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Zagorodnev, Kirill, Yevgeniy Suspitsyn, Anna Sokolenko, A. Romanko, M. Anisimova, Ilya Bizin, Ye Kuligina, and Yevgeniy Imyanitov. "APPLICATION OF THE TARGETED MULTIGENE SEQUENCING FOR THE SEARCH OF HEREDITARY BREAST CANCER MUTATIONS IN RUSSIAN PATIENTS." Problems in oncology 65, no. 3 (March 1, 2019): 349–56. http://dx.doi.org/10.37469/0507-3758-2019-65-3-349-356.
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Understanding of the molecular-genetic pathogenesis of hereditary cancer syndrome is extremely important for developing of personal therapeutic approaches and for improving the effectiveness of preventive measures. Today, the optimal solution for the search of causative germ-line mutations in hereditary breast cancer (BC) patients is the next-generation sequencing-based multigene mutational screening. The authors have assembled a targeted panel of 31 genes, based on their potential involvement in the cancer susceptibility and taking into account the frequency of pathogenic alleles in the Russian population. It includes the “canonical” genes of hereditary breast cancer (BRCA1, BRCA2, BRIP1, PALB2, TP53, ATM, NBN), the recently identified “novel” genes (BLM, FANCD2, POLE, FANCM, RAD51C, MRE11A, RECQL, as well as some other genes involved in DNA repair, apoptosis and genome stability maintenance. 94 patients with hereditary BC of unknown genetic etiology were subjected to targeted sequencing. As a result, causative germ-line mutations were identified in 21/94 (22.3%) patients. Importantly, 19 patients harbored rare non-founder BRCA1 and BRCA2 mutations. In the remaining two cases, the functions of the ATM (p.Glu73fs) and POLE (p.Leu1171fs) genes were disrupted. The obtained data are of evident clinical importance; they argue for the expanding of diagnostic panels for monitoring at-risk individuals and for moving the standards of routine clinical diagnostics towards the targeted next-generation sequencing of multigene panels.
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Stadler, Zsofia K., Francesca Battaglin, Sumit Middha, Jaclyn F. Hechtman, Christina Tran, Andrea Cercek, Rona Yaeger, et al. "Reliable Detection of Mismatch Repair Deficiency in Colorectal Cancers Using Mutational Load in Next-Generation Sequencing Panels." Journal of Clinical Oncology 34, no. 18 (June 20, 2016): 2141–47. http://dx.doi.org/10.1200/jco.2015.65.1067.
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Purpose Tumor screening for Lynch syndrome is recommended in all or most patients with colorectal cancer (CRC). In metastatic CRC, sequencing of RAS/BRAF is necessary to guide clinical management. We hypothesized that a next-generation sequencing (NGS) panel that identifies RAS/BRAF and other actionable mutations could also reliably identify tumors with DNA mismatch repair protein deficiency (MMR-D) on the basis of increased mutational load. Methods We identified all CRCs that underwent genomic mutation profiling with a custom NGS assay (MSK-IMPACT) between March 2014 and July 2015. Tumor mutational load, with exclusion of copy number changes, was determined for each case and compared with MMR status as determined by routine immunohistochemistry. Results Tumors from 224 patients with unique CRC analyzed for MMR status also underwent MSK-IMPACT. Thirteen percent (n = 28) exhibited MMR-D by immunohistochemistry. Using the 341-gene assay, 100% of the 193 tumors with < 20 mutations were MMR-proficient. Of 31 tumors with ≥ 20 mutations, 28 (90%) were MMR-D. The three remaining tumors were easily identified as being distinct from the MMR-D tumors with > 150 mutations each. Each of these tumors harbored the P286R hotspot POLE mutation consistent with the ultramutator phenotype. Among MMR-D tumors, the median number of mutations was 50 (range, 20 to 90) compared with six (range, 0 to 17) in MMR-proficient/POLE wild-type tumors (P < .001). With a mutational load cutoff of ≥ 20 and < 150 for MMR-D detection, sensitivity and specificity were both 1.0 (95% CI, 0.93 to 1.0). Conclusion A cutoff for mutational load can be identified via multigene NGS tumor profiling, which provides a highly accurate means of screening for MMR-D in the same assay that is used for tumor genotyping.
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Alemar, Barbara, Cristina Netto, Camila Bittar, Osvaldo Artigalas, Cleandra Gregorio, Marina Roberta Scheid, and Patricia Ashton-Prolla. "Germline mutational spectrum of Brazilian HBOC patients tested with hereditary cancer multigene panels." Journal of Clinical Oncology 34, no. 15_suppl (May 20, 2016): e13113-e13113. http://dx.doi.org/10.1200/jco.2016.34.15_suppl.e13113.
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Pajares, Bella, Marcos Iglesias Campos, Tamara Díaz, Rafael Jesus Peralta, Emilio Alba, and Antonia Marquez. "Genetic and clinical characterization of multigene hereditary breast and ovarian cancer (HBOC) panels in Málaga (Spain)." Journal of Clinical Oncology 39, no. 15_suppl (May 20, 2021): e22530-e22530. http://dx.doi.org/10.1200/jco.2021.39.15_suppl.e22530.
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e22530 Background: Next Generation Sequencing (NGS) technologies have transformed hereditary breast and ovarian cancer (HBOC) testing process. Several multigene panels (MP) include from 10 to 100 candidate cancer susceptibility genes, but there is a debate about what genes should and should not be tested because of lack of actionability. Few studies have been reported about MP in Europe or Spanish cancer families and no studies in Andalusian population (southern Spain). Methods: We investigated a panel of 17 known genes of high/moderate-risk for HBOC in 938 clinically suspicious HBOC Andalusian families (SEOM 2015 criteria), tested from 2017 to 2019. Multigene panel including BRCA,1 BRCA2, CHEK2, PALB2, BRIP1, ATM, MLH1, MSH2, MSH6, PMS2, CDH1, NF1, PTEN, p53, STK11, RAD51C and RAD51D was performed. Results: We identified 130 patients who carried a high- or moderate-risk pathogenic variants: 61 in BRCA2 (47%), 30 in BRCA 1 (23%), 10 in CHEK2 (8%), 7 in ATM (5%), 7 in PALB2 (5%), 4 in RAD51 (3%), 4 in BRIP1 (3%), 4 in MSH6 (3%), 2 in MLH1 (1,5%) and 1 in MSH2. We detected 220 patients carry variants of uncertain significance (VUS), with a total of 248 VUS (some patients carried more than one VUS): 46 (19%) in ATM, 38 (15%) in BRCA 2, 28 (11%) in MSH6, 19 (8%) in PMS2, 17 (7%) in BRIP1, 16 (6%) in NF1, 14 (6%) in MSH2 and 12 (5%) in CDH1 and PALB2. The most frequent criteria in the entire cohort was “High-grade epithelial non-mucinous ovarian cancer”, reported in 243 cases (26%)”, whereas “Breast cancer (BC) diagnostic under 35” was the most frequent criteria between positives (48 cases (40%)). One case carried two pathogenic variants: BRCA2 and MUTYH. Conclusions: This is the first study reporting the mutational profile of MP gene testing in Andalusia. 70% of mutations were due to BRCA1 and 2 followed by far by CHEK2, ATM and PALB2. We also identified a large amount of VUS in BRCA2, ATM and MSH6. MP improve the diagnostic in andalusian HBOC patients.
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fontana, sabrina K. kahler ribeiro, emanuele bonetti, loris bernard, mariarosaria calvello, Bernardo Bonanni, ppina Bonizzi, Paolo Veronesi, Luca Mazzarella, Viviana Galimberti, and claudia sangalli. "Abstract P6-02-11: Implementation of multigene panel testing in triple-negative breast cancer. The PERSONA-breast trial." Cancer Research 83, no. 5_Supplement (March 1, 2023): P6–02–11—P6–02–11. http://dx.doi.org/10.1158/1538-7445.sabcs22-p6-02-11.
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Abstract Kahler Ribeiro Fontana S1, Bonetti E2, Bernard L3, Calvello M4, Bonanni B4, Bonizzi G 5, Veronesi P1,6, Mazzarella L 2, Galimberti V1 Introduction Triple-negative breast cancer (TNBC) is frequently associated with germline genetic variants associated with cancer predisposition. Approximately 20% of TNBC carry a germline BRCA1 or BRCA2 mutation. Germline mutations in other genes involved in DNA repair, specifically Homologous Recombination (HRR), including ATM, BARD1, BRIP1, CHEK2, PALB2, RAD50, RAD51C, RAD51D may be associated with TNBC however remain imprecise in several populations as in Italy. In recent years, there has been an increase in multigenic panel testing thanks to better technology and the fact that genetic testing is no longer done just for prevention but they have become relevant in the clinical setting and this is especially true for triple negative disease. At the European Institute of Oncology, we conducted a prospective clinical trial, the PERSONA Breast trial, aimed at providing a more comprehensive picture of the mutational landscape and cancer risk in patients with TNBC by multigene germline genetic testing. Methods PERSONA is a prospective observational trial conducted between June 2018 and January 2022 on 313 patients with a diagnosis of TNBC ≤ 60 years and able to undergo surgery (primary or post-neoadjuvant). Peripheral blood DNA was sequenced with the Illumina TruSight Cancer panel (94 cancer predisposition genes). Genes were classified as germline actionable (n. 15) or non-actionable (n. 79) according to their associated relative risk of cancer. Genetic variants were classified according to the American College of Medical Genetics and Genomics (ACMG) guidelines and the databases of genetic variants (ClinVar, LOVD, BRCA-Exchange,). All enrolled patients were followed up six-monthly for 10 years from informed consent or to death or withdrawal of consent. Results We present preliminary germline results from a 94-gene panel testing performed on a cohort of 313 TNBC patients. The clinical data of these patients was considered for a descriptive analysis of the cohort. Data on outcome such as overall survival and disease-free survival were not yet available. Germline multigene testing detected 62 unique (i.e., n. 49 in actionable, n. 13 in non-actionable genes) pathogenic (C5) and likely pathogenic (C4) variants in 25.2% of TNBC patients (79/313). As expected, 53.2% (42/79) of TNBC patients were carriers of a C5/C4 in BRCA1. C4/C5 were identified also in other actionable genes: 13.9% (11/79) in BRCA2, 8.9% (7/79) in MUTYH, 3.8% (3/79) in PALB2, 2.5% (2/79) in MSH2, 1.3% (1/79) in PMS2, and 1.3% (1/79) in TP53. In addition, 12 TNBC patients had C4/C5 variants in non-actionable genes, and 4 were carriers of both C4/C5 variants in actionable and non-actionable genes. Multigene testing resulted in the identification of 655 (i.e., n.82 in actionable, n. 573 in non-actionable genes) variants of uncertain significance (C3 or VUS) in 89.8% (281/313) of patients. Of the 281 C3 carriers, 60 had other variants (C4 and/or C5), of an uncertain result (in whom C3 was the highest class of variant) only in 70.6% (221/313) of TNBC patients. In 13 patients (13/313; 4.1%) only benign (C1) or likely benign (C2) variants were identified. Regarding family history, 67% of BRCA1 carriers versus 30% of BRCA2 carriers were familial. Conclusion Germline multigene testing in TNBC can identify C4/C5 in actionable genes providing information for a more tailored management of TNBC. Our study showed that the rate of VUS remains high using multigene testing. Of note, VUS were mainly identified in non-actionable genes supporting the rationale of the use in the clinical setting of phenotype-specific multigene panels, including a minor, but more appropriate, number of genes. Citation Format: sabrina K. kahler ribeiro fontana, emanuele bonetti, loris bernard, mariarosaria calvello, Bernardo Bonanni, ppina Bonizzi, Paolo Veronesi, Luca Mazzarella, Viviana Galimberti, claudia sangalli. Implementation of multigene panel testing in triple-negative breast cancer. The PERSONA-breast trial [abstract]. In: Proceedings of the 2022 San Antonio Breast Cancer Symposium; 2022 Dec 6-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2023;83(5 Suppl):Abstract nr P6-02-11.
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Bapat, Bela, Connor Sweetnam, Ashleigh McBratney, Monika A. Izano, Brock Schroeder, Sheetal Walters, William Chen, Phillip G. Febbo, and Anna B. Berry. "Actionability of comprehensive genomic profiling (CGP) compared to single-gene and small panels in patients with advanced/metastatic non-small cell lung cancer (aNSCLC): A real-world study." Journal of Clinical Oncology 40, no. 16_suppl (June 1, 2022): e21114-e21114. http://dx.doi.org/10.1200/jco.2022.40.16_suppl.e21114.
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e21114 Background: Biomarker testing for patients with aNSCLC includes testing for specific alterations in single genes, hotspot multigene panels, or CGP. Historically, CGP has been used following progression on early lines of systemic therapy to identify genomic alterations not captured by single-gene/hotspot testing, or to determine clinical trial(CT) eligibility. We compared the proportion of patients with genomic alterations for which FDA has approved targeted therapies(TT) (actionable alterations) identified through CGP vs. single-gene/small panel(“small panel”) testing in the real-world setting. Methods: In a retrospective study, patients initially diagnosed-with/progressed-to aNSCLC between 1/1/2015-12/31/2020, treated in the US community health setting, were categorized based on small panel or CGP testing. Patients were followed until the earliest of last contact/death/study-end on 9/30/2021. Testing between 30 days prior to initial NSCLC diagnosis and end of follow-up was used to determine actionability based on OncoKB levels, and eligibility for two basket-CTs(ASCO-TAPUR, NCI-MATCH). Results: Of 7,242 aNSCLC patients in this study, 5,154 (72%) received molecular testing (50% only small panel; 14% CGP; and 7% with an unknown size panel), 22% of patients remained untested and 7% were tested for only PD-L1. Among CGP-tested patients evaluated for tumor mutational burden (TMB), 18% were classified as TMB-High. > 75% of patients presented with advanced cancer at initial diagnosis, 51% were female, 50% were White, and median age was 68 years. Molecular testing rate increased from 9% to 20%(CGP) and 42% to 51%(small panel) between 2015–2020. The proportion of patients with ≥1 actionable biomarker was significantly higher with CGP than small panels (34%vs.15%; p < 0.001). Of tested patients. the proportion of CT eligible patients was also significantly greater for CGP than small panels (56%vs.4%; p < 0.001). The proportion of tested patients that received an FDA-approved TT or immunotherapy(IO) within 30 days of testing was higher in CGP cohort compared to small panel (9%vs.3%; p < 0.001). Conclusions: Although rates of CGP and small panel testing are increasing over time, overall molecular testing remains underutilized, and the proportion of patients who received TT/IO post-testing is low. Use of CGP is associated with higher identification of actionable biomarkers and patients receiving TT/IO, and CT eligibility.
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Bapat, Bela, Connor Sweetnam, Ashleigh McBratney, Monika A. Izano, Brock Schroeder, Sheetal Walters, William Chen, Phillip G. Febbo, and Anna B. Berry. "Actionability of comprehensive genomic profiling (CGP) compared to single-gene and small panels in patients with advanced/metastatic non-small cell lung cancer (aNSCLC): A real-world study." Journal of Clinical Oncology 40, no. 16_suppl (June 1, 2022): e21114-e21114. http://dx.doi.org/10.1200/jco.2022.40.16_suppl.e21114.
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e21114 Background: Biomarker testing for patients with aNSCLC includes testing for specific alterations in single genes, hotspot multigene panels, or CGP. Historically, CGP has been used following progression on early lines of systemic therapy to identify genomic alterations not captured by single-gene/hotspot testing, or to determine clinical trial(CT) eligibility. We compared the proportion of patients with genomic alterations for which FDA has approved targeted therapies(TT) (actionable alterations) identified through CGP vs. single-gene/small panel(“small panel”) testing in the real-world setting. Methods: In a retrospective study, patients initially diagnosed-with/progressed-to aNSCLC between 1/1/2015-12/31/2020, treated in the US community health setting, were categorized based on small panel or CGP testing. Patients were followed until the earliest of last contact/death/study-end on 9/30/2021. Testing between 30 days prior to initial NSCLC diagnosis and end of follow-up was used to determine actionability based on OncoKB levels, and eligibility for two basket-CTs(ASCO-TAPUR, NCI-MATCH). Results: Of 7,242 aNSCLC patients in this study, 5,154 (72%) received molecular testing (50% only small panel; 14% CGP; and 7% with an unknown size panel), 22% of patients remained untested and 7% were tested for only PD-L1. Among CGP-tested patients evaluated for tumor mutational burden (TMB), 18% were classified as TMB-High. > 75% of patients presented with advanced cancer at initial diagnosis, 51% were female, 50% were White, and median age was 68 years. Molecular testing rate increased from 9% to 20%(CGP) and 42% to 51%(small panel) between 2015–2020. The proportion of patients with ≥1 actionable biomarker was significantly higher with CGP than small panels (34%vs.15%; p < 0.001). Of tested patients. the proportion of CT eligible patients was also significantly greater for CGP than small panels (56%vs.4%; p < 0.001). The proportion of tested patients that received an FDA-approved TT or immunotherapy(IO) within 30 days of testing was higher in CGP cohort compared to small panel (9%vs.3%; p < 0.001). Conclusions: Although rates of CGP and small panel testing are increasing over time, overall molecular testing remains underutilized, and the proportion of patients who received TT/IO post-testing is low. Use of CGP is associated with higher identification of actionable biomarkers and patients receiving TT/IO, and CT eligibility.
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Fields, Jessica, Dimitrios Nasioudis, Zhen Ni Zhou, Ann Carlson, Melissa Kristen Frey, Kevin Holcomb, and Eloise Chapman-Davis. "Underutilization of multigene panels among Ashkenazi Jewish patients." Journal of Clinical Oncology 35, no. 15_suppl (May 20, 2017): 1533. http://dx.doi.org/10.1200/jco.2017.35.15_suppl.1533.
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1533 Background: Approximately one in forty Ashkenazi Jewish (AJ) individuals carry a BRCA1/2 mutation and genetic screening in this population has largely focused on these two genes. With the recent rapid uptake of multigene panel testing for cancer genetic assessment, we sought to explore multigene panels in our cohort which is comprised of AJ and non-AJ patients. Methods: The results of all patients with known ancestry who underwent genetic testing and counseling at the hereditary breast and ovarian cancer center at a single institution between 7/1/2013-12/31/2016 were reviewed. Results: One thousand six hundred and fifty patients with known ancestry underwent genetic testing over the study period, including 681 AJ patients. The median age was 49 (range 20-86). AJ patients were more likely to undergo targeted testing than non-AJ patients (74% vs. 61 %, P<0.001). The use of multigene panels in AJ patients increased over time (2013 – 3.2%, 2014 – 18.7%, 2015 – 27.4%, 2016 – 48.4%, P<0.001). Mutations were more common in AJ patients (75, 11% vs. 66, 7%, P=0.003). Variants of uncertain significance (VUS) were less common in AJ patients (40, 6% vs. 124, 13%, P<0.001), even when excluding patients with single gene testing (32, 19% vs. 98, 27%, P=0.05). Among all patients, mutations in BRCA1/2 were most common (75%). The majority (69%) of non- BRCA1/2 mutations were identified on multigene panels. Rates of mutations in non- BRCA1/2 genes were the same among AJ and non-AJ patients (16, 21% vs. 20, 30%, P=0.3, Table 1). Conclusions: AJ patients have equivalent rates of non- BRCA1/2 mutations and on multigene panels have lower rates of VUS compared to non-AJ patients. However, the majority of AJ patients underwent targeted gene testing. These findings suggest consideration of a change in paradigm for genetic assessment of AJ patients with a focus on BRCA and non- BRCAassociated cancer genes through multigene panel testing. [Table: see text]
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Kapoor, Nimmi S., Jennifer Swisher, Rachel E. McFarland, Mychael Patrick, and Lisa D. Curcio. "Impact of hereditary multigene panel testing for cancer survivors." Journal of Clinical Oncology 34, no. 3_suppl (January 20, 2016): 261. http://dx.doi.org/10.1200/jco.2016.34.3_suppl.261.
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261 Background: Recently, genetic testing for hereditary cancer syndromes has seen numerous advances in testing spectrum, capability, and efficiency. This may have important implications for cancer survivors and their families. The purpose of this study is to evaluate the impact of reflex genetic testing with newer multi-gene panels on patients with prior negative BRCA1/2 tests. Methods: Data was collected retrospectively from patients who underwent multi-gene panel testing at one of three sites from a single institution between 8/2013-6/2015. Those with a personal history of breast or ovarian cancer and a prior negative BRCA1/2 test were included. Results: Of 914 patients who underwent multi-gene panel tests, 187 met study inclusion criteria. Ten patients (5.3%) were found to carry 11 pathogenic mutations, including 6 patients with mutations in CHEK2, 2 patients with mutations in PTEN, and 1 patient each with mutations in the following genes: BARD1, NF1, and RAD51C. One patient had two pathogenic mutations identified—CHEK2 and BARD1. Of 10 patients with mutations, 9 had a personal history of breast cancer diagnosed at a median age of 43 (range 35-52) and 1 had ovarian cancer diagnosed at age 65. A majority of mutation carriers underwent panel testing years after their cancer diagnosis (median 6 years, range 0.5-32 years) and none with delayed testing had undergone prophylactic contralateral mastectomy prior to the discovery of their gene mutation. All patients with mutations had a family history of at least one cancer, with most having a variety of cancer diagnoses in multiple relatives. Positive panel testing results altered clinical management in most patients, including addition of breast MRI, colonoscopy, or thyroid ultrasound depending on the gene mutation. After discovery of a PTEN mutation 19 years after her initial cancer treatment, one woman underwent bilateral prophylactic mastectomy and was found to have occult ductal carcinoma in situ. Conclusions: Cancer survivorship must incorporate advances in technology that may be beneficial even years after treatment has ended. Multi-gene panel testing can be applied in survivorship settings as a useful tool to guide screening recommendations.
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Yadav, Siddhartha, Jennifer Fulbright, Heidi Dreyfuss, Ashley Reeves, Sarah Campian, Vicky Thomas, and Dana Zakalik. "Outcomes of retesting BRCA-negative patients using multigene panels." Journal of Clinical Oncology 33, no. 28_suppl (October 1, 2015): 23. http://dx.doi.org/10.1200/jco.2015.33.28_suppl.23.
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23 Background: New technologies for identifying hereditary predisposition to breast cancer have led to the discovery of novel genes associated with cancer risk. This has prompted re-evaluation of patients who previously tested negative for BRCA1/2 gene mutations, with a possibility of discovering new genes which may impact management. This study reports on the results of retesting patients who previously were negative for BRCA1/2. Methods: Patients who tested negative for BRCA1/2 mutations who had significant personal and family history were referred back to the Cancer Genetics Center between February 1, 2012 and May 30, 2105 for discussion of additional testing. A detailed personal and family history was reviewed, and patients were counseled about the genetics and clinical implications of panel testing for multiple breast cancer genes. Panel testing using next generation sequencing technologies was ordered. Patients were seen in follow up for discussion of results and management. Results: A total of 12 pathogenic mutations were identified during the study period. The genes and frequencies of these mutations were: CHEK2(3), PALB2(3), ATM(2), APC(1), BARD(1), CDH(1), MUTYH(1). There were 33 variants of undetermined significance(VUS) in 27 patients. 5 of these were seen in patients with a known pathogenic mutation; 3 others were later classified as benign. The frequencies of these VUSs were: ATM (9), PALB2(3), BARD1 (3), PTEN(3), PMS2(3), MSH6(2), CHEK2 (1), MYH(1), RAD51(1), BRIP1(2), NF1(1), BMPR1A(1). Of the 46 patients who had their initial BRCA testing and repeat panel testing between February 1, 2012 and May 30, 2015, 6 (13%) tested positive for a pathogenic mutation. Conclusions: This study demonstrates the feasibility and potential clinical benefit of retesting individuals who previously tested negative for BRCA1/2 mutation. This approach had a significant management impact on patients and their families, with a 13% detection rate of pathogenic mutations. The success of retesting is predicated upon an infrastructure of provider and patient education, pre and post genetic counseling and serves as a model for other centers.
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Asphaug, Lars, and Hans Olav Melberg. "The Cost-Effectiveness of Multigene Panel Testing for Hereditary Breast and Ovarian Cancer in Norway." MDM Policy & Practice 4, no. 1 (January 2019): 238146831882110. http://dx.doi.org/10.1177/2381468318821103.
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Background. Expansion of routine genetic testing for hereditary breast and ovarian cancer from conventional BRCA testing to a multigene test could improve diagnostic yield and increase the opportunity for cancer prevention in both identified carriers and their relatives. We use an economic decision model to assess whether the current knowledge on non- BRCA mutation prevalence, cancer risk, and patient preferences justifies switching to a multigene panel for testing of early-onset breast cancer patients. Methods. We evaluated routine testing by BRCA testing, a 7-gene panel, and a 14-gene panel using individual-level simulations of annual health state transitions over a lifetime perspective. Breast and ovarian cancer incidence is reduced and posttreatment survival is improved when high-risk mutations are detected and risk-reducing treatment offered. Most model inputs were synthesized from published literature. Intermediate health outcomes included breast and ovarian cancer incidence rates, along with organ-specific cancer mortality. Cost-effectiveness outcomes were health sector costs and quality-adjusted life years. Results. Intermediate health outcomes improved by testing with multigene panels. At a cost-effectiveness threshold of $77,000, a 7-gene panel test with five non- BRCA genes was the optimal strategy with an incremental cost-effectiveness ratio of $53,310 per quality-adjusted life year compared to BRCA-only testing. Limitations. Unable to stratify carriers to specific mutations within genes, we can only make predictions on the gene level, with combined risk estimates for known variants. As mutation prevalence is the absolute upper bound of returns to more expansive testing, the rarity of modelled mutations makes analysis outcomes sensitive to model implementation. Conclusions. A 7-gene panel to diagnose hereditary breast and ovarian cancer in early-onset breast cancer patients can be a cost-effective alternative to current BRCA-only testing in Norway.
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Lowstuter, Katrina, Carin R. Espenschied, Duveen Sturgeon, Charité Ricker, Rachid Karam, Holly LaDuca, Julie O. Culver, et al. "Unexpected CDH1 Mutations Identified on Multigene Panels Pose Clinical Management Challenges." JCO Precision Oncology, no. 1 (November 2017): 1–12. http://dx.doi.org/10.1200/po.16.00021.
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Purpose Mutations in the CDH1 gene confer up to an 80% lifetime risk of diffuse gastric cancer and up to a 60% lifetime risk of lobular breast cancer. Testing for CDH1 mutations is recommended for individuals who meet the International Gastric Cancer Linkage Consortium (IGCLC) guidelines. However, the interpretation of unexpected CDH1 mutations identified in patients who do not meet IGCLC criteria or do not have phenotypes suggestive of hereditary diffuse gastric cancer is clinically challenging. This study aims to describe phenotypes of CDH1 mutation carriers identified through multigene panel testing (MGPT) and to offer informed recommendations for medical management. Patients and Methods This cross-sectional prevalence study included all patients who underwent MGPT between March 2012 and September 2014 from a commercial laboratory (n = 26,936) and an academic medical center cancer genetics clinic (n = 318) to estimate CDH1 mutation prevalence and associated clinical phenotypes. CDH1 mutation carriers were classified as IGCLC positive (met criteria), IGCLC partial phenotype, and IGCLC negative. Results In the laboratory cohort, 16 (0.06%) of 26,936 patients were identified as having a pathogenic CDH1 mutation. In the clinic cohort, four (1.26%) of 318 had a pathogenic CDH1 mutation. Overall, 65% of mutation carriers did not meet the revised testing criteria published in 2015. All three CDH1 mutation carriers who had risk-reducing gastrectomy had pathologic evidence of diffuse gastric cancer despite not having met IGCLC criteria. Conclusion The majority of CDH1 mutations identified on MGPT are unexpected and found in individuals who do not fit the accepted diagnostic testing criteria. These test results alter the medical management of CDH1-positive patients and families and provide opportunities for early detection and risk reduction.
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Burghel, George J., Carolyn D. Hurst, Christopher M. Watson, Phillip A. Chambers, Helen Dickinson, Paul Roberts, and Margaret A. Knowles. "Towards a Next-Generation Sequencing Diagnostic Service for Tumour Genotyping: A Comparison of Panels and Platforms." BioMed Research International 2015 (2015): 1–6. http://dx.doi.org/10.1155/2015/478017.
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Detection of clinically actionable mutations in diagnostic tumour specimens aids in the selection of targeted therapeutics. With an ever increasing number of clinically significant mutations identified, tumour genetic diagnostics is moving from single to multigene analysis. As it is still not feasible for routine diagnostic laboratories to perform sequencing of the entire cancer genome, our approach was to undertake targeted mutation detection. To optimise our diagnostic workflow, we evaluated three target enrichment strategies using two next-generation sequencing (NGS) platforms (Illumina MiSeq and Ion PGM). The target enrichment strategies were Fluidigm Access Array custom amplicon panel including 13 genes (MiSeq sequencing), the Oxford Gene Technologies (OGT) SureSeq Solid Tumour hybridisation panel including 60 genes (MiSeq sequencing), and an Ion AmpliSeq Cancer Hotspot Panel including 50 genes (Ion PGM sequencing). DNA extracted from formalin-fixed paraffin-embedded (FFPE) blocks of eight previously characterised cancer cell lines was tested using the three panels. Matching genomic DNA from fresh cultures of these cell lines was also tested using the custom Fluidigm panel and the OGT SureSeq Solid Tumour panel. Each panel allowed mutation detection of core cancer genes includingKRAS,BRAF, andEGFR. Our results indicate that the panels enable accurate variant detection despite sequencing from FFPE DNA.
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Howarth, Dt R., Sharon S. Lum, Pamela Esquivel, Carlos A. Garberoglio, Maheswari Senthil, and Naveenraj L. Solomon. "Initial Results of Multigene Panel Testing for Hereditary Breast and Ovarian Cancer and Lynch Syndrome." American Surgeon 81, no. 10 (October 2015): 941–44. http://dx.doi.org/10.1177/000313481508101006.
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Multigene panel testing for hereditary cancer risk has recently become commercially available; however, the impact of its use on patient care is undefined. We sought to evaluate results from implementation of panel testing in a multidisciplinary cancer center. We performed a retrospective review of consecutive patients undergoing genetic testing after initiating use of multigene panel testing at Loma Linda University Medical Center. From February 13 to August 25, 2014, 92 patients were referred for genetic testing based on National Comprehensive Cancer Network guidelines. Testing was completed in 90 patients. Overall, nine (10%) pathogenic mutations were identified: five BRCA1/2, and four in non-BRCA loci. Single-site testing identified one BRCA1 and one BRCA2 mutation. The remaining mutations were identified by use of panel testing for hereditary breast and ovarian cancer. There were 40 variants of uncertain significance identified in 34 patients. The use of panel testing more than doubled the identification rate of clinically significant pathogenic mutations that would have been missed with BRCA testing alone. The large number of variants of uncertain significance identified will require long-term follow-up for potential reclassification. Multigene panel testing provides additional information that may improve patient outcomes.
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Hu, Chunling, Holly LaDuca, Hermela Shimelis, Eric C. Polley, Jenna Lilyquist, Steven N. Hart, Jie Na, et al. "Multigene Hereditary Cancer Panels Reveal High-Risk Pancreatic Cancer Susceptibility Genes." JCO Precision Oncology, no. 2 (November 2018): 1–28. http://dx.doi.org/10.1200/po.17.00291.
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Purpose The relevance of inherited pathogenic mutations in cancer predisposition genes in pancreatic cancer is not well understood. We aimed to assess the characteristics of patients with pancreatic cancer referred for hereditary cancer genetic testing and to estimate the risk of pancreatic cancer associated with mutations in panel-based cancer predisposition genes in this high-risk population. Methods Patients with pancreatic cancer (N = 1,652) were identified from a 140,000-patient cohort undergoing multigene panel testing of predisposition genes between March 2012 and June 2016. Gene-level mutation frequencies relative to Exome Aggregation Consortium and Genome Aggregation Database reference controls were assessed. Results The frequency of germline cancer predisposition gene mutations among patients with pancreatic cancer was 20.73%. Mutations in ATM, BRCA2, CDKN2A, MSH2, MSH6, PALB2, and TP53 were associated with high pancreatic cancer risk (odds ratio, > 5), and mutations in BRCA1 were associated with moderate risk (odds ratio, > 2). In a logistic regression model adjusted for age at diagnosis and family history of cancer, ATM and BRCA2 mutations were associated with personal history of breast or pancreatic cancer, whereas PALB2 mutations were associated with family history of breast or pancreatic cancer. Conclusion These findings provide insight into the spectrum of mutations expected in patients with pancreatic cancer referred for cancer predisposition testing. Mutations in eight genes confer high or moderate risk of pancreatic cancer and may prove useful for risk assessment for pancreatic and other cancers. Family and personal histories of breast cancer are strong predictors of germline mutations.
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Giri, Veda N., Elias Obeid, Laura Gross, Lisa Bealin, Colette Hyatt, Sarah E. Hegarty, Susan Montgomery, et al. "Inherited Mutations in Men Undergoing Multigene Panel Testing for Prostate Cancer: Emerging Implications for Personalized Prostate Cancer Genetic Evaluation." JCO Precision Oncology, no. 1 (November 2017): 1–17. http://dx.doi.org/10.1200/po.16.00039.
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Purpose Multigene panels are commercially available for the evaluation of prostate cancer (PCA) predisposition, which necessitates tailored genetic counseling (GC) for men. Here we describe emerging results of Genetic Evaluation of Men, prospective multigene testing study in PCA to inform personalized genetic counseling, with emerging implications for referrals, cancer screening, and precision therapy. Patients and Methods Eligibility criteria for men affected by or at high risk for PCA encompass age, race, family history (FH), and PCA stage/grade. Detailed demographic, clinical, and FH data were obtained from participants and medical records. Multigene testing was conducted after GC. Mutation rates were summarized by eligibility criteria and compared across FH data. The 95% CI of mutation prevalence was constructed by using Poisson distribution. Results Of 200 men enrolled, 62.5% had PCA. Eleven (5.5%; 95% CI, 3.0% to 9.9%) had mutations; 63.6% of mutations were in DNA repair genes. FH of breast cancer was significantly associated with mutation status ( P = .004), and FH that met criteria for hereditary breast and ovarian cancer syndrome was significantly associated with PCA (odds ratio, 2.33; 95% CI, 1.05 to 5.18). Variants of uncertain significance were reported in 70 men (35.0%). Among mutation carriers, 45.5% had personal/FH concordant with the gene. A tailored GC model was developed based on emerging findings. Conclusion Multigene testing for PCA identifies mutations mostly in DNA repair genes, with implications for precision therapy. The study highlights the importance of comprehensive genetic evaluation for PCA beyond metastatic disease, including early-stage disease with strong FH. Detailed FH is important for referrals of men for genetic evaluation. The results inform precision GC and cancer screening for men and their male and female blood relatives.
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Turchiano, Antonella, Daria Carmela Loconte, Rosalba De Nola, Francesca Arezzo, Giulia Chiarello, Antonino Pantaleo, Matteo Iacoviello, et al. "Beyond BRCA1/2: Homologous Recombination Repair Genetic Profile in a Large Cohort of Apulian Ovarian Cancers." Cancers 14, no. 2 (January 12, 2022): 365. http://dx.doi.org/10.3390/cancers14020365.
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Background: Pathogenic variants in homologous recombination repair (HRR) genes other than BRCA1/2 have been associated with a high risk of ovarian cancer (OC). In current clinical practice, genetic testing is generally limited to BRCA1/2. Herein, we investigated the mutational status of both BRCA1/2 and 5 HRR genes in 69 unselected OC, evaluating the advantage of multigene panel testing in everyday clinical practice. Methods: We analyzed 69 epithelial OC samples using an NGS custom multigene panel of the 5 HRR pathways genes, beyond the genetic screening routine of BRCA1/2 testing. Results: Overall, 19 pathogenic variants (27.5%) were detected. The majority (21.7%) of patients displayed a deleterious mutation in BRCA1/2, whereas 5.8% harbored a pathogenic variant in one of the HRR genes. Additionally, there were 14 (20.3%) uncertain significant variants (VUS). The assessment of germline mutational status showed that a small number of variants (five) were not detected in the corresponding blood sample. Notably, we detected one BRIP1 and four BRCA1/2 deleterious variants in the low-grade serous and endometrioid histology OC, respectively. Conclusion: We demonstrate that using a multigene panel beyond BRCA1/2 improves the diagnostic yield in OC testing, and it could produce clinically relevant results.
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Espenschied, Carin R., Holly LaDuca, Shuwei Li, Rachel McFarland, Chia-Ling Gau, and Heather Hampel. "Multigene Panel Testing Provides a New Perspective on Lynch Syndrome." Journal of Clinical Oncology 35, no. 22 (August 1, 2017): 2568–75. http://dx.doi.org/10.1200/jco.2016.71.9260.
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Purpose Most existing literature describes Lynch syndrome (LS) as a hereditary syndrome leading to high risks of colorectal cancer (CRC) and endometrial cancer mainly as a result of mutations in MLH1 and MSH2. Most of these studies were performed on cohorts with disease suggestive of hereditary CRC and population-based CRC and endometrial cancer cohorts, possibly biasing results. We aimed to describe a large cohort of mismatch repair (MMR) mutation carriers ascertained through multigene panel testing, evaluate their phenotype, and compare the results with those of previous studies. Methods We retrospectively reviewed clinical histories of patients who had multigene panel testing, including the MMR and EPCAM genes, between March 2012 and June 2015 (N = 34,981) and performed a series of statistical comparisons. Results Overall, MSH6 mutations were most frequent, followed by PMS2, MSH2, MLH1, and EPCAM mutations, respectively. Of 528 patients who had MMR mutations, 63 (11.9%) had breast cancer only and 144 (27.3%) had CRC only. When comparing those with breast cancer only to those with CRC only, MSH6 and PMS2 mutations were more frequent than MLH1 and MSH2 mutations ( P = 2.3 × 10−5). Of the 528 patients, 22.2% met BRCA1 and BRCA2 ( BRCA1/2) testing criteria and not LS criteria, and 5.1% met neither BRCA1/2 nor LS testing criteria. MSH6 and PMS2 mutations were more frequent than MLH1 and MSH2 mutations among patients who met BRCA1/2 testing criteria but did not meet LS testing criteria ( P = 4.3 × 10−7). Conclusion These results provide a new perspective on LS and suggest that individuals with MSH6 and PMS2 mutations may present with a hereditary breast and ovarian cancer phenotype. These data also highlight the limitations of current testing criteria in identifying these patients, as well as the need for further investigation of cancer risks in patients with MMR mutations.
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Lhotova, Klara, Lenka Stolarova, Petra Zemankova, Michal Vocka, Marketa Janatova, Marianna Borecka, Marta Cerna, et al. "Multigene Panel Germline Testing of 1333 Czech Patients with Ovarian Cancer." Cancers 12, no. 4 (April 13, 2020): 956. http://dx.doi.org/10.3390/cancers12040956.
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Ovarian cancer (OC) is the deadliest gynecologic malignancy with a substantial proportion of hereditary cases and a frequent association with breast cancer (BC). Genetic testing facilitates treatment and preventive strategies reducing OC mortality in mutation carriers. However, the prevalence of germline mutations varies among populations and many rarely mutated OC predisposition genes remain to be identified. We aimed to analyze 219 genes in 1333 Czech OC patients and 2278 population-matched controls using next-generation sequencing. We revealed germline mutations in 18 OC/BC predisposition genes in 32.0% of patients and in 2.5% of controls. Mutations in BRCA1/BRCA2, RAD51C/RAD51D, BARD1, and mismatch repair genes conferred high OC risk (OR > 5). Mutations in BRIP1 and NBN were associated with moderate risk (both OR = 3.5). BRCA1/2 mutations dominated in almost all clinicopathological subgroups including sporadic borderline tumors of ovary (BTO). Analysis of remaining 201 genes revealed somatic mosaics in PPM1D and germline mutations in SHPRH and NAT1 associating with a high/moderate OC risk significantly; however, further studies are warranted to delineate their contribution to OC development in other populations. Our findings demonstrate the high proportion of patients with hereditary OC in Slavic population justifying genetic testing in all patients with OC, including BTO.
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Meshoulam Nikolaeva, Ekaterina, Raul Terés, Daniela Camacho, Aida Bujosa, Maria Borrell, Pablo Gallardo, Berta Martin, et al. "Value of multigene panel retesting of families with BRCA1/2 mutation-negative hereditary breast and ovarian cancer (HBOC)." Journal of Clinical Oncology 38, no. 15_suppl (May 20, 2020): 1582. http://dx.doi.org/10.1200/jco.2020.38.15_suppl.1582.
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1582 Background: Despite the use of clinical eligibility criteria and mutation predictive models, a great proportion of families are negative for germline mutations in BRCA1/2 genes. Traditionally, risk assessment of inconclusive results included the recommendation of high-risk surveillance protocol, the update of incident cancer cases in the family and the consideration of additional testing to rule out the possibility of phenocopy. More recently, next generation sequencing multigene panels have become a standard practice in cancer genetics clinics worldwide. We addressed the value of multigene panel retesting of BRCA1/2 negative HBOC families in our institution. Methods: After genetic counseling session and informed consent, a total of 137 individuals (119 probands and 18 extra cancer-affected relatives) from distinct BRCA1/2 negative families were retested using a panel containing 11 breast and ovarian cancer susceptibility genes ( BRCA1/2, PALB2, ATM, CHEK2, PTEN, TP53, STK11, BRIP1, RAD51C, RAD51D). Results: According to the BOADICEA model, the remaining probability of mutation in BRCA1/2 or PALB2 genes in our cohort was 5.5% (0.1-61). The reasons for considering retesting were the addition of any incident cancer diagnosis in 33 cases (24%), a prior study with a low sensitivity screening technique (dHPLC) in 6 families (5%) and the expansion of the study to other putative breast and ovarian susceptibility genes in 98 families (71%). Overall, 3 pathogenic (2 BRCA2, 1 CHEK2) and 8 likely pathogenic variants (1 BRCA2, 4 CHEK2 and 3 ATM) were found. The prevalence was 8%. The detection rate among 19 families with a > 10% remaining probability of mutation in BRCA1/2 and PALB2 genes was 26%. The 3 clinically significant variants in BRCA2 were detected in 2 families and 1 updated cancer family history (BOADICEA remaining probability of 59, 61 and 12%, respectively). Cascade testing was subsequently done in 15 relatives resulting 8 in mutation carriers and 9 true negatives. Conclusions: Our results support the value of updating cancer incident cases and considering expanded panels in selected families.
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Kuang, Xiaying, Ying Lin, Nan Shao, Liang Yu, Zhen Shan, Shuyin Chen, Xinyi Shi, Hao Liu, and Jing Liu. "Clinical significance of pathogenic variants in germline BRCA wild type patients at risk for hereditary breast cancer." Journal of Clinical Oncology 37, no. 15_suppl (May 20, 2019): e13127-e13127. http://dx.doi.org/10.1200/jco.2019.37.15_suppl.e13127.
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e13127 Background: Approximately, 10% of breast cancer (BC) are related to inherited germline mutations. BRCA1/2, the most recognized and tested genes, are responsible for 50% of hereditary BC. Genetic testing for hereditary BC has changed significantly. Increasing evidence suggests parallel multigene testing. Methods: NGS-based germline BRCA status assessment was performed on 209 high risk BC patients with at least one of the following risk factors: triple negative BC, early onset ( < -45), with a family history of BC, bilateral BC and male BC. Multigene-panel testing was subsequently offered to patients with at least 2 of the risk factors and WT germline BRCA. Capture-base targeted sequencing was performed on white blood cells using a panel consisting of 53 hereditary cancer-related genes, spanning 229kb of human genome. Results: Among the 209 patients screened, only 12 patients had pathogenic BRCA1/2 mutation. Next, we investigated the prevalence of non- BRCA pathogenic germline pathogenic mutations in patients with at least 2 risk factors. Thirty-seven patients met the criteria and only 23 patients had sufficient WBC DNA for sequencing. This cohort had a median age of 42, with a majority carrying infiltrating ductal carcinoma. Except for one bilateral BC patient who had stage IV disease, all other patients had early stage disease. We identified 5 pathogenic mutations from 5 patients spanning 4 genes: PALB2, PTEN, ATM and WRN, resulting in a prevalence rate of 20% for pathogenic germline mutations in high risk germline BRCA WT BC patients. Two patients carried mutations in PALB2, one with a frameshift and another with a splice mutation. Mutation types for PTEN, ATM and WRN were splice mutation, stop gain mutation and frameshift mutation, respectively. All 5 patients were diagnosed with BC before the age of 40. Three of them had bilateral BC; one had triple negative BC and another patient had a family history of BC. Conclusions: Our study confirms the clinical significance of testing non- BRCA genes, and suggests multigene panel testing for patients at risk for hereditary BC. Such approach increases the identification of hereditary BC, thus impacting clinical decision-making.
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Hall, Michael J., Michelle J. McSweeny, Kim Rainey, Hannah Campbell, Chau Nguyen, and Catherine Neumann. "Risks and implications of multiple actionable pathogenic germline variants discovered by panel-based cancer predisposition testing." Journal of Clinical Oncology 41, no. 4_suppl (February 1, 2023): 792. http://dx.doi.org/10.1200/jco.2023.41.4_suppl.792.
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792 Background: Multi-gene hereditary cancer panels have revolutionized how patients with germline mutations are identified by testing multiple genes at the same time. Despite the availability of panel testing, many patients with a known familial mutation will only undergo single site genetic testing due to limitations in guideline recommendations and insurance coverage. This approach risks a failure to detect additional pathogenic variants and an inappropriate management of cancer risk. In our clinical experience, a subset of patients pursue multigene testing despite a known familial mutation. Our group has identified patients who carry more than one mutation and mutations that would have been missed if the patients had only undergone single site testing. We investigated the patients and families from our risk assessment clinic with multiple familial mutations and determined how medical management may have been changed due to the presence of multiple mutations in family. Methods: The Fox Chase Cancer Center Risk Assessment Program (RAP) Registry was queried to identify patients who carry more than one mutation. Pedigrees of patients and families identified with multiple germline mutations were reviewed. Screening management guidelines were determined from the most recent NCCN guidelines published at the time the patient tested (Genetic/Familial High-Risk Assessment: Breast, Ovarian, and Pancreatic and Genetic/Familial High-Risk Assessment: Colorectal). The RAP Registry is an IRB approved protocol (IRB 09-831). Results: 70 patients were found to carry at least 2 mutations (excluding patients with biallelic MUTYH mutations) since introducing multi-gene panel testing in 2014. The most common second mutation was the I1307K variant in the APC gene at 20% (14/70). We also identified 20 patients who would have received incomplete genetic risk assessment if they only underwent single site testing and screening management changed in 60% (12/20) of these patients. 35% (7/20) of these patients did not meet NCCN criteria for additional germline testing beyond single site testing. Conclusions: Multi-gene hereditary cancer panels identify patients and families with multiple germline mutations. Patients undergoing single site cascade testing are at risk of receiving inaccurate risk assessment based on incomplete ascertainment of germline cancer risks. Detection of additional actionable mutations will frequently lead to changes in medical management.
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Yadav, Siddhartha, and Fergus J. Couch. "Germline Genetic Testing for Breast Cancer Risk: The Past, Present, and Future." American Society of Clinical Oncology Educational Book, no. 39 (May 2019): 61–74. http://dx.doi.org/10.1200/edbk_238987.
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The field of germline genetic testing for breast cancer (BC) risk has evolved substantially in the last decade. The introduction of multigene panel testing (MGPT) led to an urgent need to understand the cancer risk associated with several genes included in the panels. Although the research on understanding the cancer risk associated with mutations in several genes continues, there is also a need to understand the modifying effects of race and ethnicity, family history, and BC pathology on the prevalence of germline mutations and associated BC risk. Furthermore, polygenic risk scores (PRSs) to predict BC risk in patients with or without germline mutations in cancer-predisposition genes are now available for clinical use, although data on the clinical utility of PRSs are lacking. In patients with advanced BC associated with BRCA1/2 mutation, olaparib and talazoparib are now approved for treatment. In addition, molecular profiling studies are being used to clarify the BC tumor biology in mutation carriers to identify potential therapeutic options. In this article, we discuss these advances in the field of germline genetic testing and highlight current limitations and implications for clinical care.
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Whitman, Julia, Brandon Shih, Amie Blanco, Salina Chan, Alan Paciorek, Jacqueline Desjardin, Mallika Sachdev Dhawan, Li Zhang, and Emily Bergsland. "Emerging value of multigene panels for germline testing in patients with neuroendocrine tumors." Journal of Clinical Oncology 36, no. 4_suppl (February 1, 2018): 226. http://dx.doi.org/10.1200/jco.2018.36.4_suppl.226.
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226 Background: Neuroendocrine tumors (NETs) are known to be associated with hereditary syndromes stemming from MEN1, VHL, SDH or TSC mutations. Recent data suggest that additional germline mutations may be relevant, implying a role of germline testing with multigene panels. We examined genetic counseling (GC) referral and testing patterns, test results, and their changes over time in NET patients (pts). Methods: Retrospective chart review was conducted in 236 NET pts referred to UCSF Cancer Genetics and Prevention Program 2004-2017. Univariate logistic models were used to assess relationship between binary outcome and covariate. STATA was used for analysis and statistical significance was based on p < 0.05. Results: 139 referred pts (59%) followed up with GC. Pts with >1 family members diagnosed with cancer were more likely to attend GC [OR=2.75, p=0.010]. Among 107 pts tested, small bowel NETs were less associated with testing than pancreatic NETs [OR=0.15, p=0.001]. Single-gene tests were routine until 2015, when panels up to 130 genes became standard. Overall, 31 pts (29% of 107 tested) had a pathogenic/likely pathogenic (P/LP) result. There was no significant difference between single and multi-gene tests in identifying P/LP mutations (likely due to changes in threshold for testing over time), but greater diversity in P/LP mutations was noted with larger panels. Functional tumors showed lower rate of P/LP mutations than non-functional [OR=0.17, p=0.037]. Conclusions: Only 59% of referred pts followed up with GC, suggesting significant barriers to testing exist. Of those tested, 29% harbored a P/LP mutation. Germline mutations not traditionally associated with NETs were identified, highlighting the potential importance of larger panels to detect rare mutations. [Table: see text]
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Mikhaylenko, Dmitry S., Alexander S. Tanas, Dmitry V. Zaletaev, and Marina V. Nemtsova. "Application Areas of Traditional Molecular Genetic Methods and NGS in relation to Hereditary Urological Cancer Diagnosis." Journal of Oncology 2020 (June 17, 2020): 1–12. http://dx.doi.org/10.1155/2020/7363102.
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Next generation sequencing (NGS) is widely used for diagnosing hereditary cancer syndromes. Often, exome sequencing and extended gene panel approaches are the only means that can be used to detect a pathogenic germline mutation in the case of multiple primary tumors, early onset, a family history of cancer, or a lack of specific signs associated with a particular syndrome. Certain germline mutations of oncogenes and tumor suppressor genes that determine specific clinical phenotypes may occur in mutation hot spots. Diagnosis of such cases, which involve hereditary cancer, does not require NGS, but may be made using PCR and Sanger sequencing. Diagnostic criteria and professional community guidelines developed for hereditary cancers of particular organs should be followed when ordering molecular diagnostic tests for a patient. This review focuses on urological oncology associated with germline mutations. Clinical signs and genetic diagnostic laboratory tests for hereditary forms of renal cell cancer, prostate cancer, and bladder cancer are summarized. While exome sequencing, or, conversely, traditional molecular genetic methods are the procedure of choice in some cases, in most situations, sequencing of multigene panels that are specifically aimed at detecting germline mutations in early onset renal cancer, prostate cancer, and bladder cancer seems to be the basic solution for molecular genetic diagnosis of hereditary cancers.
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Horton, Carrie, Holly LaDuca, and Patrick Reineke. "BAP1 tumor predisposition syndrome: Preliminary data from a laboratory-based multigene panel testing cohort." Journal of Clinical Oncology 35, no. 6_suppl (February 20, 2017): 490. http://dx.doi.org/10.1200/jco.2017.35.6_suppl.490.
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490 Background: Germline mutations in BAP1 have recently been shown to cause a tumor predisposition syndrome characterized by renal cell carcinoma (RCC), uveal melanoma, cutaneous melanoma, and mesothelioma. However, mutations have thus far been identified in highly enriched cohorts and the tumor spectrum among individuals with a broader phenotype undergoing multi-gene panel testing (MGPT) has not been described. Other genes associated with familial RCC have been established, such as FLCN (Birt-Hogg Dube syndrome) and VHL (von Hippel Lindau), but the proportion of BAP1 mutations in individuals with RCC is not yet known. Here we aim to describe the clinical features of individuals with BAP1 mutations identified from a clinical laboratory cohort, and to estimate the frequency of BAP1 mutations in individuals with kidney cancer. Methods: Since May 2015, a total of 6956 tests have been ordered that include BAP1 at our diagnostic laboratory. Retrospective data review yielded molecular and clinical details for individuals with identified mutations. Results: Thirteen individuals with BAP1 mutations have been identified. Cancer diagnoses in probands and family members consist of breast cancer (reported in 69.2% of kindreds), RCC (61.5%), melanoma (61.5%), mesothelioma (46.2%), lung cancer (46.2%), non-melanoma skin cancer (30.8%), and cholangiocarcinoma (15.4%). Among probands with kidney cancer undergoing MGPT (n = 1012), there is no difference in mutation rate of BAP1 compared to VHL (n = 3; OR 2.01 p = 0.51) or FLCN (n = 10; OR 0.598 p = 0.45). Conclusions: Cancer histories in our laboratory-selected cohort of BAP1 mutation carriers are consistent with those reported in the clinical literature, lending credence to the notion that BAP1 tumor predisposition syndrome is highly penetrant and consists of a constellation of several core cancers. The observation of breast, lung, non-melanoma skin cancer, and cholangiocarcinoma has also been reported in the literature and warrants further study. Our results suggest that BAP1 mutations are found at a similar frequency as other well-known kidney cancer genes, supporting its position as an important differential when considering genetic testing for RCC.
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Maksemous, Neven, Robert A. Smith, Heidi G. Sutherland, Bridget H. Maher, Omar Ibrahim, Garth A. Nicholson, Elisabeth P. Carpenter, Rod A. Lea, M. Zameel Cader, and Lyn R. Griffiths. "Targeted next generation sequencing identifies a genetic spectrum of DNA variants in patients with hemiplegic migraine." Cephalalgia Reports 2 (January 1, 2019): 251581631988163. http://dx.doi.org/10.1177/2515816319881630.
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Objective: Hemiplegic migraine in both familial (FHM) and sporadic (SHM) forms is a rare subtype of migraine with aura that can be traced to mutations in the CACNA1A, ATP1A2 and SCN1A genes. It is characterised by severe attacks of typical migraine accompanied by hemiparesis, as well as episodes of complex aura that vary significantly between individuals. Methods: Using a targeted next generation sequencing (NGS) multigene panel, we have sequenced the genomic DNA of 172 suspected hemiplegic migraine cases, in whom no mutation had previously been found by Sanger sequencing (SS) of a limited number of exons with high mutation frequency in FHM genes. Results: Genetic screening identified 29 variants, 10 of which were novel, in 35 cases in the three FHM genes ( CACNA1A, ATP1A2 and SCN1A). Interestingly, in this suspected HM cohort, the ATP1A2 gene harboured the highest number of variants with 24/35 cases (68.6%), while CACNA1A ranked the second gene, with 5 variants identified in 7/35 cases (20%). All detected variants were confirmed by SS and were absent in 100 non-migraine healthy control individuals. Assessment of variants with the American College of Medical Genetics and Genomics guidelines classified 8 variants as pathogenic, 3 as likely pathogenic and 18 as variants of unknown significance. Targeted NGS gene panel increased the diagnostic yield by fourfold over iterative SS in our diagnostics facility. Conclusion: We have identified 29 potentially causative variants in an Australian and New Zealand cohort of suspected HM cases and found that the ATP1A2 gene was the most commonly mutated gene. Our results suggest that screening using NGS multigene panels to investigate ATP1A2 alongside CACNA1A and SCN1A is a clinically useful and efficient method.
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Ramamurthy, Chethan, Mark A. Hitrik, Lyudmila DeMora, Andrea Forman, Kim Rainey, Michelle Savage, Susan Montgomery, et al. "Are we still adjusting to multigene panel testing? An NCI-designated cancer center's 2-year experience." Journal of Clinical Oncology 35, no. 15_suppl (May 20, 2017): 1585. http://dx.doi.org/10.1200/jco.2017.35.15_suppl.1585.
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1585 Background: Genetic testing for hereditary cancer predisposition has rapidly changed over the past few years with the introduction of multigene panel testing. Multigene testing has evolved from disease-agnostic comprehensive (C) panels alone to include disease-specific but expanded (DSE) panels as well as guideline-based (GB) panels. We analyzed trends in utilization of genetic testing over a two-year period in one NCI-designated Cancer Center, hypothesizing that over time genetic testing usage would trend toward more disease-specific panels. Methods: We conducted a retrospective analysis of our program’s database for all germline genetic tests ordered from 9/1/2013 to 8/31/2015 (n = 619; 246 in year 1, and 373 in year 2). Tests were categorized into three groups based on specificity: GB (range: 2-12 genes tested), DSE (12-35 genes tested), and C (28-80 genes tested). The Chi-square test was used to analyze test types ordered in year 1 (9/1/2013-8/31/2014) and year 2 (9/1/2014 – 8/31/2015) and the proportions of resulting mutation types. Results: A total of 604 germline genetic tests met the inclusion criteria: 39 GB (20 year 1, 19 year 2), 171 DSE (43 year 1, 128 year 2), and 394 C (180 year 1, 214 year 2). Compared to year 1, a larger proportion of DSE tests (35% v. 18%, p < 0.001), and a smaller proportion of C tests (59% v. 74%, p < 0.001) and GB tests (5% vs. 8%, p = 0.146) were ordered. DSE panels revealed a pathogenic variant (PV) at a rate of 16% and a variant of unknown significance (VUS) at a rate of 24%. C tests revealed a PV and VUS at rates of 14% and 29%, respectively. GB tests revealed a PV and VUS at rates of 21% and 18%, respectively. No statistically significant differences in detection rates of mutation types (PV or VUS) were found between GB, DSE, or C tests. Conclusions: The rates of PV detection were not significantly different between test types, but the profile of tests ordered changed over time to favor DSE panels. Exploration of factors contributing to changing trends in genetic testing are warranted as counselors and clinicians adapt to the quickly expanding number of genes associated with hereditary cancer risks, many of them moderate-risk, and the evolving landscape of multigene panel testing.
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Pintican, Roxana Maria, Angelica Chiorean, Magdalena Duma, Diana Feier, Madalina Szep, Dan Eniu, Iulian Goidescu, and Sorin Dudea. "Are Mutation Carrier Patients Different from Non-Carrier Patients? Genetic, Pathology, and US Features of Patients with Breast Cancer." Cancers 14, no. 11 (June 2, 2022): 2759. http://dx.doi.org/10.3390/cancers14112759.
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The purpose of this study is to evaluate the relationship between the pathogenic/likely pathogenic mutations, US features, and histopathologic findings of breast cancer in mutation carriers compared to non-carrier patients. Methods: In this retrospective study, we identified 264 patients with breast cancer and multigene panel testing admitted to our clinic from January 2018 to December 2020. Patient data US findings, US assessment of the axilla, multigene panel tests, histopathology, and immunochemistry reports were reviewed according to the BI-RADS lexicon. Results: The study population was comprised of 40% pathogenic mutation carriers (BRCA1, BRCA2, CHEK2, ATM, PALB, TP 53, NBN, MSH, BRIP 1 genes) and 60% mutation-negative patients. The mean patient age was 43.5 years in the carrier group and 44 years in the negative group. Carrier patients developed breast cancer with benign morphology (acoustic enhancement, soft elastography appearance) compared to non-carriers (p < 0.05). A tendency towards specific US features was observed for each mutation. BRCA1 carriers were associated with BC with microlobulated margins, hyperechoic rim, and soft elastography appearance (p < 0.05). Estrogen receptor (ER)-negative tumors were associated with BRCA1, TP53, and RAD mutations, while BRCA2 and CHEK2 were associated with ER-positive tumors. Conclusions: Patients with pathogenic mutations may exhibit BC with benign US features compared to negative, non-carrier patients. BRCA1, TP53, and RAD carriers account for up to one third of the ER tumors from the carrier group. Axillary US performed worse in depicting involved lymph nodes in carrier patients, compared to negative patients.
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Zhou, Zhen Ni, Melissa K. Frey, Dimitrios Nasioudis, Ann Carlson, Jessica Fields, Kevin Holcomb, and Eloise Chapman-Davis. "Patterns of genetic screening for hereditary cancer syndromes: Effect of Supreme Court’s ruling invalidating single gene patent rights." Journal of Clinical Oncology 35, no. 15_suppl (May 20, 2017): 1580. http://dx.doi.org/10.1200/jco.2017.35.15_suppl.1580.
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1580 Background: In 6/2013 the Supreme Court ruled that isolated DNA sequences found in nature could not be patented, resulting in rapid uptake of multigene panels. We sought to explore trends in genetic testing since this ruling. Methods: Results of all patients undergoing genetic testing and counseling at a single institution between 7/1/13 and 12/31/16 were reviewed. Associations between categorical variables were evaluated by chi-square tests or Fisher's exact tests as appropriate for category size. Results: 1663 patients underwent genetic testing over the study period. The median age was 49 years (range 18-86). Use of multigene panels versus targeted gene testing increased significantly in the years following the Supreme Court ruling (Table 1, P<0.001). While the percentage of patients found to have pathogenic mutations remained stable over the study period (9%), detection of variants of uncertain significance (VUS) increased significantly (Table 1, P<0.001). In 2013 BRCA1/2 mutations accounted for 91% of identified mutations; however this number decreased over time (2014-83%, 2015-70%, 2016-58%, P=0.01). Use of multigene panels detected 71% of mutations in non- BRCA1/2 genes such as CHEK(19), APC(44), MSH6(1), P53(1), and PTEN(1). Patients with a personal history of breast and/or ovarian cancer were more likely to have targeted testing than patients with other cancer types (590, 66% vs. 9, 33%, P=0.001). Conclusions: The uptake of multigene panels has increased since the 2013 Supreme Court ruling. While this technology allowed for the identification of many cancer-related genes that would be missed on targeted BRCA1/2 testing, it also resulted in a significantly increased detection of VUS, a finding with unknown clinical implications. [Table: see text]
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Foote, Jonathan R., Micael Lopez-Acevedo, Adam H. Buchanan, Angeles Alvarez Secord, Paula S. Lee, Cynthia Fountain, Evan R. Myers, David E. Cohn, Shelby D. Reed, and Laura J. Havrilesky. "Cost Comparison of Genetic Testing Strategies in Women With Epithelial Ovarian Cancer." Journal of Oncology Practice 13, no. 2 (February 2017): e120-e129. http://dx.doi.org/10.1200/jop.2016.011866.
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Purpose: The advent of multigene panels has increased genetic testing options for women with epithelial ovarian cancer (EOC). We designed a decision model to compare costs and probabilities of identifying a deleterious mutation or variant of uncertain significance (VUS) using different genetic testing strategies. Methods: A decision model was developed to compare costs and outcomes of two testing strategies for women with EOC: multigene testing (MGT) versus single-gene testing for BRCA1/2. Outcomes were mean cost and number of deleterious mutations and VUSs identified. Model inputs were obtained from published genetic testing data in EOC. One-way sensitivity analyses and Monte Carlo probabilistic sensitivity analyses were performed. Results: No family history model: MGT cost $1,160 more on average than BRCA1/2 testing and identified an additional 3.8 deleterious mutations for every 100 women tested. For each additional deleterious mutation identified, MGT cost $30,812 and identified 5.4 additional VUSs. Family history model: MGT cost $654 more on average and identified an additional 7.0 deleterious mutations for every 100 women tested. For each additional deleterious mutation identified, MGT cost $9,909 and identified 2.6 additional VUSs. Conclusion: MGT was associated with a higher additional cost per deleterious mutation identified and a higher ratio of VUS burden to actionable information in women with no family history as compared with women with a family history. Family history should be considered when determining an initial genetic testing platform in women with EOC.
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Horcasitas, Darling J., Holly LaDuca, Amal Yussuf, Ginger Chisholm, Jonah R. Chavez, Annette Campbell Fontaine, and Laura Panos Smith. "Exploring a possible relationship of germline CDKN2A mutations with breast cancer in a multigene panel cohort." Journal of Clinical Oncology 35, no. 15_suppl (May 20, 2017): e23218-e23218. http://dx.doi.org/10.1200/jco.2017.35.15_suppl.e23218.
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e23218 Background: Germline mutations in CDKN2A have been known to increase the risk of melanoma and pancreatic cancer compared to the general population. With the advent of multi-gene panels, individuals who may not have melanoma or pancreatic cancer are undergoing CDKN2A analysis. Previous studies in homogenous populations have suggested that breast cancer risks may also be increased in CDKN2A. This study aims to further evaluate a possible relationship of CDKN2A mutations with breast cancer through a series of case-control comparisons. Methods: Clinical histories and molecular results were retrospectively reviewed for patients undergoing CDKN2A analysis as part of two diagnostic pan-cancer panels at a single laboratory to ascertain CDKN2A mutation carriers (n = 104) and patients negative for all genes analyzed (n = 20,280). Patients with a personal and/or family history (1st and 2nd degree relatives) of pancreatic cancer and/or melanoma were excluded from case-control analysis. Results: The majority of CDKN2A mutation carriers (82.6%, n = 86/104) had a personal history of cancer documented on the test requisition form. The most common cancers were breast (n = 38, 52.8%), melanoma (n = 37, 43.0%) and pancreatic (n = 6, 7.1%). The average age of breast cancer diagnosis in this cohort was 49.3 years (range 25-84). Family history of breast, melanoma, and/or pancreatic cancer was reported for 54.9%, 46.1%, and 34.3% of CDKN2A mutation carriers, respectively. Females with breast cancer were not more likely to test positive for a CDKN2A mutation than females with cancer other than breast (OR = 0.84, p = 0.79) or unaffected females (OR = 1.02, p = 1). Conclusions: Although CDKN2A mutations were not significantly associated with breast cancer in this cohort, these findings do not necessarily rule out an association of CDKN2A mutations with breast cancer, particularly if risks are moderate or if genotype-phenotype correlations exist. Additional studies involving breast cancer cases unselected for age and family history and/or longitudinal studies of CDKN2A carriers are needed to better understand the relationship between CDKN2A and breast cancer risk.
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Senthilraja, Manickavasagam, Aaron Chapla, Felix K. Jebasingh, Dukhabhandhu Naik, Thomas V. Paul, and Nihal Thomas. "Parallel Multi-Gene Panel Testing for Diagnosis of Idiopathic Hypogonadotropic Hypogonadism/Kallmann Syndrome." Case Reports in Genetics 2019 (October 27, 2019): 1–3. http://dx.doi.org/10.1155/2019/4218514.
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Kallmann syndrome (KS)/Idiopathic hypogonadotropic hypogonadism (IHH) is characterized by hypogonadotropic hypogonadism and anosmia or hyposmia due to the abnormal migration of olfactory and gonadotropin releasing hormone producing neurons. Multiple genes have been implicated in KS/IHH. Sequential testing of these genes utilising Sanger sequencing is time consuming and not cost effective. The introduction of parallel multigene panel sequencing of small gene panels for the identification of causative gene variants has been shown to be a robust tool in the clinical setting. Utilizing multiplex PCR for the four gene KS/IHH panel followed by NGS, we describe herewith two cases of hypogonadotropic hypogonadism with a Prokineticin receptor 2 (PROKR2) gene and KAL1 gene mutation. The subject with a PROKR2 mutation had a normal perception of smell and normal olfactory bulbs on imaging. The subject with a KAL1 gene mutation had anosmia and a hypoplastic olfactory bulb.
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Jahn, Stephan W., Karl Kashofer, Iris Halbwedl, Gerlinde Winter, Laila El-Shabrawi-Caelen, Thomas Mentzel, Gerald Hoefler, and Bernadette Liegl-Atzwanger. "Mutational dichotomy in desmoplastic malignant melanoma corroborated by multigene panel analysis." Modern Pathology 28, no. 7 (March 13, 2015): 895–903. http://dx.doi.org/10.1038/modpathol.2015.39.
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Sharma Bhai, Pratibha, Deepak Sharma, Renu Saxena, and Ishwar C. Verma. "Next-Generation Sequencing Reveals a Nonsense Mutation (p.Arg364Ter) in MRE11A Gene in an Indian Patient with Familial Breast Cancer." Breast Care 12, no. 2 (2017): 112–14. http://dx.doi.org/10.1159/000457786.
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Background: The MRN complex consisting of MRE11A-RAD50-NBS1 proteins is involved in the repair of double-strand breaks, and mutations in genes coding for the MRN complex have been identified in families with breast and ovarian cancer. Case Report: In a BRCA-negative family with positive history of breast and endometrial cancer, next-generation sequencing-based panel testing identified a mutation in the MRE11A gene (NM_005590 c.1090C>T: p.Arg364Ter). This mutation results in a shorter mutated protein lacking 2 DNA binding domains (the GAR domain and the RAD50 binding site), abolishing the function of protein. Conclusion: This case provides insight into the role of the MRE11A gene in causing breast cancer susceptibility in families, and supports the use of multigene panel testing in cases with hereditary predisposition to breast cancer.
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Esplin, Edward D., Rebecca Truty, Shan Yang, Sarah M. Nielsen, Margaret Klint, Stephen E. Lincoln, Nhu Ngo, Kingshuk Das, Jewel Samadder, and Robert Luke Nussbaum. "Effect of access to germline genetic testing on pancreatic cancer precision treatment across disease stage and ethnicity." Journal of Clinical Oncology 38, no. 15_suppl (May 20, 2020): e16783-e16783. http://dx.doi.org/10.1200/jco.2020.38.15_suppl.e16783.
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e16783 Background: PARP inhibitor (PARPi) treatment was recently approved for pancreatic cancer (PaCa) patients with germline mutations in 2 DNA damage repair (DDR) genes. Despite criteria recommending germline multigene panel testing for all PaCa patients, barriers to testing remain, including among underserved populations, which limit access to precision therapies. We initiated a sponsored testing program that increases access to germline genetic testing for PaCa in two ways: 1) offering a comprehensive multigene panel, and 2) removing the barrier of cost. Here we present initial results from this program, including the diagnostic yield in patients across stages of PaCa and clinical utility of the findings. Methods: We retrospectively analyzed de-identified data from 966 PaCa patients tested on an 84 gene panel as part of the program to date. The only inclusion criterion was a willingness to participate in the sponsored program by the patient and the provider who ordered the testing. Data included likely pathogenic (LP) and pathogenic (P) mutations, disease stage and ethnicity. Results: In total, 166 (17%) patients were positive for P/LP germline mutations in 30 genes. Mutation rate by ethnicity was: Caucasian 17%, African American 12%, Hispanic 16%, Ashkenazi Jewish 20%, Asian 3%. Only 25% of patients with P/LP variants reported a family history of cancer. There was no statistical difference in mutation rates by stage (p = 0.11) [Table]. In positive patients, 83 (78%) had mutations conferring potential eligibility for DDR gene-specific precision therapies or clinical treatment trials. 28 (26%) were potentially eligible for olaparib due to BRCA1/2 mutations, 8 (7%) were potentially eligible for pembrolizumab, and 47 (44%) for PARPi clinical trials. Conclusions: This study found 8.5% of all PaCa patients tested are potentially eligible for germline-based precision therapies and/or clinical treatment trials. Of mutation positive patients, 75% did not report a family history of cancer. The positive rate was not statistically different between patients with stage I and stage IV PaCa, underscoring the recommendation to test all patients with PaCa. This program had a 1.5% increased relative uptake among African American patients compared to a standard insurance reimbursement delivery model. These data suggest reducing barriers improves PaCa patient access to genetic information that enables precision therapy. [Table: see text]
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Palmer, Julie R., Eric C. Polley, Chunling Hu, Esther M. John, Christopher Haiman, Steven N. Hart, Mia Gaudet, et al. "Contribution of Germline Predisposition Gene Mutations to Breast Cancer Risk in African American Women." JNCI: Journal of the National Cancer Institute 112, no. 12 (May 19, 2020): 1213–21. http://dx.doi.org/10.1093/jnci/djaa040.
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Abstract Background The risks of breast cancer in African American (AA) women associated with inherited mutations in breast cancer predisposition genes are not well defined. Thus, whether multigene germline hereditary cancer testing panels are applicable to this population is unknown. We assessed associations between mutations in panel-based genes and breast cancer risk in 5054 AA women with breast cancer and 4993 unaffected AA women drawn from 10 epidemiologic studies. Methods Germline DNA samples were sequenced for mutations in 23 cancer predisposition genes using a QIAseq multiplex amplicon panel. Prevalence of mutations and odds ratios (ORs) for associations with breast cancer risk were estimated with adjustment for study design, age, and family history of breast cancer. Results Pathogenic mutations were identified in 10.3% of women with estrogen receptor (ER)-negative breast cancer, 5.2% of women with ER-positive breast cancer, and 2.3% of unaffected women. Mutations in BRCA1, BRCA2, and PALB2 were associated with high risks of breast cancer (OR = 47.55, 95% confidence interval [CI] = 10.43 to >100; OR = 7.25, 95% CI = 4.07 to 14.12; OR = 8.54, 95% CI = 3.67 to 24.95, respectively). RAD51D mutations were associated with high risk of ER-negative disease (OR = 7.82, 95% CI = 1.61 to 57.42). Moderate risks were observed for CHEK2, ATM, ERCC3, and FANCC mutations with ER-positive cancer, and RECQL mutations with all breast cancer. Conclusions The study identifies genes that predispose to breast cancer in the AA population, demonstrates the validity of current breast cancer testing panels for use in AA women, and provides a basis for increased referral of AA patients for cancer genetic testing.
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Maxwell, Perry, Seán O. Hynes, Marc Fuchs, Stephanie Craig, Claire McGready, Fiona McLean, Stephen McQuaid, Jacqueline James, and Manuel Salto-Tellez. "Practical guide for the comparison of two next-generation sequencing systems for solid tumour analysis in a universal healthcare system." Journal of Clinical Pathology 72, no. 3 (January 31, 2018): 225–31. http://dx.doi.org/10.1136/jclinpath-2017-204917.
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AimsAlthough there have been excellent reports in the literature of validating next-generation sequencing, comparisons between two systems are not often published due to cost and time. We set out to establish that targetable mutations could be reliably detected with different gene panels and different chemistries using a common bioinformatics pipeline for meaningful comparisons to be made.MethodsAfter running selected formalin-fixed, paraffin-embedded samples through QPCR, Sanger sequencing and the 50 gene hotspot v2 panel from Life Technologies to determine standard-of-care variants, we compared the Oncomine panel from Life Technologies performed on a Personal Genome Machine (PGM) and the eight-gene actionable panel from Qiagen performed on a MiSeq platform. We used a common bioinformatics program following the creation of respective VCF files.ResultsBoth panels were accurate to above 90%, the actionable panel workflow was easier to perform but the lowest effective starting DNA load was obtained on the Oncomine workflow at 4 ng. Such minimal DNA can help with samples where there is limited material such as those for lung cancer molecular studies. We also discuss gene panel content and propose that increasing the gene profile of a panel will not benefit clinical laboratories where standard-of-care testing is all that is required.ConclusionsOnce recognised, it may be cost-effective for such laboratories to begin validation with an appropriate bioinformatics pipeline for targeted multigene hotspot molecular testing.
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Pramanik, Raja, Avinash Upadhyay, Sachin Khurana, Lalit Kumar, Prabhat S. Malik, Sunesh Kumar, M. D. Ray, et al. "Comprehensive Germline Genomic Profiling of Patients with Ovarian Cancer: A Cross-Sectional Study." Indian Journal of Medical and Paediatric Oncology 43, no. 04 (August 2022): 361–68. http://dx.doi.org/10.1055/s-0042-1746197.
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Abstract Introduction Ovarian cancer is the third most common cancer among Indian women. The data on the hereditary predisposition of these cancers and the clinical outcomes of those with pathogenic mutations is meager in India. Objective The aim of the current study was to analyze the germline-genetic profile, clinicopathological characteristics, and outcomes of patients with ovarian cancer who were referred for genetic counseling at our Institute. Materials and Methods It was a cross-sectional observational study. Patients with histological diagnosis of carcinoma ovary at our institute who were referred for genetic counseling from July 2017 to June 2020 were included in the study. All patients underwent pretest counseling. Most patients underwent multigene panel testing with reflex multiplication ligation-dependent probe amplification for large genomic rearrangements, while some received testing for BRCA1 and BRCA2 only. The variants were classified as pathogenic or benign based on American College of Medical Genetics (ACMG) guidelines. Data regarding the demographic profile, clinical characteristics, histopathological findings, family history, treatment received, and outcomes were extracted from the medical record system files. Results One hundred and one patients were referred to the genetic clinic and underwent genetic counseling. All patients were advised for genetic testing; however, only 72 (71%) underwent testing. A multigene panel testing was done in 51 (70%) patients, and only BRCA1 and BRCA2 genes were tested in 21 (30%). Among the 72 patients who underwent a genetic test, the median age was 47 years (range, 28–82). The most common histopathology was serous (90%), while 85% were diagnosed having stage 3 and 4 ovarian cancer. A pathogenic/likely pathogenic (P/LP) BRCA or non-BRCA mutation was detected in 32 (44%) patients. Six patients (8%) had a variant of unknown significance (VUS). Among P/LP mutations, 85% were in the BRCA gene (75% in BRCA1 and 10% in BRCA2), while 15% were in non-BRCA gene mutations (RAD51, PALB2, MER11, HMMR). Disease-free survival and overall survival were not different in mutation-positive and mutation-negative cohorts. Conclusions We report 44% P/LP mutations in this selected cohort of patients with carcinoma ovaries. BRCA mutations constituted 85% of all the mutations, while 15% of mutations were in non-BRCA genes.
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Thompson, Ella R., Simone M. Rowley, Na Li, Simone McInerny, Lisa Devereux, Michelle W. Wong-Brown, Alison H. Trainer, et al. "Panel Testing for Familial Breast Cancer: Calibrating the Tension Between Research and Clinical Care." Journal of Clinical Oncology 34, no. 13 (May 1, 2016): 1455–59. http://dx.doi.org/10.1200/jco.2015.63.7454.
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Purpose Gene panel sequencing is revolutionizing germline risk assessment for hereditary breast cancer. Despite scant evidence supporting the role of many of these genes in breast cancer predisposition, results are often reported to families as the definitive explanation for their family history. We assessed the frequency of mutations in 18 genes included in hereditary breast cancer panels among index cases from families with breast cancer and matched population controls. Patients and Methods Cases (n = 2,000) were predominantly breast cancer-affected women referred to specialized Familial Cancer Centers on the basis of a strong family history of breast cancer and BRCA1 and BRCA2 wild type. Controls (n = 1,997) were cancer-free women from the LifePool study. Sequencing data were filtered for known pathogenic or novel loss-of-function mutations. Results Excluding 19 mutations identified in BRCA1 and BRCA2 among the cases and controls, a total of 78 cases (3.9%) and 33 controls (1.6%) were found to carry potentially actionable mutations. A significant excess of mutations was only observed for PALB2 (26 cases, four controls) and TP53 (five cases, zero controls), whereas no mutations were identified in STK11. Among the remaining genes, loss-of-function mutations were rare, with similar frequency between cases and controls. Conclusion The frequency of mutations in most breast cancer panel genes among individuals selected for possible hereditary breast cancer is low and, in many cases, similar or even lower than that observed among cancer-free population controls. Although multigene panels can significantly aid in cancer risk management and expedite clinical translation of new genes, they equally have the potential to provide clinical misinformation and harm at the individual level if the data are not interpreted cautiously.
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González-Santiago, S., T. Ramón y Cajal, E. Aguirre, J. E. Alés-Martínez, R. Andrés, J. Balmaña, B. Graña, A. Herrero, G. Llort, and A. González-del-Alba. "SEOM clinical guidelines in hereditary breast and ovarian cancer (2019)." Clinical and Translational Oncology 22, no. 2 (December 30, 2019): 193–200. http://dx.doi.org/10.1007/s12094-019-02262-0.
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AbstractMutations in BRCA1 and BRCA2 high penetrance genes account for most hereditary breast and ovarian cancer, although other new high-moderate penetrance genes included in multigene panels have increased the genetic diagnosis of hereditary breast and ovarian cancer families by 50%. Multigene cancer panels provide new challenges related to increased frequency of variants of uncertain significance, new gene-specific cancer risk assessments, and clinical recommendations for carriers of mutations of new genes. Although clinical criteria for genetic testing continue to be largely based on personal and family history with around a 10% detection rate, broader criteria are being applied with a lower threshold for detecting mutations when there are therapeutic implications for patients with breast or ovarian cancer. In this regard, new models of genetic counselling and testing are being implemented following the registration of PARP inhibitors for individuals who display BRCA mutations. Massive sequencing techniques in tumor tissue is also driving a paradigm shift in genetic testing and potential identification of germline mutations. In this paper, we review the current clinical criteria for genetic testing, as well as surveillance recommendations in healthy carriers, risk reduction surgical options, and new treatment strategies in breast cancer gene-mutated carriers.
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Fasching, Peter A., Siddhartha Yadav, Chunling Hu, Marius Wunderle, Lothar Häberle, Steven N. Hart, Matthias Rübner, et al. "Mutations in BRCA1/2 and Other Panel Genes in Patients With Metastatic Breast Cancer —Association With Patient and Disease Characteristics and Effect on Prognosis." Journal of Clinical Oncology 39, no. 15 (May 20, 2021): 1619–30. http://dx.doi.org/10.1200/jco.20.01200.
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PURPOSE Among patients with metastatic breast cancer (mBC), the frequency of germline mutations in cancer susceptibility genes and the clinical relevance of these mutations are unclear. In this study, a prospective cohort of patients with mBC was used to determine mutation rates for breast cancer (BC) predisposition genes, to evaluate the clinical characteristics of patients with mutations, and to assess the influence of mutations on patient outcome. PATIENTS AND METHODS Germline DNA from 2,595 patients with mBC enrolled in the prospective PRAEGNANT registry was evaluated for mutations in cancer predisposition genes. The frequencies of mutations in known BC predisposition genes were compared with results from a prospective registry of patients with nonmetastatic BC sequenced using the same QIAseq method and with public reference controls. Associations between mutation status and tumor characteristics, progression-free survival, and overall survival were assessed. RESULTS Germline mutations in 12 established BC predisposition genes (including BRCA1 and BRCA2) were detected in 271 (10.4%) patients. A mutation in BRCA1 or BRCA2 was seen in 129 patients (5.0%). BRCA1 mutation carriers had a higher proportion of brain metastasis (27.1%) compared with nonmutation carriers (12.8%). Mutations were significantly enriched in PRAEGNANT patients with mBC compared with patients with nonmetastatic BC (10.4% v 6.6%, P < .01). Mutations did not significantly modify progression-free survival or overall survival for patients with mBC. CONCLUSION Multigene panel testing may be considered in all patients with mBC because of the high frequency of germline mutations in BRCA1/2 and other BC predisposition genes. Although the prognosis of mutation carriers and nonmutation carriers with mBC was similar, differences observed in tumor characteristics have implications for treatment and for future studies of targeted therapies.
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Bisgin, Atil, Ibrahim Boga, Mustafa Yilmaz, Gulbin Bingol, and Derya Altintas. "The Utility of Next-Generation Sequencing for Primary Immunodeficiency Disorders: Experience from a Clinical Diagnostic Laboratory." BioMed Research International 2018 (2018): 1–5. http://dx.doi.org/10.1155/2018/9647253.
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Introduction. Primary immune deficiency disorders (PIDs) are a group of diseases with profound defects in immune cells. The traditional diagnostics have evolved from clinical evaluation, flow cytometry, western blotting, and Sanger sequencing to focusing on small groups of genes. However, this is not sufficient to confirm the suspicion of certain PIDs. Our innovative approach to diagnostics outlines the algorithm for PIDs and the clinical utility of immunophenotyping with a custom-designed multigene panel. Materials and Methods. We have designed a diagnostic algorithm based on flow cytometry studies to classify the patients; then the selected multigene panel was sequenced. In silico analysis for mutations was carried out using SIFT, Polyphen-2, and MutationTaster. Results and Discussion. The causative mutation was identified in 46% of PIDs. Based on these results, this new algorithm including immune phenotyping and NGS for PIDs was suggested for the clinical use. Conclusions. This study provides a thorough validation of diagnostic algorithm and indicates that still the traditional methods can be used to collect significant information related to design of most current diagnostics. The benefits of such testing are for diagnosis and prevention including the prenatal and preimplantation diagnosis, prognosis, treatment, and research.
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Bernstein-Molho, Rinat, Amihood Singer, Yael Laitman, Iris Netzer, Shelley Zalmanoviz, and Eitan Friedman. "Multigene panel testing in unselected Israeli breast cancer cases: mutational spectrum and use of BRCA1/2 mutation prediction algorithms." Breast Cancer Research and Treatment 176, no. 1 (April 12, 2019): 165–70. http://dx.doi.org/10.1007/s10549-019-05228-6.
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Youssef, Amira Salah El-Din, Mohamed A. Abdel-Fattah, Mai M. Lotfy, Auhood Nassar, Mohamed Abouelhoda, Ahmed O. Touny, Zeinab K. Hassan, et al. "Multigene Panel Sequencing Reveals Cancer-Specific and Common Somatic Mutations in Colorectal Cancer Patients: An Egyptian Experience." Current Issues in Molecular Biology 44, no. 3 (March 18, 2022): 1332–52. http://dx.doi.org/10.3390/cimb44030090.
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This study aims at identifying common pathogenic somatic mutations at different stages of colorectal carcinogenesis in Egyptian patients. Our cohort included colonoscopic biopsies collected from 120 patients: 20 biopsies from patients with inflammatory bowel disease, 38 from colonic polyp patients, and 62 from patients with colorectal cancer. On top of this, the cohort included 20 biopsies from patients with non-specific mild to moderated colitis. Targeted DNA sequencing using a customized gene panel of 96 colorectal related genes running on the Ion Torrent NGS technology was used to process the samples. Our results revealed that 69% of all cases harbored at least one somatic mutation. Fifty-seven genes were found to carry 232 somatic non-synonymous variants. The most frequently pathogenic somatic mutations were localized in TP53, APC, KRAS, and PIK3CA. In total, 16 somatic mutations were detected in the CRC group and in either the IBD or CP group. In addition, our data showed that 51% of total somatic variants were CRC-specific variants. The average number of CRC-specific variants per sample is 2.4. The top genes carrying CRC-specific mutations are APC, TP53, PIK3CA, FBXW7, ATM, and SMAD4. It seems obvious that TP53 and APC genes were the most affected genes with somatic mutations in all groups. Of interest, 85% and 28% of the APC and TP53 deleterious somatic mutations were located in Exon 14 and Exon 3, respectively. Besides, 37% and 28% of the total somatic mutations identified in APC and TP53 were CRC-specific variants, respectively. Moreover, we identified that, in 29 somatic mutations in 21 genes, their association with CRC patients was unprecedented. Ten detected variants were likely to be novel: six in PIK3CA and four variants in FBXW7. The detected P53, Wnt/βcatenin, Angiogenesis, EGFR, TGF-β and Interleukin signaling pathways were the most altered pathways in 22%, 16%, 12%, 10%, 9% and 9% of the CRC patients, respectively. These results would contribute to a better understanding of the colorectal cancer and in introducing personalized therapies for Egyptian CRC patients.
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Price, Kristin S., Ashley Svenson, Elisabeth King, Kaylene Ready, and Gabriel A. Lazarin. "Inherited Cancer in the Age of Next-Generation Sequencing." Biological Research For Nursing 20, no. 2 (January 11, 2018): 192–204. http://dx.doi.org/10.1177/1099800417750746.
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Next-generation sequencing (NGS) technology has led to the ability to test for multiple cancer susceptibility genes simultaneously without significantly increasing cost or turnaround time. With growing usage of multigene testing for inherited cancer, ongoing education for nurses and other health-care providers about hereditary cancer screening is imperative to ensure appropriate testing candidate identification, test selection, and posttest management. The purpose of this review article is to (1) provide an overview of how NGS works to detect germline mutations, (2) summarize the benefits and limitations of multigene panel testing, (3) describe risk categories of cancer susceptibility genes, and (4) highlight the counseling considerations for patients pursuing multigene testing.
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Goidescu, Iulian Gabriel, Gabriela Caracostea, Dan Tudor Eniu, and Florin Vasile Stamatian. "Prevalence of deleterious mutations among patients with breast cancer referred for multigene panel testing in a Romanian population." Medicine and Pharmacy Reports 91, no. 2 (April 26, 2018): 157–65. http://dx.doi.org/10.15386/cjmed-894.
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Aim. Multigene panel testing for Hereditary Breast and Ovarian Cancer (HBOC) using next generation sequencing is becoming more common in medical care.We report our experience regarding deleterious mutations of high and moderate-risk breast cancer genes (BRCA1/2, TP53, STK11, CDH1, PTEN, PALB2, CHEK2, ATM), as well as more recently identified cancer genes, many of which have increased risk but less well-defined penetrance.Methods. Genetic testing was performed in 130 consecutive cases with breast cancer referred to our clinic for surgical evaluation and who met the 2016 National Comprehensive Cancer Network (NCCN) criteria for genetic testing.Results. 82 patients had pathogenic/likely pathogenic mutations and VUS mutations, and 48 were negative; 36 of the pathogenic mutations were in the high-risk genes and 16 were in the moderate risk genes and only 5 cases in the intermediary risk group.From the VUS mutation group 21 cases were in the intermediary risk group, 9 cases were in the moderate risk group and only 7 cases in high risk group.The most frequent BRCA1 variant was c.3607C>T (7 cases) followed by c.5266dupC and c.4035delA (each in 4 cases). Regarding BRCA-2 mutations we identified c.9371A>T and c.8755-1G>A in 6 cases and we diagnosed VUS mutations in 3 cases.Conclusion. Our study identified 2 mutations in the BRCA1 gene that are less common in the Romanian population, c.3607C>T and c.4035delA. Both variants had particular molecular phenotypes, c.3607C>T variant respecting the triple negative pattern of BRCA1 breast cancer while c.4035delA were Luminal B HER positive.
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Nunziato, Marcella, Anna Balato, Anna Ruocco, Valeria D’Argenio, Roberta Di Caprio, Nicola Balato, Fabio Ayala, and Francesco Salvatore. "A Familial Novel Putative-Pathogenic Mutation Identified in Plaque-Psoriasis by a Multigene Panel Analysis." International Journal of Molecular Sciences 24, no. 5 (March 1, 2023): 4743. http://dx.doi.org/10.3390/ijms24054743.
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Psoriasis is a chronic multifactorial skin disorder with an immune basis. It is characterized by patches of skin that are usually red, flaky and crusty, and that often release silvery scales. The patches appear predominantly on the elbows, knees, scalp and lower back, although they may also appear on other body areas and severity may be variable. The majority of patients (about 90%) present small patches known as “plaque psoriasis”. The roles of environmental triggers such as stress, mechanical trauma and streptococcal infections are well described in psoriasis onset, but much effort is still needed to unravel the genetic component. The principal aim of this study was to use a next-generation sequencing technologies-based approach together with a 96 customized multigene panel in the attempt to determine if there are germline alterations that can explain the onset of the disease, and thus to find associations between genotypes and phenotypes. To this aim, we analyzed a family in which the mother showed mild psoriasis, and her 31-year-old daughter had suffered from psoriasis for several years, whereas an unaffected sister served as a negative control. We found variants already associated directly to psoriasis in the TRAF3IP2 gene, and interestingly we found a missense variant in the NAT9 gene. The use of multigene panels in such a complex pathology such as psoriasis can be of great help in identifying new susceptibility genes, and in being able to make early diagnoses especially in families with affected subjects.
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Park, Seung-min, Dawson J. Wong, Chin Chun Ooi, David M. Kurtz, Ophir Vermesh, Amin Aalipour, Susie Suh, et al. "Molecular profiling of single circulating tumor cells from lung cancer patients." Proceedings of the National Academy of Sciences 113, no. 52 (December 12, 2016): E8379—E8386. http://dx.doi.org/10.1073/pnas.1608461113.
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Circulating tumor cells (CTCs) are established cancer biomarkers for the “liquid biopsy” of tumors. Molecular analysis of single CTCs, which recapitulate primary and metastatic tumor biology, remains challenging because current platforms have limited throughput, are expensive, and are not easily translatable to the clinic. Here, we report a massively parallel, multigene-profiling nanoplatform to compartmentalize and analyze hundreds of single CTCs. After high-efficiency magnetic collection of CTC from blood, a single-cell nanowell array performs CTC mutation profiling using modular gene panels. Using this approach, we demonstrated multigene expression profiling of individual CTCs from non–small-cell lung cancer (NSCLC) patients with remarkable sensitivity. Thus, we report a high-throughput, multiplexed strategy for single-cell mutation profiling of individual lung cancer CTCs toward minimally invasive cancer therapy prediction and disease monitoring.
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Kapoor, Nimmi S., Lisa D. Curcio, Carlee A. Blakemore, Amy K. Bremner, Rachel E. McFarland, John G. West, and Kimberly C. Banks. "Benefits and safety of multigene panel testing in patients at risk for hereditary breast cancer." Journal of Clinical Oncology 33, no. 28_suppl (October 1, 2015): 16. http://dx.doi.org/10.1200/jco.2015.33.28_suppl.16.
Full textAbstract:
16 Background: Recently introduced multi-gene panel testing including BRCA1 and BRCA2 genes (BRCA1/2) for hereditary cancer risk has raised concerns with the ability to detect all deleterious BRCA1/2 mutations compared to older methods of sequentially testing BRCA1/2 separately. The purpose of this study is to evaluate rates of pathogenic BRCA1/2mutations and variants of uncertain significance (VUS) between previous restricted algorithms of genetic testing and newer approaches of multi-gene testing. Methods: Data was collected retrospectively from 966 patients who underwent genetic testing at one of three sites from a single institution. Test results were compared between patients who underwent BRCA1/2testing only (limited group, n = 629) to those who underwent multi-gene testing with 5-43 cancer-related genes (panel group, n = 337). Results: Deleterious BRCA1/2 mutations were identified in 37 patients, with equivalent rates between limited and panel groups (4.0% vs 3.6%, respectively, p = 0.86). Thirty-nine patients had a BRCA1/2 VUS, with similar rates between limited and panel groups (4.5% vs 3.3%, respectively, p = 0.49). On multivariate analysis, there was no difference in detection of either BRCA1/2 mutations or VUS between both groups. Of patients undergoing panel testing, an additional 3.9% (n = 13) had non-BRCA pathogenic mutations and 13.4% (n = 45) had non-BRCA VUSs. Mutations in PALB2, CHEK2, and ATM were the most common non-BRCA mutations identified. Conclusions: Multi-gene panel testing detects pathogenic BRCA1/2 mutations at equivalent rates as limited testing and increases the diagnostic yield. Panel testing increases the VUS rate, mainly due to non-BRCA genes. Patients at risk for hereditary breast cancer can safely benefit from upfront, more efficient, multi-gene panel testing.