42%) in each sample that did not express mRNA for the targeted gene. Increased levels (average mRNA molecules per cell) of BRCA2 ∆17_18 were observed in the cells containing the known spliceogenic variant BRCA2c.7988 A>T, but cells containing BRCA1c.671-2 A>G were not found to express significantly increased levels of BRCA1 ∆11, as had been shown previously. Instead, we show for each variant carrier sample that a higher proportion of cells expressed the targeted splicing event compared to control cells. These results indicate that BRCA1/2 mRNA is expressed stochastically, suggesting that previously reported results using RT-PCR may have been influenced by the number of cells with BRCA1/2 mRNA expression and may not represent an elevation of constitutive mRNA expression. Detection of mRNA expression in single cells allows for a more comprehensive understanding of how spliceogenic variants influence the expression of mRNA isoforms. However, further research is required to assess the utility of this technology to measure the expression of predicted spliceogenic BRCA1 and BRCA2 variants in a diagnostic setting.
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Caleca, Laura, Mara Colombo, Thomas van Overeem Hansen, Conxi Lázaro, Siranoush Manoukian, Michael T. Parsons, Amanda B. Spurdle, and Paolo Radice. "GFP-Fragment Reassembly Screens for the Functional Characterization of Variants of Uncertain Significance in Protein Interaction Domains of the BRCA1 and BRCA2 Genes." Cancers 11, no. 2 (January 28, 2019): 151. http://dx.doi.org/10.3390/cancers11020151.
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Genetic testing for BRCA1 and BRCA2 genes has led to the identification of many unique variants of uncertain significance (VUS). Multifactorial likelihood models that predict the odds ratio for VUS in favor or against cancer causality, have been developed, but their use is conditioned by the amount of necessary data, which are difficult to obtain if a variant is rare. As an alternative, variants mapping to the coding regions can be examined using in vitro functional assays. BRCA1 and BRCA2 proteins promote genome protection by interacting with different proteins. In this study, we assessed the functional effect of two sets of variants in BRCA genes by exploiting the green fluorescent protein (GFP)-reassembly in vitro assay, which was set-up to test the BRCA1/BARD1, BRCA1/UbcH5a, and BRCA2/DSS1 interactions. Based on the findings observed for the validation panels of previously classified variants, BRCA1/UbcH5a and BRCA2/DSS1 binding assays showed 100% sensitivity and specificity in identifying pathogenic and non-pathogenic variants. While the actual efficiency of these assays in assessing the clinical significance of BRCA VUS has to be verified using larger validation panels, our results suggest that the GFP-reassembly assay is a robust method to identify variants affecting normal protein functioning and contributes to the classification of VUS.
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Schwartz, Zachary Phillip, Mae Zakhour, Andrew John Li, Christine S. Walsh, Bj Rimel, Monica Alvarado, Scott E. Lentz, and Ilana Cass. "Comparison of risk-reducing surgery in women with BRCA and non-BRCA ovarian cancer susceptibility genes." Journal of Clinical Oncology 37, no. 15_suppl (May 20, 2019): 1547. http://dx.doi.org/10.1200/jco.2019.37.15_suppl.1547.
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1547 Background: Risk reducing gynecologic surgery (RRSO) is standard of care for women with BRCA mutations. The optimal management for women with non-BRCA ovarian cancer susceptibility mutations remains unclear. We sought to characterize the practice patterns for these women at our two institutions. Methods: Women with germline ovarian cancer susceptibility genes who had a RRSO were identified from 1/2000-1/2019 in an IRB approved study. All patients were asymptomatic with no suspicion for malignancy at time of RRSO. Clinico-pathologic characteristics were extracted from the medical records. Continuous variables were analyzed with Kruskal-Wallis and categorical variables analyzed with chi square and t-tests. Results: 152 BRCA1, 95 BRCA2, and 63 Non-BRCA mutation carriers were identified—50 Lynch (22 MLH1, 13 MSH2, 13 MSH6, 2 PMS2) and 13 Other (6 BRIP1, 2 RAD51C, 5 RAD51D). There was no difference between age at testing, age at RRSO, and interval between testing and RRSO between groups. Genetic counseling was higher in Non-BRCA patients. Family history of ovarian cancer was more common in women with BRCA1 and Other germline mutations compared to BRCA2 and Lynch. Family and personal history of breast cancer was high in all groups except Lynch carriers. Prophylactic mastectomy was seen mostly in BRCA mutation carriers. Concomitant hysterectomy was performed in the majority of women (BRCA1 59%, BRCA2 57%, and Other 62%), with the highest frequency in Lynch carriers (86%, p<.01). Occult cancer was only seen in BRCA mutation carriers: BRCA1 (7%), BRCA2 (2%), Lynch (0%), Other (0%). Conclusions: In this cohort, women with Non-BRCA mutations are managed similarly to women with BRCA mutations. We observed no occult cancers in Non-BRCA patients. The optimal role of surgery as a risk reducing strategy in this group requires further study. [Table: see text]
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Mitamura, Takashi, Masayuki Sekine, Masami Arai, Yuka Shibata, Momoko Kato, Shiro Yokoyama, Hiroko Yamashita, et al. "Risk factors for lymph node metastasis of ovarian, fallopian tube and primary peritoneal cancer in hereditary breast and ovarian cancer syndrome." Japanese Journal of Clinical Oncology 50, no. 12 (July 17, 2020): 1380–85. http://dx.doi.org/10.1093/jjco/hyaa124.
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Abstract Background To establish an individualized surgical strategy for lymphadenectomy in ovarian cancer patients with the germline BRCA1 and BRCA2 pathogenic variants (BRCA1+ and BRCA2+), we investigated the clinicopathological characteristics that are involved in the increased risk of lymph node metastasis. Methods We retrospectively reviewed the data of Japanese women registered in the database of the Japanese Hereditary Breast and Ovarian Cancer Consortium, who underwent BRCA1 and BRCA2 genetic testing. Results We evaluated the predictors of lymph node metastasis in all patients with the information of age at the diagnosis, disease site, histological subtype, 2014 FIGO stage, personal breast cancer history and family history; 233, 153 and 32 patients in the BRCA− (no pathogenic variant), BRCA1+ and BRCA2+ groups, respectively. The prevalence of lymph node metastasis was not markedly different between BRCA− (20.0%), BRCA1+ (18.4%) and BRCA2+ (26.2%). Multivariate analysis revealed an absence of a family history of ovarian cancer as an independent predictor for an increased risk of lymph node metastasis in BRCA1+, and the prevalence of lymph node metastasis was 11.7 and 42.0% in the groups with and without a family history of ovarian cancer, respectively. This subgroup without a family history of ovarian cancer did not show any correlation with a particular variant of BRCA1, including two common variants of c.188 T > A and c.2800C > T. Conclusions This study suggested that certain genetic factors related to the penetrance of hereditary breast and ovarian cancer syndrome altered the frequency of lymph node metastasis in BRCA1+ ovarian cancer, and family history may be useful to personalize the indication of lymphadenectomy.
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Graeser, Monika K., Christoph Engel, Kerstin Rhiem, Dorothea Gadzicki, Ulrich Bick, Karin Kast, Ursula G. Froster, et al. "Contralateral Breast Cancer Risk in BRCA1 and BRCA2 Mutation Carriers." Journal of Clinical Oncology 27, no. 35 (December 10, 2009): 5887–92. http://dx.doi.org/10.1200/jco.2008.19.9430.
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Purpose To estimate the risk for contralateral breast cancer in members of BRCA1- and BRCA2-positive families and to determine predictive risk factors. Patients and Methods A retrospective, multicenter, cohort study was performed from 1996 until 2008 and comprised 2,020 women with unilateral breast cancer (index patients, n = 978; relatives, n = 1.42) from 978 families who had a BRCA1 or BRCA2 mutation. Cox regression analysis was applied to assess the association of age at first breast cancer with time from first to contralateral breast cancer, stratified by the affected BRCA gene. Results The cumulative risk for contralateral breast cancer 25 years after first breast cancer was 47.4% (95% CI, 38.8% to 56.0%) for patients from families with BRCA1 or BRCA2 mutations. Members of families with BRCA1 mutations had a 1.6-fold (95% CI, 1.2-fold to 2.3-fold) higher risk of contralateral breast cancer than members of families with BRCA2 mutations. Younger age at first breast cancer was associated with a significantly higher risk of contralateral breast cancer in patients with BRCA1 mutation, and a trend was observed in patients with BRCA2 mutation. After 25 years, 62.9% (95% CI, 50.4% to 75.4%) of patients with BRCA1 mutation who were younger than 40 years of age at first breast cancer developed contralateral breast cancer, compared with only 19.6% (95% CI, 5.3% to 33.9%) of those who were older than 50 years of age at first breast cancer. Conclusion Contralateral breast cancer risk depends on age at first breast cancer and on the affected BRCA gene, and this risk should be considered in treatment planning.
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Castro, Elena, David Olmos, Chee Leng Goh, Ed Saunders, Daniel Leongamornlert, Malgorzata Tymrakiewicz, Elizabeth Bancroft, et al. "BRCA carrier status as an independent prognostic factor associated with earlier biochemical relapse in local prostate cancer." Journal of Clinical Oncology 30, no. 15_suppl (May 20, 2012): 1545. http://dx.doi.org/10.1200/jco.2012.30.15_suppl.1545.
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1545 Background: Biochemical relapse after local treatment for prostate cancer (PCa) indicates recurrent disease and is associated with shorter survival. Germline BRCA mutations are associated with worse PCa outcomes. BRCA carriers are currently treated with the same protocols used for non-carriers. We analyzed biochemical-progression free survival (bPFS) after conventional treatment for localized PCa in a cohort of BRCA patients (pts). Methods: In this retrospective case-control study, each BRCA carrier (9 BRCA1 and 34 BRCA2) treated with radical prostatectomy (RP) or external beam radiotherapy (RT) was matched with 3 non-carriers (NC) by age at diagnosis (±5 yrs), TNM stage, Gleason score, presenting PSA, local treatment , androgen-deprivation therapy (ADT) and year of treatment (±3 yrs). All NC were screened for BRCA1 and BRCA2 mutations. Biochemical failure was reviewed according to ASTRO and NCCN criteria. The Kaplan-Meier method and a multivariate Cox regression model adjusted by matching factors were employed. Results: 172 pts were included. Median follow-up was 76 months (ms). Median age at diagnosis was 58 yrs (43-75). Tumour stages were I 11%, IIA 19%, IIB 28%, III 28%, IV 14%. 80 pts received RT (18 BRCA2, 5 BRCA1, 57NC) and 85% also received ADT (70% for ≥6 months). 92 pts underwent RP (16 BRCA2, 4 BRCA1 and 72 NC), and 9% of them received ADT (<6months). Overall, median bPFS was 71ms. For those treated with RT, median bPFS was 65ms in NC vs 39ms in BRCA carriers (p=0.023). bPFS was not affected by ADT duration. Median bPFS after RP was 65ms in BRCA carriers. No difference was observed in 3yrs-bPFS between BRCA carriers and NC (73% vs 76%). The adjusted MVA confirmed the independent prognostic value of tumour stage (p=0.004) and BRCA status (p=0.032) for bPFS. Among BRCA carriers, the risk was greater when the analysis was limited to BRCA2 pts (p=0.013, HR 2.1,.95%CI 1.2-3.7). Conclusions: Our results suggest that BRCA carriers with PCa have worse local disease control than NC when treated with RT, regardless of ADT duration. No differences in bPFS were observed in pts treated with RP after >6 yrs median follow-up. These results may have implications for tailoring clinical management for these patients.
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Liu, Ying L., Julia Lindsay Boland, Karen Anne Cadoo, Claire Frances Friedman, Jason A. Konner, Roisin Eilish O'Cearbhaill, Carol Aghajanian, and Dmitriy Zamarin. "Response to immune checkpoint inhibition and survival in BRCA-associated recurrent ovarian cancer." Journal of Clinical Oncology 37, no. 15_suppl (May 20, 2019): 2615. http://dx.doi.org/10.1200/jco.2019.37.15_suppl.2615.
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2615 Background: Alterations in the DNA mismatch repair pathway increase susceptibility to immune checkpoint inhibition (ICI). Tumors with BRCA-related DNA repair defects may have increased antigenicity, which could drive response to ICI. Responses to ICI in ovarian cancer (OC) have been modest. We seek to evaluate the association of BRCA mutations with response to ICI and survival in recurrent OC. Methods: A single-center, retrospective review identified 103 women with recurrent OC and known BRCA mutation status (90 germline and 33 somatic testing) who received ICI between 1/2013-7/2018 (98 on study). Clinical characteristics and duration of ICI (Long > = 24 vs. Short < 24 weeks) were compared by BRCA status. Kaplan Meier survival analysis was used to calculate progression-free (PFS) and overall survival (OS) from start of ICI, and CoxPH models/logrank test were used to assess survival differences by BRCA status. Results: Deleterious germline (g) or somatic (s) BRCA 1/2 mutations were present in 29 (28%) women (12 g BRCA1, 9 g BRCA2, 3 s BRCA1, 5 s BRCA2, 1 g BRCA1/s BRCA1, 3 g BRCA2/s BRCA2, and 1 g BRCA2/s BRCA1). Patients (pts) with BRCA mutations had more lines of treatment prior to ICI (median 5 vs. 4, p = 0.03) and a longer time from diagnosis to ICI (median 54 vs. 38.5 months (mo), p = 0.01), but there were no significant differences in other variables including histology (86% high grade serous), stage at diagnosis (96% Stage III/IV), and platinum status (83% resistant), p > 0.05. Four pts (15%) with BRCA mutations had long duration of ICI as compared with 20 pts (27%) in those without mutations, p = 0.20. Median PFS was 2.2 mo (95% CI 1.7-2.7) in those with BRCA mutations and 3.4 mo (95% CI 2.1-4.0) in those without mutations, HR 1.22 (95% CI 0.78-1.91, p = 0.38). At a median follow-up of 23.3 mo, median OS was 21.3 mo (95% CI 13.7-31.8) in those with BRCA mutations and 19.8 mo (95% CI 13.8-25.3) in those without. This was not significantly different, HR 1.00 (95% CI 0.54-1.87, p = 0.99), after adjustment for prior lines and time from diagnosis to ICI. Conclusions: In our study of heavily pretreated OC pts receiving ICI, BRCA 1/2 mutations were not associated with improved response or survival. These findings should be validated in larger studies.
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Tabaliuk, Y. O., L. A. Rybchenko, B. T. Klimuk, and S. V. Klymenko. "Screening for mutations in BRCA1 and BRCA2 genes and related perspectives for the healthcare system." Visnik ukrains'kogo tovaristva genetikiv i selekcioneriv 18, no. 1-2 (January 29, 2021): 44–57. http://dx.doi.org/10.7124/visnyk.utgis.18.1-2.1354.
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In the article there were looked some aspects of the knowledge regarding mutations in BRCA1 BRCA2 genes that have been accumulated since the first report on role of these genes in the development of breast and ovarian cancer. Most of them have practical worth related to the detection of mutations, as well as the prevention and treatment of associated ovarian cancer (the article focuses specifically on ovarian cancer, conditioned to relatively less amount of information on this pathology). There has been paid attention to the rational assignment of a genetic test on the presence of mutations in BRCA genes.Keywords: ovarian cancer, mutations in BRCA1 BRCA2 genes, screening of the presence mutations in BRCA1 BRCA2 genes.
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Dufloth, Rozany Mucha, Sílvia Carvalho, Juliana Karina Heinrich, Júlia Yoriko Shinzato, César Cabello dos Santos, Luiz Carlos Zeferino, and Fernando Schmitt. "Analysis of BRCA1 and BRCA2 mutations in Brazilian breast cancer patients with positive family history." Sao Paulo Medical Journal 123, no. 4 (2005): 192–97. http://dx.doi.org/10.1590/s1516-31802005000400007.
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CONTEXT AND OBJECTIVE: BRCA1 and BRCA2 are the two principal hereditary breast cancer susceptibility genes, and the prevalence of their mutations among Brazilian women is unknown. The objective was to detect BRCA1 and BRCA2 mutations in Brazilian patients with breast cancer, so as to establish genetic profiles. DESIGN AND SETTING: Cross-sectional study, in Centro de Atenção Integral à Saúde da Mulher, Universidade Estadual de Campinas, Brazil, and Institute of Pathology and Molecular Immunology, University of Porto, Portugal. METHODS: Thirty-one breast cancer patients with positive family history (criteria from the Breast Cancer Linkage Consortium) were studied, and genomic DNA was extracted from peripheral blood. Single-strand conformation polymorphism was used for the analysis of exons 2, 3, 5, and 20 of BRCA1. Cases showing PCR products with abnormal bands were sequenced. Exon 11 of BRCA1 and exons 10 and 11 of BRCA2 were directly sequenced in both directions. RESULTS: Four mutations were detected: one in BRCA1 and three in BRCA2. The BRCA1 mutation is a frameshift located at codon 1756 of exon 20: 5382 ins C. Two BRCA2 mutations were nonsense mutations located at exon 11: S2219X and the other was an unclassified variant located at exon 11: C1290Y. CONCLUSION: The BRCA1 or BRCA2 mutation prevalence found among women with breast cancer and such family history was 13% (4/31). Larger studies are needed to establish the significance of BRCA mutations among Brazilian women and the prevalence of specific mutations.
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Ayoub, Jean-Pierre, Hans Wildiers, Michael Friedlander, Banu K. Arun, Hyo S. Han, Shannon Puhalla, Yaroslav Shparyk, et al. "Safety and efficacy of veliparib plus carboplatin/paclitaxel in patients with HER2-negative metastatic or locally advanced breast cancer: subgroup analyses by germline BRCA1/2 mutations and hormone receptor status from the phase-3 BROCADE3 trial." Therapeutic Advances in Medical Oncology 13 (January 2021): 175883592110596. http://dx.doi.org/10.1177/17588359211059601.
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Purpose: To evaluate efficacy and safety of veliparib combined with carboplatin/paclitaxel in patients with advanced human epidermal growth factor receptor 2 (HER2)-negative, germline BRCA (g BRCA)-associated breast cancer defined by hormone receptor (HR) and g BRCA1/ 2 mutation status. Patients and Methods: In this phase-3, double-blind, placebo-controlled trial, patients ( N = 509) with advanced HER2-negative breast cancer and g BRCA1/2 mutations were randomized 2:1 to receive veliparib plus carboplatin/paclitaxel or placebo plus carboplatin/paclitaxel. Patients who discontinued chemotherapy prior to disease progression continued receiving blinded veliparib/placebo monotherapy. The primary endpoint was investigator-assessed progression-free survival (PFS). Subgroup analyses of PFS stratified by HR and g BRCA1/2 mutation status were prespecified. Results: In the intention-to-treat population, there were similar proportions of patients with g BRCA1 versus g BRCA2 mutations (51% vs 49%) and HR+ disease versus triple-negative breast cancer (TNBC) (52% vs 48%). Median PFS was longer in the veliparib arm compared with the placebo arm for all subgroups (HR+: 13.0 vs 12.5 months, hazard ratio (95% confidence interval (CI)): 0.69 (0.52, 0.93), p = 0.013; TNBC: 16.6 vs 14.1 months, hazard ratio (95% CI): 0.72 (0.52, 1.00), p = 0.052; g BRCA1: 14.2 vs 12.6 months, hazard ratio (95% CI): 0.75 (0.55, 1.03), p = 0.073; g BRCA2: 14.6 vs 12.6 months, hazard ratio (95% CI): 0.69 (0.50, 0.95); p = 0.021). Benefit was durable, with improved PFS rates at 2 years (HR+, 27.5% vs 15.3%; TNBC, 40.4% vs 25.0%) and 3 years (HR+, 17.5% vs 8.6%; TNBC, 35.3% vs 13.0%) in all subgroups. g BRCA status ( BRCA1 vs BRCA2) did not substantially affect the carboplatin/paclitaxel ± veliparib toxicity profile. Conclusion: Veliparib plus carboplatin/paclitaxel resulted in durable benefit in subgroups defined by HR status or by g BRCA1 versus g BRCA2 mutation. Overall, addition of veliparib to carboplatin/paclitaxel was tolerable, and there were no clinically meaningful differences in adverse events between the g BRCA1 versus g BRCA2 and HR+ versus TNBC subgroups. Trial Registration: NCT02163694, https://clinicaltrials.gov/ct2/show/NCT02163694
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Dall'era, Marc, Christopher P. Evans, Chong-Xian Pan, Mamta Parikh, Primo Lara, and John McPherson. "Are prostate cancer patients with BRCA1 and BRCA2 mutations safe for active surveillance?" Journal of Clinical Oncology 37, no. 7_suppl (March 1, 2019): 19. http://dx.doi.org/10.1200/jco.2019.37.7_suppl.19.
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19 Background: Active surveillance (AS) is recommended as a treatment option for men presenting with low risk (Gleason 3+3) and some intermediate risk (Gleason 3+4) prostate cancer. BRCA1 or 2 germline mutations have been implicated in prostate cancer pathogenesis. It is unknown if germline BRCA1/2 mutations in AS candidacy are associated with more aggressive histologic grade, higher stage or other worse genetic alterations, such as RB1 and p53 deletions. Methods: We analyzed sequencing data from 498 men who underwent radical prostatectomy from The Cancer Genome Atlas (TCGA) data set. The primary outcome was the difference in the proportions of AS candidates among subjects with and without BRCA homodeletions. Tests for differences in the proportions were conducted using Fisher’s Exact Test. Equivalence tests for proportions of AS candidates were conducted using the two-one sided tests (TOST) method. As a secondary outcome we studied the associated coincident mutations in the men with BRCA1 and BRCA2 homodeletions. Results: Forty-one men (8%) of the cohort had homodeletion of BRCA1 or BRCA2. Ten men (2%) had complete loss of BRCA1 while 31 (6%) had loss of BRCA2. Rates of candidacy for AS based on histology and stage (defined as stage T2, Gleason 6) are not different between subjects with and without BRCA 1 or 2 homodeletions, within an equivalence margin of 10 percentage points. These findings are similar when the AS criteria are modified to add Gleason 3+4 subjects. Fifty percent of men with organ confined (pT2), 3+3 and 3+4 prostate cancer with BRCA1 or BRCA2 homodeletions had concomitant RB1 deletions compared with 16.5% of the entire cohort (p = 0.002). This was primarily driven by BRCA2 deletions co-occurrent with RB1 deletions (log OR: 2.4, p < 0.001). Twenty-nine percent of men from this group had concomitant p53 deletions compared to 7.5% of the entire cohort (p = 0.004). Conclusions: Men with prostate cancer and BRCA1 or BRCA2 homodeletions present with similar stage and grade tumors than men without these deletions. Despite having low or low intermediate grade histology, BRCA1 and BRCA2 deleted tumors are enriched with deletions in RB1 and TP53, both of which are associated with more aggressive phenotypes and treatment resistance.
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Oh, Mok, Ali McBride, Seongseok Yun, Sandipan Bhattacharjee, Marion Slack, Joanne M. Jeter, and Ivo Abraham. "BRCA1 and BRCA2 gene mutations and colorectal cancer risk: Systematic review and meta-analysis." Journal of Clinical Oncology 36, no. 4_suppl (February 1, 2018): 605. http://dx.doi.org/10.1200/jco.2018.36.4_suppl.605.
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605 Background: The risks of breast and ovarian cancer associated with BRCA1 and BRCA2 mutations are well established. Investigations of the association of BRCA mutations and the risk of colorectal cancer(CRC) have yielded conflicting results. We performed a systematic review of published and unpublished studies evaluating BRCA and CRC risk, and meta-analyses to quantify overall CRC risk and in subgroups of BRCA mutation carriers. Methods: Eligible studies were retrieved from PubMed/MEDLINE, Embase, Cochrane, Scopus, and ProQuest Dissertation & Theses. Unadjusted odds ratios were used to derive pooled estimates of CRC risk overall (combined BRCA1/BRCA2) and in subgroups defined by mutation type, comparison group, and study design. Both fixed and random effects models were estimated with the latter having priority. We followed the guidelines summarized in the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) as well as the Meta-analysis of Observational Studies in Epidemiology (MOOSE) statements. Results: A total of 18 studies were included in the systematic review: 7 cohort studies comparing to the general population, 5 case-control studies, 4 cohort studies involving pedigree analysis, and 2 kin-cohort studies. Fourteen studies included in the systematic review were used in the meta-analysis. The overall BRCA1/BRCA2 meta-analysis revealed an increased CRC risk in a fixed-effects (OR = 1.22, 95%CI = 1.01-1.48, p = 0.041, I2= 19.5%) but not in a random-effects model (OR = 1.20, 95%CI = 0.96-1.50, p = 0.111). In subgroup random-effects meta-analyses, BRCA1 was associated with increased CRC risk (OR = 1.48, 95%CI = 1.13-1.94, p = 0.005, I2= 3.7%) but BRCA2 was not. Analyses stratified by study design and comparator found no association between BRCA mutation and CRC risk (all 95%CIs crossing 1, all p > 0.05). Conclusions: Although studies differed in their findings about the association between BRCA mutations and CRC risk, meta-analyses revealed a potential 1.22-fold greater risk of CRC in BRCA mutation carriers. This elevated CRC risk was attributable largely to a 1.48-fold greater risk in BRCA1 mutation but not in BRCA2 carriers, regardless of age.
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Shweash, Muhannad, Saddam Jumaa Naseer, Maisam Khider Al-anii, and Thulfiqar Fawwaz Mutar. "A MOLECULAR-BASED APPROACH TO INVESTIGATE BREAST CANCER 1 AND BREAST CANCER 2 STATUS IN OVARIAN CANCER AMONG IRAQI WOMEN." Asian Journal of Pharmaceutical and Clinical Research 11, no. 7 (July 7, 2018): 199. http://dx.doi.org/10.22159/ajpcr.2018.v11i7.25217.
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Objective: Cancer ovary is one of the fatal gynecologic malignancies worldwide. Since breast cancer (BRCA) genes are considered tumor suppressor genes and play important roles in cancer by repairing of chromosomal damage with the error repair of DNA breaks. Therefore, breast cancer 1 (BRCA1) and breast cancer 2 (BRCA2) gene mutations strongly enhance the development of ovarian cancer risk among women. Here, we report that both genes are an essential mediator of progress ovarian cancer, to determine the influence of BRCA1 and BRCA2 mutations in the improvement of ovarian cancer.Methods: A total of 25 subjects were chosen for the genetic studies, and three groups were recruited: fifteen ovarian cancer patients group, five healthy controls, and five first-degree relatives to a known case of ovarian cancer patients.Results: A genetic analysis revealed that a strong correlation exists between both gene mutations’ status in ovarian cancer, and BRCA gene mutations (185delAG, 5382insC, and 4153delA in BRCA1 and 6174delT in BRCA2) remained to establish to have a relatively high frequency among people in this study among ovarian cancer patients. Furthermore, seven patients with ovarian cancer carried all of the four investigated mutations, and five had three mutations.Conclusion: Otherwise, BRCA gene frequency showed low prevalence among first-degree relatives, and to a lesser extent among healthy controls, with only a few had all of the mutations combined. These data demonstrate for the first time a molecular link between BRCA1 and BRCA2 mutations in ovarian cancer progression in Iraq.
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Trombetta, Mark, Katherine Kotinsley, and Thomas B. Julian. "Breast conservation surgery and radiation for a patient with synchronous primary breast cancers and BRCA1/BRCA2 positivity: is mastectomy required?" Journal of Radiotherapy in Practice 11, no. 1 (March 18, 2011): 62–65. http://dx.doi.org/10.1017/s1460396911000021.
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AbstractThe role of breast conservation in patients expressing BRCA1 and BRCA2 genetic mutations is controversial. A patient who was found to have bilateral synchronous breast cancers and expressed a BRCA genetic mutation was recently evaluated. The patient had a strong desire for breast preservation. This case and a review of the pertinent literature are presented to discuss the role of breast conservation and radiation in patients with BRCA1 or BRCA2 genetic mutations.