To see the other types of publications on this topic, follow the link: Gene mutation/breast disease.
Journal articles on the topic 'Gene mutation/breast disease'
Create a spot-on reference in APA, MLA, Chicago, Harvard, and other styles
Consult the top 50 journal articles for your research on the topic 'Gene mutation/breast disease.'
Next to every source in the list of references, there is an 'Add to bibliography' button. Press on it, and we will generate automatically the bibliographic reference to the chosen work in the citation style you need: APA, MLA, Harvard, Chicago, Vancouver, etc.
You can also download the full text of the academic publication as pdf and read online its abstract whenever available in the metadata.
Browse journal articles on a wide variety of disciplines and organise your bibliography correctly.
1
Ahn, TaeJin, and Taesung Park. "Pathway-Driven Discovery of Rare Mutational Impact on Cancer." BioMed Research International 2014 (2014): 1–10. http://dx.doi.org/10.1155/2014/171892.
Full textAbstract:
Identifying driver mutation is important in understanding disease mechanism and future application of custom tailored therapeutic decision. Functional analysis of mutational impact usually focuses on the gene expression level of the mutated gene itself. However, complex regulatory network may cause differential gene expression among functional neighbors of the mutated gene. We suggest a new approach for discovering rare mutations that have real impact in the context of pathway; the philosophy of our method is iteratively combining rare mutations until no more mutations can be added under the condition that the combined mutational event can statistically discriminate pathway level mRNA expression between groups with and without mutational events. Breast cancer patients with somatic mutation and mRNA expression were analyzed by our approach. Our approach is shown to sensitively capture mutations that change pathway level mRNA expression, concurrently discovering important mutations previously reported in breast cancer such as TP53, PIK3CA, and RB1. In addition, out of 15,819 genes considered in breast cancer, our approach identified mutational events of 32 genes showing pathway level mRNA expression differences.
2
QAMAR, MUHAMMAD FIAZ, FARAH REHMAN, SABEEN ILYAS, and Seher Abbas. "BREAST CANCER PATIENTS;." Professional Medical Journal 20, no. 06 (December 15, 2013): 1019–25. http://dx.doi.org/10.29309/tpmj/2013.20.06.1736.
Full textAbstract:
Objective: Genetic factors contribute to the high rates with breast cancer patients. Our objective was to screen themutations in the BRCA 1 gene in exon 20. Design: A diagnostic study. Place and Duration of Study: The study was carried out inmolecular biology lab, Department of Zoology, GC University Lahore and Institute of Molecular Biology and Biotechnology (IMBB),University of Lahore over a period of one year from July 2011 to Aug 2012. Patients and Methods: To screen for mutation in the BRCA1gene, blood samples were collected from 22 different patients suffering from breast cancer from the Anmol Hospital and Sir Ganga RamHospital Lahore. The collected samples were processed to screen any mutation in exon 20 which is indicative of the fact that exon 20 isnot a hotspot for mutations. Results: In our study of 22 females, we have found no mutation in the gene. It is becoming increasingly clearthat breast cancer is a multifaceted and heterogeneous disease and histopathological characteristics of breast cancer are controlled bysubsets of genetic alterations, providing convincing hints of genotypic–phenotypic correlations between morphological patterns andmolecular changes. BRCA has emerged as the master regulator of the genome through its ability to regulate and coordinate various stepsof DNA damage response. Women who carry a mutation of the gene have greatly increased chance of developing breast cancer. Thepopulation of Pakistan has been substantially screened for somatic and germline mutations in BRCA. Conclusions: Breast cancer is themost common cancer of women in Pakistan. One every 8th women is found to carry the disease. A female may develop the diseasethrough inherited mutations in the BRCA1 gene. The absence of mutation maybe attributed to small sample size of the study or may be dueto the fact that the size of the gene is so large that a single axon may not be enough to screen for mutations.
3
Arakelyan, Arsen, Ani Melkonyan, Siras Hakobyan, Uljana Boyarskih, Arman Simonyan, Lilit Nersisyan, Maria Nikoghosyan, Maxim Filipenko, and Hans Binder. "Transcriptome Patterns of BRCA1- and BRCA2- Mutated Breast and Ovarian Cancers." International Journal of Molecular Sciences 22, no. 3 (January 28, 2021): 1266. http://dx.doi.org/10.3390/ijms22031266.
Full textAbstract:
Mutations in the BRCA1 and BRCA2 genes are known risk factors and drivers of breast and ovarian cancers. So far, few studies have been focused on understanding the differences in transcriptome and functional landscapes associated with the disease (breast vs. ovarian cancers), gene (BRCA1 vs. BRCA2), and mutation type (germline vs. somatic). In this study, we were aimed at systemic evaluation of the association of BRCA1 and BRCA2 germline and somatic mutations with gene expression, disease clinical features, outcome, and treatment. We performed BRCA1/2 mutation centered RNA-seq data analysis of breast and ovarian cancers from the TCGA repository using transcriptome and phenotype “portrayal” with multi-layer self-organizing maps and functional annotation. The results revealed considerable differences in BRCA1- and BRCA2-dependent transcriptome landscapes in the studied cancers. Furthermore, our data indicated that somatic and germline mutations for both genes are characterized by deregulation of different biological functions and differential associations with phenotype characteristics and poly(ADP-ribose) polymerase (PARP)-inhibitor gene signatures. Overall, this study demonstrates considerable variation in transcriptomic landscapes of breast and ovarian cancers associated with the affected gene (BRCA1 vs. BRCA2), as well as the mutation type (somatic vs. germline). These results warrant further investigations with larger groups of mutation carriers aimed at refining the understanding of molecular mechanisms of breast and ovarian cancers.
4
Tang, E., A. Kwong, C. Wong, F. Law, C. Wong, E. Ng, E. Ma, and J. M. Ford. "Novel de novo BRCA1 mutation in a woman with early onset breast cancer." Journal of Clinical Oncology 27, no. 15_suppl (May 20, 2009): e22143-e22143. http://dx.doi.org/10.1200/jco.2009.27.15_suppl.e22143.
Full textAbstract:
e22143 Background: Germline mutations in BRCA1/2 account for a significant portion of hereditary breast/ovarian cancer. Mutation carriers usually have a family history of breast/ovarian cancer or early onset disease. Rarely, germline mutations are found only in the probands but not in any family members. Such de novo mutations have been reported in diseases such as hemophilia A, thalassaemia and familial adenomatous polyposis. De novo mutations in the BRCA1 or BRCA2 genes are rare and the few reported have been in BRCA2. Here, we describe de novo as well as novel mutation of the BRCA1 gene in a breast cancer patient. Methods: Blood DNA samples from a 30 year old Chinese woman with breast cancer and no family history of cancer was tested for a BRCA1/2 mutation by full gene sequencing and Multiple Ligation-dependent Probe Amplification (MLPA). Family members were analyzed for the same mutation. Paternity was determined by a set of highly polymorphic short tandem repeat (STR) markers. Results: Full gene sequencing found no deleterious mutation. MLPA revealed a large deletion of exons 1 to 12 of BRCA1 in the proband. MLPA performed on 5 family members: proband's mother and father (who were 1st degree relative- cousins), stepmother (mother's biological sister), 2 sisters (1, same parents; 1, same father and stepmother) found no similar deletion. By using a set of highly polymorphic STR markers, the proband's father and mother were confirmed to be her biological parents. Conclusions: We report a novel de novo BRCA1 deletion mutation encompassing exons 1 - 12 in a Chinese breast cancer patient of early onset with no family history. Identification of this large deletion confirms the importance of pursuing rearrangement testing if full gene sequencing fails to detect a point mutation or short insertion deletion. The mutation found in this study is de novo. This may simply be a random mutation event which occurred in the parents' germ cells during their lifetime which passed onto one of their offspring or maybe a result of gene inversion or splicing deficiency. The relations of such mutations with consanguineous marriage cannot be ruled out. Mutation screening is important in early onset breast cancer patients even if there is no family history. No significant financial relationships to disclose.
5
Wisesty, U. N., T. R. Mengko, and A. Purwarianti. "Gene mutation detection for breast cancer disease: A review." IOP Conference Series: Materials Science and Engineering 830 (May 19, 2020): 032051. http://dx.doi.org/10.1088/1757-899x/830/3/032051.
Full text
6
Oleksenko, Viktor, Kazim Aliev, and K. Malyy. "BRCA GENES MUTATIONS’ OF HEREDITARY BREAST CANCER IN CRIMEA." Problems in oncology 66, no. 5 (May 1, 2020): 507–13. http://dx.doi.org/10.37469/0507-3758-2020-66-5-507-513.
Full textAbstract:
Introduction. The hereditary predisposition to the growth of breast cancer (BC), associated with germline mutations of DNA genes repair (BRCA(1,2)), is characterized by a variety of polymorphism variants, with a tendency to a certain specificity in different population groups. In regions with a mixed population composition, such as Crimean Peninsula, the problem of the relationship of specific mutations and a population group is not only of scientific interest, but also has rather important practical significance from the point of view of diagnostic and prognostic criteria design for the breast cancer incidence. The aim of the study was to determine the frequency of occurrence of BRCA1 (5382insC, 4153delA, 185delAG) and BRCA2 (6174delT) genes mutations in two population groups having a breast cancer and living in the Crimea - Slavic and Crimean Tatar, with clinical signs of a hereditary disease. Materials and methods. 283 DNA samples were studied, collected from the blood of patients with clinical signs of hereditary breast cancer, of which 208 were Slavic and 75 were Crimean Tatar population group. The control group consisted of 256 DNA samples collected from the blood of healthy women, of which 196 were Slavic and 60 were Crimean Tatar population group. The study was carried out using real-time polymerase chain reaction (PCR-RT) by allelic discrimination, with the analysis of melting curves. Morphological verification of the diagnosis was carried out by a set of methods for determining the histological variant and tumor immunophenotyping according to the standard diagnostic program. Results. Mutations were detected in 23 breast cancer cases; these mutations were determined exclusively in the Slavic group. The 5382insC BRCA1 gene mutation was prevailed (21/10,1%), and 185delAG BRCA1 mutations one case and 6174delT BRCA2 mutation one case were obtained. None of the gene mutation was not registered in the Crimean Tatar population group. Immunohistochemi-cally triple negative breast cancer was determined in 86.4% of mutations cases. Only one case of mutation was recorded in the control group - 5382insC of the BRCA1 gene in the Slavic population group (0,4%). Conclusion. The frequency of occurrence of the “founder mutation” 5382insC BRCA1 gene mutation in breast cancer patients from Slavic population group corresponds to the average Russian and European levels, the frequency of other variants of the studied mutations, 185delAG BRCA1 gene and 6174delT BRCA2 gene, is recorded much less frequently, and the 4153delA mutation was not observed in the studied samples. The absence of mutations in the studied markers of the Crimean Tatars population group, including those with a hereditary predisposition to breast cancer, indicates differences in the mutation spectrum and necessitates the continuation of studies with an expansion of the mutation spectrum, with the prospect of full-genome (BRCA1) or genome-wide DNA sequencing of patients.
7
Kailasam, Karthik, Mohammad Omaira, Hardik Satish Chhatrala, and Marie Ravichandar. "Prognostic implication of GATA3 gene mutation on survival in invasive ductal carcinoma of the breast." Journal of Clinical Oncology 35, no. 15_suppl (May 20, 2017): e13114-e13114. http://dx.doi.org/10.1200/jco.2017.35.15_suppl.e13114.
Full textAbstract:
e13114 Background: GATA3 encodes a transcription factor, which is involved in activation and suppression of genes involved in cell maturation. GATA3 is necessary in the adult mammary gland to maintain the integrity and function of the luminal epithelium. Methods: METABRIC project funded by cancer research UK, the British Columbia cancer foundation and the Canadian breast cancer foundation mapped 173 gene mutations and amplifications in 2,433 primary breast tumors. Retrospective analysis was done for patients with invasive ductal carcinoma of the breast in the age group 30-60; to study the effect of GATA3 mutation on survival. Median survival was obtained from Kaplan-Meier plot, and mortality between groups was compared by Odds ratio (OR). Results: A total of 1500 patients across all age groups had invasive ductal carcinoma. 650 were within the age group 30-60; of which 234 died due to the disease, 360 were alive and 55 died due to other causes. 398 patients (61.2%) tested positive for estrogen receptor (ER) and 521 patients (80.2%) were negative for HER2 (human epidermal growth factor receptor 2). TP53 (50%) and PIK3CA (36%) mutations were more prevalent. GATA3 mutation was found in 79 patients (12.34%); among which, all 79 patients tested positive for ER (100%) and 74 patients (94.9%) negative for HER2. 10 patients (12.7%) died due to the disease, 62 patients (78.5%) were alive and 7 patients (8.9%) died due to other causes. Hence, patients with GATA3 mutations were more likely to survive (OR 4.66; CI 2.33-9.29 p < 0.0001) than patients without the mutation. The median survival for patients with GATA3 mutation (300 months) was also greater than patients without the mutation (219 months). In addition, patients with GATA3 mutation were more likely to be ER positive and HER2 negative. Conclusions: In the mammary gland, GATA3 is required for luminal epithelial cell differentiation. Loss of GATA3 results in de-differentiation to stem cell phenotype. It is found that GATA3 mutation correlates with a better prognosis compared to more common TP53 and PIK3CA gene mutations.
8
Darooei, Mina, Subhadra Poornima, Bibi Umae Salma, Gayatri R. Iyer, Akhilesh N. Pujar, Srirambhatla Annapurna, Ashwin Shah, Srinivas Maddali, and Qurratulain Hasan. "Pedigree and BRCA gene analysis in breast cancer patients to identify hereditary breast and ovarian cancer syndrome to prevent morbidity and mortality of disease in Indian population." Tumor Biology 39, no. 2 (February 2017): 101042831769430. http://dx.doi.org/10.1177/1010428317694303.
Full textAbstract:
Global burden of breast cancer is expected to increase to >2 million new cases every year by 2030 and 10% of these are likely to have hereditary breast and ovarian cancer syndrome. Identifying these individuals by pedigree and BRCA1/2 mutation analyses will enable us to offer targeted mutation testing and appropriate counseling. This study from a tertiary care hospital showed that of the 127 breast cancer patients on treatment during 2014–2015, 24 of them fulfilled the criteria of hereditary breast and ovarian cancer syndrome after detailed verbal autopsy and pedigree analysis, and BRCA1 and 2 next-generation sequencing done after pre-test counseling revealed mutations in 13 cases (54%), these included 9 BRCA1 mutations (69%) and 4 BRCA2 mutation (31%). Subsequent post-test counseling recommended targeted mutation analysis for 64 high-risk members in these 13 families with pathogenic mutations, which will help in surveillance for early detection, appropriate management, and prevention of the disease by decreasing the burden to both family and nation. Results from this preliminary study highlight the importance of genetic counseling, pedigree analysis, and genetic testing. It can be recommended that all oncology units should have a genetic counseling service for providing appropriate support to oncologists, patients, and families to prevent unnecessary testing; however, breast cancer screening program is incomplete without evaluating for hereditary breast and ovarian cancer syndrome.
9
Kluźniak, Wojciech, Dominika Wokołorczyk, Bogna Rusak, Tomasz Huzarski, Aniruddh Kashyap, Klaudia Stempa, Helena Rudnicka, et al. "Inherited Variants in BLM and the Risk and Clinical Characteristics of Breast Cancer." Cancers 11, no. 10 (October 13, 2019): 1548. http://dx.doi.org/10.3390/cancers11101548.
Full textAbstract:
Bloom Syndrome is a rare recessive disease which includes a susceptibility to various cancers. It is caused by homozygous mutations of the BLM gene. To investigate whether heterozygous carriers of a BLM mutation are predisposed to breast cancer, we sequenced BLM in 617 patients from Polish families with a strong family history of breast cancer. We detected a founder mutation (c.1642C>T, p.Gln548Ter) in 3 of the 617 breast cancer patients (0.49%) who were sequenced. Then, we genotyped 14,804 unselected breast cancer cases and 4698 cancer-free women for the founder mutation. It was identified in 82 of 14,804 (0.55%) unselected cases and in 26 of 4698 (0.55%) controls (OR = 1.0; 95%CI 0.6–1.6). Clinical characteristics of breast cancers in the BLM mutation carriers and non-carriers were similar. Loss of the wild-type BLM allele was not detected in cancers from the BLM mutation carriers. No cancer type was more common in the relatives of mutation carriers compared to relatives of non-carriers. The BLM founder mutation p.Gln548Ter, which in a homozygous state is a cause of Bloom syndrome, does not appear to predispose to breast cancer in a heterozygous state. The finding casts doubt on the designation of BLM as an autosomal dominant breast cancer susceptibility gene.
10
Testa, Ugo, Germana Castelli, and Elvira Pelosi. "Breast Cancer: A Molecularly Heterogenous Disease Needing Subtype-Specific Treatments." Medical Sciences 8, no. 1 (March 23, 2020): 18. http://dx.doi.org/10.3390/medsci8010018.
Full textAbstract:
Breast cancer is the most commonly occurring cancer in women. There were over two-million new cases in world in 2018. It is the second leading cause of death from cancer in western countries. At the molecular level, breast cancer is a heterogeneous disease, which is characterized by high genomic instability evidenced by somatic gene mutations, copy number alterations, and chromosome structural rearrangements. The genomic instability is caused by defects in DNA damage repair, transcription, DNA replication, telomere maintenance and mitotic chromosome segregation. According to molecular features, breast cancers are subdivided in subtypes, according to activation of hormone receptors (estrogen receptor and progesterone receptor), of human epidermal growth factors receptor 2 (HER2), and or BRCA mutations. In-depth analyses of the molecular features of primary and metastatic breast cancer have shown the great heterogeneity of genetic alterations and their clonal evolution during disease development. These studies have contributed to identify a repertoire of numerous disease-causing genes that are altered through different mutational processes. While early-stage breast cancer is a curable disease in about 70% of patients, advanced breast cancer is largely incurable. However, molecular studies have contributed to develop new therapeutic approaches targeting HER2, CDK4/6, PI3K, or involving poly(ADP-ribose) polymerase inhibitors for BRCA mutation carriers and immunotherapy.
11
Omarini, Claudia, Maria Elisabetta Filieri, Stefania Bettelli, Samantha Manfredini, Shaniko Kaleci, Cecilia Caprera, Cecilia Nasso, et al. "Mutational Profile of Metastatic Breast Cancer Tissue in Patients Treated with Exemestane Plus Everolimus." BioMed Research International 2018 (July 24, 2018): 1–8. http://dx.doi.org/10.1155/2018/3756981.
Full textAbstract:
Background.Everolimus has been shown to overcome endocrine resistance in hormone receptor positive advanced breast cancer patients. Predictive biomarkers of everolimus efficacy have been investigated in primary breast cancer tissue without finding univocal results. The goal of this study was to investigate the mutational burden in the metastatic site of endocrine-resistant tumors treated with everolimus plus exemestane.Patients and Methods.Mass Array Sequenom platform was used to analyse genetic status of 18 cancer-related genes in 25 archival tumor specimens from metastatic lesions and available primary matched breast cancer tissue of patients treated with everolimus and exemestane for advanced disease. An exploratory analysis of everolimus efficacy in terms of progression free survival benefit and single gene mutation was carried out.Results. The overall detection rate of mutation was 30% and 38% from metastatic and primary breast cancer samples, respectively.AKT1E17Kwas the most frequent mutated gene. No primary breast cancer and matched relapse maintained the same mutation profile. Considering molecular pathways, the most of the genes belong to PI3K pathway (AKT1E17K,PI3KCAE545K, andKITG565R,S709F). In patients with detected mutations in breast and/or recurrence tissue the median PFS was 5,6 months while in the subgroup of patients with no mutations the median PFS was 7,5 months.Conclusions. The mutational status of breast cancer recurrence allows the identification of some genes potentially correlating tumor response/resistance to everolimus. The most frequently mutated genes were involved in the PI3K/AKT/mTOR pathway highlighting that the deregulation of this pathway in the relapse plays a crucial role in the mechanisms of everolimus resistance/sensitivity. Owing to the small sample size and the retrospective nature of the study, these correlations need to be validated in a large prospective study.
12
Amer, Asmaa, Ahmed Nagah, Tianhai Tian, and Xinan Zhang. "Mutation Mechanisms of Breast Cancer among the Female Population in China." Current Bioinformatics 15, no. 3 (May 23, 2020): 253–59. http://dx.doi.org/10.2174/1574893615666191220141548.
Full textAbstract:
Background: Cancer is a genetic disease caused by the accumulation of gene mutations. It is important to derive the number of driver mutations that are needed for the development of human breast cancer, which may provide insights into the tumor diagnosis and therapy. Objective: This work is designed to investigate whether there is any difference for the mutation mechanism of breast cancer between the patients in the USA and those in China. We study the mechanisms of breast cancer development in China, and then compare these mechanisms with those in the USA. Methods: This work designed a multistage model including both gene mutation and clonal expansion of intermediate cells to fit the dataset of breast cancer in China from 2004 to 2009. Results: Our simulation results show that the maximum number of driver mutations for breast epithelium stem cells of females in China is 13 which is less than the 14 driver mutations of females in the USA. In addition, the two-hit model is the optimal one for the tumorigenesis of females in China, which is also different from the three-hit model that was predicted as the optimal model for the tumorigenesis of females in the USA. Conclusion: The differences of the mutation mechanisms between China and the USA reflect a variety of lifestyle, genetic influences, environmental exposure, and the availability of mammography screening.
13
Wu, Yanmei, Xiaodong Pan, Juan Dou, Quan Zhang, Yuantong Li, Yuan Sheng, and Xishui Liu. "A novel germline BRCA1 mutation identified in a family with hereditary breast and ovarian cancer syndrome." Clinical Medicine Insights: Oncology 15 (January 2021): 117955492110285. http://dx.doi.org/10.1177/11795549211028569.
Full textAbstract:
Pathogenic germline mutations occurring in the BRCA1 (MIM:113705) and BRCA2 (MIM: 600185), which always result in truncated protein or nonsense-mediated mRNA decay, have been identified to increase the risk of hereditary breast, ovarian, pancreatic, prostate, and melanoma cancers. Recent studies show that BRCA1/2 germline mutations also contribute to half of all hereditary breast and ovarian cancer (HBOC). In this case series, we reported a novel frameshift mutation of the BRCA1 gene. This novel frameshift mutation occurs in exon10 of BRCA1 and may result in a lack of the serine cluster domain and BRCA1 C-terminus domain, which mediates the function of BRCA1 in DNA repair and are responsible for activation function of BRCA1. The mutation was present in a Chinese hereditary male/female breast and ovarian cancer family characterized by a high incidence of breast cancer and/or ovarian cancer among the relatives and by a high incidence of triple negative breast cancer (TNBC). Our findings speculate that BRCA1 E1148Rfs*7 mutation may be related to the occurrence of HBOC and even TNBC. Interestingly, three cases of TNBC with this novel BRCA1 mutation in this case series showed a good disease-free survival, one of them has a disease-free survival up to 7 years. Therefore, further study is required to confirm that whether this mutation is associated with good prognosis of HBOC.
14
Iyevleva, Aglaya, Tatiana Gorodnova, Svetlana Aleksakhina, Elena Anisimova, Larisa Gigolaeva, Anna Sokolenko, Kirill Zagorodnev, et al. "Detection of TP53 mutations in plasma of ovarian cancer and breast cancer patients." Problems in oncology 67, no. 2 (April 30, 2021): 260–67. http://dx.doi.org/10.37469/0507-3758-2021-67-2-260-267.
Full textAbstract:
Background. The analysis of circulating tumor DNA provides wide opportunities for monitoring the results of cancer treatment. Somatic mutations in TP53 gene are present in almost all breast carcinomas developing in hereditary BRCA1 mutation carriers, as well as in the majority of high-grade serous ovarian tumors, which makes it possible to use them for effective monitoring of these diseases.
The aim of the study was to analyze the content of tumor-specific TP53 mutations in plasma of patients with high-grade serous ovarian cancer (OC) and BRCA1-associated breast cancer (BC).
Materials and methods. At least one plasma sample was obtained from 10 patients with OC and 7 patients with BRCA1-associated BC. The primary intratumoral status of TP53 gene was determined in the archival tumor material by targeted next generation sequencing. Digital droplet PCR was applied for testing of plasma samples for the presence of tumor-specific TP53 mutations, and in one case, BRAF V600E mutation.
Results. All 8 plasma samples obtained from OC patients at the time of disease progression, before or during neoadjuvant chemotherapy, were positive for TP53 mutations. In contrast, 8 OC plasma samples obtained during remission, after surgery, or after neoadjuvant chemotherapy did not contain tumor-specific mutations. In breast cancer, circulating tumor DNA was detected in 2 of 4 samples obtained before treatment, and was not detected after the end of therapy or in remission.
Conclusion. There is a good correlation between the presence of tumor-specific TP53 mutations in circulating DNA and the disease status in OC patients, therefore TP53 is a promising marker for clinical monitoring of ovarian cancer. In breast cancer, circulating tumor DNA is less abundant, therefore TP53 mutations cannot be reliably detected by digital droplet PCR in the plasma of patients with moderate disease burden.
15
Niyomnaitham, Suvimol, Napa Parinyanitikul, Ekkapong Roothumnong, Worapoj Jinda, Norasate Samarnthai, Taywin Atikankul, Bhoom Suktitipat, Wanna Thongnoppakhun, Chanin Limwongse, and Manop Pithukpakorn. "Tumor mutational profile of triple negative breast cancer patients in Thailand revealed distinctive genetic alteration in chromatin remodeling gene." PeerJ 7 (February 25, 2019): e6501. http://dx.doi.org/10.7717/peerj.6501.
Full textAbstract:
Background Triple negative breast cancer (TNBC) is a breast cancer subtype characterized by absence of both hormonal receptors and human epithelial growth factor receptor 2 (HER2). TNBC accounts for 15–20% of breast cancer. TNBC is associated with more aggressive disease and worse clinical outcome. Though the underlying mechanism of TNBC is currently unclear, the heterogeneity of clinical characteristics in various population may relate to the difference in tumor mutational profile. There were studies on TNBC gene mutations in various ethnic groups but the tumor genome data on Thai TNBC patients is currently unknown. This study aims to investigate mutational profile of Thai TNBC. Methods The patients were Thai individuals who were diagnosed with primary breast carcinoma between 2014 and 2017. All surgically removed primary tumor tissues were carefully examined by pathologists and archived as formalin-fixed paraffin-embedded tumor. TNBC was defined by absence of hormonal receptors and HER2 by immunohistochemistry. Genomic DNA was extracted, enriched and sequenced of all exomes on the Illumina HiSeq. Genomic data were then processed through bioinformatics platform to identify genomic alterations and tumor mutational burden. Results A total of 116 TNBC patients were recruited. Genomic analysis of TNBC samples identified 81,460 variants, of which 5,906 variants were in cancer-associated genes. The result showed that Thai TNBC has higher tumor mutation burden than previously reported data. The most frequently mutated cancer-associated gene was TP53 similar to other TNBC cohorts. Meanwhile KMT2C was found to be more commonly mutated in Thai TNBC than previous studies. Mutational profile of Thai TNBC patients also revealed difference in many frequently mutated genes when compared to other Western TNBC cohorts. Conclusion This result supported that TNBC breast cancer patients from various ethnic background showed diverse genome alteration pattern. Although TP53 is the most commonly mutated gene across all cohorts, Thai TNBC showed different gene mutation frequencies, especially in KMT2C. In particular, the cancer gene mutations are more prevalent in Thai TNBC patients. This result provides important insight on diverse underlying genetic and epigenetic mechanisms of TNBC that could translate to a new treatment strategy for patients with this disease.
16
Brueffer, Christian, Sergii Gladchuk, Christof Winter, Johan Vallon-Christersson, Cecilia Hegardt, Jari Häkkinen, Anthony M. George, et al. "Defining the mutational landscape of 3,217 primary breast cancer transcriptomes through large-scale RNA-seq within the Sweden Cancerome Analysis Network: Breast Project (SCAN-B; NCT03430492)." Journal of Clinical Oncology 38, no. 15_suppl (May 20, 2020): 518. http://dx.doi.org/10.1200/jco.2020.38.15_suppl.518.
Full textAbstract:
518 Background: Breast cancer is a disease of genomic alterations, of which the complete panorama of somatic mutations and how these relate to molecular subtypes and therapy response is incompletely understood. The Sweden Cancerome Analysis Network-Breast project (SCAN-B; ClinicalTrials.gov NCT02306096) is a multi-center population-based ongoing prospective observational study elucidating the global transcriptomic profiles for thousands of patients and tumors using RNA sequencing. Since September 2010, over 15,000 patients with breast cancer have been enrolled at 9 hospitals across a wide geography of Sweden, comprising greater than 90% of all eligible patients in the catchment area. Methods: Within SCAN-B, we developed an optimized bioinformatics pipeline for detection of single nucleotide variants and small insertions and deletions from RNA-seq data. From this, we describe the mutational landscape of 3,217 primary breast cancer transcriptomes, and relate it to patient overall survival in a real-world setting (median follow-up 75 months, range 2-105 months). Results: We demonstrate that RNA-seq can be used to call mutations in important breast cancer genes such as PIK3CA, TP53, ESR1, and ERBB2, as well as mutation status of key molecular pathways and tumor mutational burden, identify mutations in one or more potentially druggable genes in 85.3% percent of cases, and reveal significant relationships to patient outcome within specific treatment groups. To make this rich and growing mutational portraiture of breast cancer available for the wider research community, we developed an open source interactive web application, SCAN-B MutationExplorer, publicly accessible at http://oncogenomics.bmc.lu.se/MutationExplorer . Conclusions: These results add another dimension to the use of RNA-seq as a potential clinical tool, where both gene expression-based signatures and gene mutation-based biomarkers can be interrogated simultaneously and in real-time within one week of tumor sampling.
17
Borg, Åke, Anne Dørum, Ketil Heimdal, Lovise Mæhle, Eivind Hovig, and Pål Møller. "BRCA1 1675delA and 1135insA Account for One Third of Norwegian Familial Breast-Ovarian Cancer and Are Associated with Later Disease Onset than Less Frequent Mutations." Disease Markers 15, no. 1-3 (1999): 79–84. http://dx.doi.org/10.1155/1999/278269.
Full textAbstract:
A total of 845 women from breast-ovarian cancer kindreds were enrolled in a clinical follow-up program for early disease diagnosis; 35 women were prospectively identified with cancer. In order to estimate the role of genetic factors for cancer predisposition in this well-defined set of patients, considered as representative for familial breast-ovarian cancer in the Norwegian population, the BRCA1 gene was investigated for germline mutations. The entire coding region of BRCA1 was analysed using a protein truncation test, direct sequencing and a screen for known large genomic deletions and insertions. Twenty one (60%) of the 35 patients were identified as carriers of 11 distinct BRCA1 mutations. Two previously described founder mutations, 1675delA and 1135insA, were found to account for more than half (11/21) of all BRCA1 cases and for almost one third (11/35) of all breast and ovarian cancers. Supported by a previous population-based analysis of these founder mutations in ovarian cancer, our findings suggest that a significant proportion of women at risk for developing inherited breast and ovarian cancer can be identified. This is particularly obvious in certain geographic regions where these founder mutations are prevalent. Women carrying the two founder mutations had a significantly older age of disease onset as compared to women with other BRCA1 mutations. This observation indicates that BRCA mutation penetrance estimates from populations with strong founder effects may be biased. One reason why some deleterious mutations are allowed to prevail in a population may be coupled to penetrance and the fact that they seldom induce disease in women in child-bearing ages. Eleven out of 12 (92%) breast cancers in BRCA1 mutation carriers were estrogen receptor negative, versus 4 out of 9 (44%) in mutation negative patients (p = 0.03). Histopathological characteristics of the prospectively detected cancers indicated an unfavourable prognosis in mutation carriers.
18
Paik, Hyun-June, Youn Joo Jung, Dong Il Kim, Seungju Lee, Chang Shin Jung, Seok Kyung Kang, Jae-Joon Kim, So Yeon Oh, Ji Hyeon Joo, and Hyun Yul Kim. "Clinicopathological Features of BRCA1/2 Mutation-Positive Breast Cancer." Oncology 99, no. 8 (2021): 499–506. http://dx.doi.org/10.1159/000515790.
Full textAbstract:
<b><i>Purpose:</i></b> The <i>BRCA1/2</i> gene is the most well-known and studied gene associated with hereditary breast cancer. <i>BRCA1/2</i> genetic testing is widely performed in high-risk patients of hereditary breast cancer in Korea. This study aimed to investigate the clinicopathological characteristics of <i>BRCA1/2</i> mutation-positive breast cancer patients. <b><i>Methods:</i></b> The clinical data of 188 Korean breast cancer patients who underwent genetic testing of <i>BRCA1/2</i> mutation between March 2015 and February 2020 at Pusan National University Yangsan Hospital were retrospectively reviewed. The characteristics of breast cancer according to the expression of <i>BRCA1</i> and <i>BRCA2</i> mutations were analyzed using the Health Insurance Review and Assessment Service guideline criteria and other clinicopathological factors. <b><i>Results:</i></b> The factor associated with <i>BRCA1/2</i> gene expression was cancer stage, and mutation expression was significantly decreased in stage I compared to stage 0 (<i>p</i> = 0.033; odds ratio [OR], 0.169; 95% confidence interval [CI], 0.033–0.867), and there was a tendency to increase in stage II (<i>p</i> = 0.780; OR, 1.150; 95% CI, 0.432–3.064). <i>BRCA1</i> was significantly associated with triple-negative breast cancer (TNBC) (<i>p</i> = 0.004; OR, 5.887; 95% CI, 1.778–19.498). Gene expression of <i>BRCA2</i> was significantly reduced under 40 years of age (<i>p</i> = 0.040; OR, 0.198; 95% CI, 0.042–0.930). There was no difference in disease-free survival (<i>p</i> = 0.900) and overall survival (<i>p</i> = 0.733) between the <i>BRCA1/2</i> mutation-positive and -negative groups. <b><i>Conclusion:</i></b> In this study, the clinicopathological characteristics of breast cancer patients with <i>BRCA1/2</i> gene mutations were identified. <i>BRCA1</i> gene expression was highly correlated with TNBC. <i>BRCA1/2</i> mutation did not have a poor prognosis regarding recurrence and death.
19
Wu, Jiande, Tarun K. K. Mamidi, Lu Zhang, and Chindo Hicks. "Delineation of the Germline and Somatic Mutation Interaction Landscape in Triple-Negative and Non-Triple-Negative Breast Cancer." International Journal of Genomics 2020 (July 7, 2020): 1–16. http://dx.doi.org/10.1155/2020/2641370.
Full textAbstract:
Background. Breast cancer development and progression involve both germline and somatic mutations. High-throughput genotyping and next-generation sequencing technologies have enabled discovery of genetic risk variants and acquired somatic mutations driving the disease. However, the possible oncogenic interactions between germline genetic risk variants and somatic mutations in triple-negative breast cancer (TNBC) and non-triple-negative breast cancer (non-TNBC) have not been characterized. Here, we delineated the possible oncogenic interactions between genes containing germline and somatic mutations in TNBC and non-TNBC and investigated whether there are differences in gene expression and mutation burden between the two types of breast cancer. Methods. We addressed this problem by integrating germline mutation information from genome-wide association studies with somatic mutation information from next-generation sequencing using gene expression data as the intermediated phenotype. We performed network and pathway analyses to discover molecular networks and signalling pathways enriched for germline and somatic mutations. Results. The investigation revealed signatures of differentially expressed and differentially somatic mutated genes between TNBC and non-TNBC. Network and pathway analyses revealed functionally related genes interacting in gene regulatory networks and multiple signalling pathways enriched for germline and somatic mutations for each type of breast cancer. Among the signalling pathways discovered included the DNA repair and Androgen and ATM signalling pathways for TNBC and the DNA damage response, molecular mechanisms of cancer, and ATM and GP6 signalling pathways for non-TNBC. Conclusions. The results show that integrative genomics is a powerful approach for delineating oncogenic interactions between genes containing germline and genes containing somatic mutations in TNBC and non-TNBC and establishes putative functional bridges between genetic and somatic alterations and the pathways they control in the two types of breast cancer.
20
Cummings, Shelly, Jenny Peterson, Elisha Hughes, Rajesh R. Kaldate, Sonia Chen, Jeffrey T. Trost, Christopher Arnell, Jennifer R. Saam, Benjamin Roa, and Priscilla H. Fernandes. "Mutation analysis of PALB2 in high-risk and lower-risk patients negative for BRCA1 and BRCA2 mutations." Journal of Clinical Oncology 30, no. 27_suppl (September 20, 2012): 30. http://dx.doi.org/10.1200/jco.2012.30.27_suppl.30.
Full textAbstract:
30 Background: PALB2 has been identified as a breast cancer susceptibility gene conferring ~ 2-4 fold increased risk of breast cancer. A number of studies have estimated the PALB2 mutation prevalence to range from 0.5% - 2.9% in populations of breast cancer patients. We performed an analysis to determine the PALB2 mutation prevalence in a large U.S. referral testing population. Methods: DNA samples were anonymized from two subsets of patients: 955 early onset breast cancer patients with severe family history, and 524 patients with later onset of breast cancer and/or less severe family history. All patients were negative for deleterious sequence mutations or large rearrangements in BRCA1 and BRCA2. Results: We identified 10 disease associated PALB2 mutations in the high risk group of 955 patients and 2 deleterious PALB2 mutations in the lower risk group of 524 patients. Identified PALB2 mutations included 8 nonsense, 3 frameshift mutations and a splice site mutation. The mutation prevalence for the high risk population was 1.05% (95% C.I., 0.5 -1.92) whereas that for the lower risk population was 0.38% (95% C.I., 0.05-1.37). The observed rate of PALB2 variants of unknown significance (VUS) identified in this study was ~5% (78 VUS were in 75 of the 1479 patients that were tested). Our variant classification program which successfully decreased the VUS rate in BRCA1 and BRCA2 is similarly expected to enhance mutation classification on an on-going basis for PALB2 genetic testing. Conclusions: Genetic testing for PALB2 may be indicated as a reflex test for breast cancer patients who test negative for BRCA1 and BRCA2.
21
Chen, Bo, Guochun Zhang, Guangnan Wei, Yulei Wang, Liping Guo, Jiali Lin, Kai Li, et al. "Heterogeneity of genomic profile in patients with HER2-positive breast cancer." Endocrine-Related Cancer 27, no. 3 (March 2020): 153–62. http://dx.doi.org/10.1530/erc-19-0414.
Full textAbstract:
HER2-positive breast cancer is a biologically and clinically heterogeneous disease. Based on the expression of hormone receptors (HR), breast tumors can be further categorized into HR positive and HR negative. Here, we elucidated the comprehensive somatic mutation profile of HR+ and HR− HER2-positive breast tumors to understand their molecular heterogeneity. In this study, 64 HR+/HER2+ and 43 HR-/HER2+ stage I-III breast cancer patients were included. Capture-based targeted sequencing was performed using a panel consisting of 520 cancer-related genes, spanning 1.64 megabases of the human genome. A total of 1119 mutations were detected among the 107 HER2-positive patients. TP53, CDK12 and PIK3CA were the most frequently mutated, with mutation rates of 76, 61 and 49, respectively. HR+/HER2+ tumors had more gene amplification, splice site and frameshift mutations and a smaller number of missense, nonsense and insertion-deletion mutations than HR-/HER2+ tumors. In KEGG analysis, HR+/HER2+ tumors had more mutations in genes involved in homologous recombination (P = 0.004), TGF-beta (P = 0.007) and WNT (P = 0.002) signaling pathways than HR-/HER2+ tumors. Moreover, comparative analysis of our cohort with datasets from The Cancer Genome Atlas and Molecular Taxonomy of Breast Cancer International Consortium revealed the distinct somatic mutation profile of Chinese HER2-positive breast cancer patients. Our study revealed the heterogeneity of somatic mutations between HR+/HER2+ and HR-/HER2+ in Chinese breast cancer patients. The distinct mutation profile and related pathways are potentially relevant in the development of optimal treatment strategies for this subset of patients.
22
Chen, Jian, Zhaohua Gong, Dengjun Sun, Shujie Song, Weiwei Zhang, Ningning Luo, Qin Zhang, Guanghua Lu, Yingxue Qi, and Yaqing Wu. "The real-world BRCA1/2 germline mutations in Chinese solid tumors." Journal of Clinical Oncology 39, no. 15_suppl (May 20, 2021): e22500-e22500. http://dx.doi.org/10.1200/jco.2021.39.15_suppl.e22500.
Full textAbstract:
e22500 Background: Breast cancer susceptibility genes BRCA1 and 2 are tumor suppressor genes and they play an important role in DNA damage response and repair during homologous recombination. Hereditary breast and ovarian cancer (HBOC) syndrome is an autosomal dominant disease due to BRCA1 and 2 germline mutation. Germline mutations of BRCA1 and 2 genes significantly increase the risk of developing breast cancer, ovarian cancer, prostate cancer and a broad range of cancers. PARP inhibitor (PARPi) monotherapy and combinations have shown promising efficacy against a variety of cancer types with BRCA mutations. Nevertheless, the knowledge of incidence of BRCA1 and 2 germline mutations in solid tumor remains poorly understood. Herein, next generation sequencing of 539-gene profiling was performed to explore the incidence of BRCA1 and 2 germline mutations in Chinese solid tumors. Methods: We retrospectively analyzed the BRCA1 and BRCA2 germline mutations from a comprehensive 539-gene profiling of 8535 Chinese patients with pan-cancer. 539-gene profiling contains the somatic mutations in tumor tissue or blood ctDNA and the germline mutations in blood leukocyte. We screened out the pathogenic and likely pathogenic mutations in BRCA germline mutations, and calculated the mutation frequency and the median age in every cancer type. Results: In 8535 patients with pan-cancer, 110 patients were found pathogenic or likely pathogenic germline mutations in BRCA gene and the mutation frequency was 1.29%, of which 40 BRCA1 mutations and 70 BRCA2 mutations were found in patients, respectively. The total median age was 58.15. Eliminated a few types of cancers that had a smaller number (less than 50), the higher frequency of mutations contained ovarian cancer (14.78%, media age 58), prostatic cancer (6%, media age 58.33), breast cancer (5.2% media age 57.33). The details of the top 8 cancer types with mutation frequency and media age were shown in Table. Conclusions: This was the first report of the incidence of BRCA1 and 2 germline mutations in Chinese solid tumors, which expanded the understanding of BRCA1/2 and provided a direction for clinical trial design of PARPi monotherapy and combinations.[Table: see text]
23
Felix, Gabriela Espirito Santo, Yonglan Zheng, Rodrigo Santa Cruz Guindalini, Taisa Manuela Bonfim Machado-Lopes, Jing Zhang, Juliana Côrtes, Pollyanna Carozo Oliveira, et al. "BROCA gene panel testing in African descendants from northeastern Brazil: Genetic susceptibility profile of an admixed population." Journal of Clinical Oncology 35, no. 15_suppl (May 20, 2017): 1572. http://dx.doi.org/10.1200/jco.2017.35.15_suppl.1572.
Full textAbstract:
1572 Background: The rising global burden of breast cancer (BC) in developing countries demands innovative interventions to accelerate progress in cancer control and prevention. Given the high rates of aggressive young onset breast cancer in Brazil, we sought to examine genetic susceptibility to the disease in the State of Bahia in the Northeast of Brazil, which has the largest population of African descendants. Methods: We screened cases, high-risk breast cancer patients with and without family history of breast cancer, and controls (cancer-free women) for twenty-eight breast cancer susceptibility genes using a validated targeted capture and multiplex sequencing approach – the BROCA panel. Each participant gave informed consent under IRB approved protocols and provided clinical-pathological and epidemiological data. Results: A total of 292 consecutive and unrelated individuals (173 cases and 119 controls) were included. Nearly 2/3rds of the cases (116/173) and about 90% of the controls (108/119) self-reported as African-descendant. Mutations considered pathogenic were identified in 37 (21.4%) cases and in one control (0.84%, RAD51C c.266insA), OR = 27.75 and p = 0.008. The mutated genes in cases were BRCA1 (in 12 patients), BRCA2 (10), ATM (3), PALB2 (3), BRIP1 (3), BRCA2/ BARD1 (1), FAM175A (1), FANCM (1), NBN (1), SLX4 (1) and TP53 (1). Three recurrent mutations accounted for 12.4% (9/37) of the total: 3 BRCA1 c.3331_3334delCAAG (known European mutation), 3 BRCA1 c.211A > G (known Galician mutation), and 3 PALB2c.1671_1674delTATT (novel mutation). Conclusions: Mutations in BRCA1 and BRCA2 (64.85%) or another breast cancer gene (35.15%) occur in one in five high-risk breast cancer patients in the largest study of Northeastern Brazil to date, and a significant proportion were recurrent mutations of European origin, which can be explained by the admixture pattern of the Brazilian population. This result underscores the importance of using multigene panel in cancer genetic epidemiologic research of understudied populations where unexpected findings, such as the recurrent and novel variant in PALB2 c.1671_1674delTATT, can be detected.
24
Pushkarev, A. V., N. I. Sultanbaeva, V. A. Pushkarev, A. F. Nasretdinov, K. V. Menshikov, Sh I. Musin, I. R. Minniakhmetov, I. R. Gilyazova, A. A. Izmailov, and A. V. Sultanbaev. "Spectrum and frequency of BRCA1, BRCA2, CHEK2, PALB2, RAD50 mutations in breast cancer patients in the Republic of Bashkortostan." Kazan medical journal 101, no. 5 (October 27, 2020): 691–97. http://dx.doi.org/10.17816/kmj2020-691.
Full textAbstract:
Aim. To assess the spectrum and frequency of mutations in patients with hereditary breast cancer from the Republic of Bashkortostan.
Methods. The material for the study was sections of fresh frozen, formalin-fixed and paraffin-embedded tumor tissue from 100 unrelated patients with a histologically confirmed diagnosis of breast cancer. The study was carried out using two methods: real-time polymerase chain reaction and next-generation sequencing-NGS.
Results. By using real-time polymerase chain reaction (PCR), the 5382insC mutation in the BRCA1 gene was detected in 12 cases. By using a next-generation sequencing method (NGS), highly penetrant mutations in BRCA1, BRCA2, CHEK2, PALB2 and RAD50 were revealed in 16 patients. In total, these methods detected mutations in 28 patients. Out of a total of probands in the BRCA1 gene, mutations were detected in 13 patients, that included 12 patients with the 5382insC mutation, and 1 patient with c.3143delG. In the BRCA2 gene, mutations were revealed in 3 patients, of which c.6621_6622del in 2 patients and c.-39-1_-39delGA in 1 patient. Mutations in CHEK2 were detected in 5 patients: c.470TC in 3 patients, c.444+1GA in 2 patients. The 1592delT mutation in PALB2 was found in 4 patients. The c.2157delA mutation in RAD50 was detected in 3 patients.
Conclusion. Pathogenic mutations in BRCA1/2, CHEK2, PALB2 and RAD50 were found in 28 patients with a hereditary feature of the disease; the identification of highly penetrant mutations in probands allowed us to determine their relatives, probable carriers of mutations, which were referred for genetic counselling.
25
Dhary Kamel, Maryam, Abbas Abdullah Mohammed, and Ali Abdulhafidh Ibrahim. "Sequence and Structure Analysis of CRP of Lung and Breast Cancer Using Bioinformatics Tools and Techniques." Biosciences, Biotechnology Research Asia 15, no. 1 (March 25, 2018): 163–74. http://dx.doi.org/10.13005/bbra/2620.
Full textAbstract:
In the present study, bioinformatics approach has been adopted to explore the sequences and structures analysis of CRP of lung and breast cancer and compares with normal sequence from NCBI. The present study was aimed to investigate the possibility of using CRP as a marker for patients with lung and breast cancer. Also the effect of mutation on the physicochemical properties and structure of CRP. 40 blood and serum samples were examined from patients with lung and breast cancer (aged between 23and 45 years old). Qualitative test was done to detect the presence of CRP in the patient’s serum. The qualitative test showed that 3 (7.5%) patients give positive result and 37(92.5%) patients with lung and breast cancer give negative result to presence of CRP in the serum.In patient with lung cancer five missense mutations and four deletion mutations detected. While in the patient with lung cancer four missense mutations ,six deletion mutations and eight insertion mutation detected by BLAST.One point mutation appeared in all patients at same site and has same effect, this meaning there are relationship between this mutation and cancer disease. This mutation recorded in NCBI, DDBJ and ENA with the numbers LC276938 and LC276937. The present study determined the physico-chemical properties of CRP such as their hydrophilic nature; alpha–helical structure and 3D structure. The results of present study Show that CRP consider non-specific marker for patient with Lung and breast cancer.Also the mutations on CRP gene effected on the structure and physico-chemical properties of C-reactive protein.
26
Shatova, Yu S., E. A. Chebotareva, E. Yu Zlatnik, I. A. Novikova, D. I. Vodolazhskiy, and E. A. Dzhenkova. "Some clinical morphological and molecular genetic aspects in patients with clinical signs of hereditary breast cancer." Kazan medical journal 99, no. 2 (April 15, 2018): 224–29. http://dx.doi.org/10.17816/kmj2018-224.
Full textAbstract:
Aim. To study the clinical morphological and molecular genetic characteristics of clinically hereditary breast cancer with and without verified mutation of BRCA1, BRCA2 compared to sporadic breast cancer.
Methods. The study included 191 female patients with verified breast cancer stage I-IIA and clinical signs of hereditary breast cancer. In order to identify mutations in genes ВRCA1/2 molecular genetic analysis of deoxyribonucleic acid from peripheral blood leukocytes was performed.
Results. The total frequency of mutations in the genes BRCA1 and ВRCA2 amounted 14.1% of the total number of examined patients. The most common mutation in clinically hereditary breast cancer among residents of the Rostov Region was 5382insC in BRCA1 gene, which corresponds to the nationwide data. Also common features of hereditary breast cancer compared to sporadic breast cancer were identified: young age at the time of disease manifestation, high prevalence of triple-negative cancer, history of infertility, increased level of p53 and androgen receptor expression, decreased level of aneuploid cell and proliferation index in the tumor.
Conclusion. In a number of clinical morphological and molecular genetic parameters, clinically hereditary breast cancer differs from sporadic breast cancer. These indicators in the future can be used as criteria for selection of patients with clinically hereditary breast cancer without confirmed BRCA1/2 mutation by standard panels for in-depth genetic testing.
27
Wu, Qian, Wenjing Jian, Xumei Yao, Xintong Xie, Hanjie Fang, Shengkai Geng, Shufeng Song, et al. "Genetic mutation analysis of plasma circulating tumor DNA by ultra-deep sequencing in breast benign lesions and cancers." Journal of Clinical Oncology 37, no. 15_suppl (May 20, 2019): e14572-e14572. http://dx.doi.org/10.1200/jco.2019.37.15_suppl.e14572.
Full textAbstract:
e14572 Background: Mammography screening for breast cancer results in large number of impalpable lesions without clear determination of the malignancy. Analysis of breast cancer related gene mutations in blood circulating tumor DNA (ctDNA) may provide clarification. This analysis aims to provide insights into the feasibility of the approach. Methods: The clinical trial was conducted at top tier teaching hospitals in China to recruit patients with breast diseases for surgery. Eligible patients were consented and the breast lesions were pathologically diagnosed. Peripheral blood was collected prior to surgical resection. For breast cancer patients, samples of resected tissue were also collected. The samples were analyzed using our proprietary NGS technique called systematic error correction sequencing (Sec-Seq) (detailed in Abstract ##e23057, ASCO 2018). Results: In total, 69 patients with breast lesions (57 malignant and 12 benign) were included in this analysis. Tumor gDNA and plasma ctDNA were analyzed by deep NGS sequencing using a panel of 62 breast cancer-associated genes. The average sequencing depth is 35000. After deduplication, the average number of unique reads is 1500. Detection limit for mutant allele frequency was set at 0.2% for ctDNA and 1% for tumor tissue. For ctDNA mutation detection, 2 out of 12 patients with benign diseases were found with mutations while 10 out of 55 breast cancer patients had no mutations, resulting in an overall sensitivity of 82% and specificity of 83%. By cancer stage, the two Stage 0 (carcinoma in situ) patients had no mutation, and the range of mutations detected is between 53% to 75% from Stage I to III. The tumor tissue samples have higher rate of mutations (only 2 cancer patients, 1 Stage 0 and 1 Stage 2, had no mutations). 15% patients have at least one common mutation detected in both the tumor tissue and ctDNA, and 27% patients have mutations in the same genes in the two matching samples. The concordance increases as the clinical stage advances. The most commonly mutated genes are previously reported breast cancer drivers of PIK3CA (79% of tumor and 18% of ctDNA samples), TP53 (56% and 39%), and BRCA1 (6% and 15%). Conclusions: In this hypothesis generating analysis, we showed the feasibility of plasma ctDNA sequencing for gene mutation detection in early stage breast cancer and differentiation from the benign breast diseases. Although with limited number of samples, the data encourage further improvement of the gene panel and the validation of ctDNA assay as a non-invasive approach to the cancer screening. Clinical trial information: ChiCTR1800017345.
28
Schwartzberg, Lee S., and Lesli A. Kiedrowski. "Olaparib in hormone receptor-positive, HER2-negative metastatic breast cancer with a somatic BRCA2 mutation." Therapeutic Advances in Medical Oncology 13 (January 2021): 175883592110069. http://dx.doi.org/10.1177/17588359211006962.
Full textAbstract:
The oral poly(adenosine diphosphate-ribose) polymerase inhibitor olaparib is approved for the treatment of patients with human epidermal growth factor 2-negative (HER2−) metastatic breast cancer (mBC) and a germline breast cancer susceptibility gene (BRCA) mutation who have been treated with chemotherapy. This case report describes a 63-year-old postmenopausal woman with somatic BRCA2-mutated mBC who responded to olaparib treatment following multiple prior lines of therapy. The patient presented in January 2012 with locally advanced, hormone receptor-positive (HR+), HER2− BC which, despite initial response to neoadjuvant chemotherapy, recurred as bone disease in February 2014, and subsequently skin (June 2016) and liver (October 2016) metastases. A comprehensive 592-gene next-generation sequencing panel (Caris Life Sciences), performed on a skin biopsy, detected a pathogenic frameshift mutation in BRCA2 (H3154fs, c.9460delC), which was not identified in a 28-gene hereditary cancer germline analysis (Myriad Genetics, Inc.), and was therefore considered to be a somatic mutation. In January 2017, cell-free DNA (cfDNA) analysis (Guardant Health, Inc.) confirmed the BRCA2 H3154fs mutation in plasma. After several lines of chemotherapy and endocrine therapy, deriving clinical benefit from eribulin and capecitabine, the disease progressed by October 2017, and olaparib (300 mg orally twice daily) was initiated in January 2018. By April 2018, the liver lesions had shrunk by 80% and a >90% response in multiple skin lesions was noted. Clinical response was maintained for 8 months, followed by progression in the skin in September 2018. Biopsy of recurrent lesions revealed a novel BRCA2 mutation, E3152del (c.9455_9457delAGG), predicted to restore the open reading frame and presumably the mechanism of resistance to olaparib. Further likely resistance mutations were noted in subsequent cfDNA analyses. This case demonstrated a clinical response with olaparib as a later-line therapy for HR+, HER2− mBC with a somatic BRCA2 mutation.
29
Adedokun, B., Y. Zheng, P. Ndom, A. Gakwaya, T. Makumbi, A. Sallam, O. Olopade, and D. Huo. "Prevalence and Spectrum of Breast Cancer Inherited Mutations in Uganda and Cameroon Women." Journal of Global Oncology 4, Supplement 2 (October 1, 2018): 43s. http://dx.doi.org/10.1200/jgo.18.60600.
Full textAbstract:
Background: Breast cancer among indigenous Africans is characterized by higher prevalence of triple-negative disease and poor prognosis. A previous study in Nigeria reported a strikingly high prevalence of deleterious germline mutations in BRCA1 and BRCA2 among Nigerian women with breast cancer. It is unknown if this is true in other sub-Saharan African countries. Aim: The objective of this study is to determine the frequency of germline mutations among an unselected sample of women in Africa. Methods: We conducted a case-control study of breast cancer in Uganda and Cameroon to investigate genetic and nongenetic risk factors for breast cancer. Breast cancer cases were enrolled in two tertiary hospitals in the two countries, unselected for age at diagnosis and family history. Controls who were free of breast cancer were enrolled in the same hospitals and matched to cases on age. A 24-gene sequencing panel was used to test germline mutations in cases and controls. Results: There were 176 cases and 177 controls with a mean age at diagnosis of 46.2 years for cases and mean age at interview of 46.7 years for controls. Among cases, 18.2% carried a pathogenic mutation in a breast cancer gene: 6.3% in BRCA1, 6.3% in BRCA2, 1.7% in ATM, 1.1% in PALB2, 0.6% in BARD1, 0.6% in CDH1, 0.6% in TP53, and 1.2% in any of 17 other genes. Among controls, 2.3% carried a pathogenic mutation in one of the 24 susceptibility genes. Cases were 9.6-fold more likely to carry a mutation compared with controls (odds ratio=9.61, 95% confidence interval: 3.28-38.1; P < 0.001). The mean age of breast cancer cases with pathogenic BRCA1 mutations was 38.3 years compared with 46.7 years among other cases without such mutations ( P = 0.03). There was a trend that cases with a positive family history had higher chance of carrying a mutation (33.3%) than cases without (17.1%), but few cases reported a positive family history. Conclusion: Our findings confirm the earlier report of a high proportion of deleterious mutations in BRCA1 and BRCA2 among breast cancer patients in sub-Saharan Africa. As most of these women present with advanced breast cancer, there is an urgent need to improve access to genomic testing and life saving cancer medicines including chemotherapy and clinical trials of novel agents like PARP inhibitors. Given the high burden of inherited breast cancer, genetic risk assessment should be integrated into cancer control plans in sub-Saharan Africa.
30
Abulkhair, Omalkhair A. M. "BRCA 1 and BRCA 2 mutations in Saudi breast cancer patients (single institution)." Journal of Clinical Oncology 32, no. 26_suppl (September 10, 2014): 10. http://dx.doi.org/10.1200/jco.2014.32.26_suppl.10.
Full textAbstract:
10 Background: Breast cancer is the commonest malignancy among Saudi females accounting for 25% of all female cancers with a median age at diagnosis of 47 years (1,2). In Saudi, breast cancer showed an increased incidence attributed to many factors such as different lifestyles, reproductive pattern, family history, which was reported to account for 59%, dietary or cultural practice of Saudi women (2,3,4,5). The multifunctional and highly penetrant BRCA 1 and BRCA 2 are the two major breast cancer pre-disposition genes, accounting for about 20% of breast cancer families (6,7). To our knowledge, the prevalence of BRCA 1 and BRCA 2 mutations in native Saudi population is sparse (8,9). Our aim is to describe the findings of BRCA mutation testing in native Saudi patients with breast cancer in a large Ministry of National Guard Health Affairs (NGHA) community-based teaching hospital. Methods: In this study, 75 out of 516 patients with breast cancer who were clinically and histopathologically diagnosed at NGHA from October 2010 to April 2014 were included. Selection criteria: aged ≤ 40 years bilateral breast cancer, triple-negative breast cancer, strongly first degree family history at young age and male breast cancer. Molecular alterations were performed by direct gene sequencing, multiple ligation – dependent probe amplification (MLPA) at Bioscentia human genetic testing in Germany. Results: 75 native Saudi were enrolled and test performed for them. 18 patients (24%) were found to have mutation of which 10 in BRCA One and six in BRCA 2. Two have both BRCA 1 and BRCA 2. Seven patients have the same with deleterious mutations in BRCA 1 gene. Two of them are mother and daughter and other five are unrelated. The mean age of breast cancer diagnosis in the mutation carriers was 38 years. Triple negative breast cancer (TNBC) diagnosed in six patients, bilateral breast cancer diagnosed in one, first-degree family history in eight and second degree in 10 patients and four with no family history. Conclusions: BRCA 1 and BRCA 2 mutations are an important contributor to the etiology of breast cancer in Saudi women. A mutation in BRCA 1, C 1648 > C p, Asn550His in exon 10 has been reported as disease causing (11) and it is found in our study in seven patients. Such mutation might be specific for Saudi, so further studies are highly recommended.
31
Millikan, R., B. Hulka, A. Thor, Y. Zhang, S. Edgerton, X. Zhang, H. Pei, M. He, L. Wold, and L. J. Melton. "p53 mutations in benign breast tissue." Journal of Clinical Oncology 13, no. 9 (September 1995): 2293–300. http://dx.doi.org/10.1200/jco.1995.13.9.2293.
Full textAbstract:
PURPOSE Patients with benign breast biopsies that exhibit atypical epithelial proliferation or fibroadenoma may be at increased risk for invasive breast cancer. We hypothesized that molecular markers might also be useful to evaluate the malignant potential of nonneoplastic breast tissue. PATIENTS AND METHODS Study subjects belonged to a cohort of 6,805 women who underwent biopsy for nonmalignant breast disease at the Mayo Clinic and Rochester-affiliated hospitals between 1967 and 1981. As part of a nested case-control study that compared subjects who developed invasive breast cancer with those who did not, we analyzed a sample of 60 benign breast biopsies for the following markers: HER-2/neu and p53 over-expression by immunohistochemistry, HER-2/neu and PRAD-1 amplification using differential polymerase chain reaction (PCR), and p53 mutation using single-strand conformation analysis (SSCA) and direct DNA sequencing by asymmetric PCR. RESULTS None of 60 biopsies showed amplification of HER-2/neu or PRAD-1. Five samples exhibited low-level immunoreactivity to the HER-2/neu protein product. Fourteen samples exhibited focal or diffuse immunoreactivity to the p53 protein. Point mutations in the p53 gene were found in five samples: three of these samples exhibited mutations that altered the amino acid sequence. Only two of five samples with p53 mutation exhibited p53 overexpression. Histologic diagnoses on three samples with nonconservative p53 mutation were, respectively, nonproliferative fibrocystic change, papillomatous hyperplasia, and fibroadenoma. CONCLUSION The clinical significance of p53 mutation, p53 overexpression, and low-level HER-2/neu expression in benign breast tissue remains to be determined. Further research will be necessary to evaluate whether these markers could serve as useful adjuncts to histology in evaluation of the malignant potential of benign breast tissue.
32
Fentiman, Ian S. "Male breast cancer: a neglected disease." Breast Cancer Management 8, no. 4 (December 1, 2019): BMT32. http://dx.doi.org/10.2217/bmt-2019-0020.
Full textAbstract:
Male breast cancer (MBC) is rare, tending to afflict sedentary men, with adolescent obesity being a risk factor. Men fare worse compared with matched females with breast cancer. The preponderance of ER+ve disease affects the molecular profile: most cases have luminal A tumors. Through male ignorance and risk-taking, delay is frequent and this lacuna needs addressing with health education. The major gene mutation responsible for MBC is BRCA2. Five single nucleotide polymorphisms (SNPs) are significantly and uniquely associated with MBC risk with two located in the 8q24.21 regions. Mastectomy is being gradually replaced by nipple-preserving surgery and radiotherapy but this trend could be expedited with neoadjuvant endocrine therapy. Significant advances will occur only after expansion of collaborative groups and this is a matter of pressing importance.
33
Skop, Michelle, Justin Lorentz, Mobin Jassi, Danny Vesprini, and Gillian Einstein. "“Guys Don’t Have Breasts”: The Lived Experience of Men Who Have BRCA Gene Mutations and Are at Risk for Male Breast Cancer." American Journal of Men's Health 12, no. 4 (February 5, 2018): 961–72. http://dx.doi.org/10.1177/1557988317753241.
Full textAbstract:
Men with BRCA1 or BRCA2 gene mutations are at increased risk of developing breast cancer and may have an indication for breast cancer screening using mammography. Since breast cancer is often viewed as a woman’s disease, visibilizing and understanding men’s experience of having a BRCA mutation and specifically, of screening for breast cancer through mammography, were the objectives of this research study. The theoretical framework of interpretive phenomenology guided the process of data collection, coding, and analysis. Phenomenology is both a philosophy and research method which focuses on understanding the nature of experience from the perspectives of people experiencing a phenomenon, the essence of and commonalities among people’s experiences, and the ways in which people experience the world through their bodies. Data were collected via in-depth interviews with a purposive sample of 15 male participants recruited from the Male Oncology Research and Education (MORE) Program. This article reports findings about participants’ use of gender-specific language to describe their breasts, awareness of the ways in which their bodies changed overtime, and experiences of undergoing mammograms. This study is the first to describe men with BRCA’s perceptions of their breasts and experiences of mammography in a high-risk cancer screening clinic. This study sheds light on an under-researched area—breasts and masculinities—and could potentially lead to improved clinical understanding of men’s embodied experiences of BRCA, as well as suggestions for improving the delivery of male breast cancer screening services.
34
Corman, Vinciane, Iulia Potorac, Florence Manto, Sarah Dassy, Karin Segers, Albert Thiry, Vincent Bours, Adrian F. Daly, and Albert Beckers. "Breast cancer in a male-to-female transsexual patient with a BRCA2 mutation." Endocrine-Related Cancer 23, no. 5 (May 2016): 391–97. http://dx.doi.org/10.1530/erc-16-0057.
Full textAbstract:
Breast cancer is rare in male patients. Certain predisposing factors, be they genetic (e.g., BRCA2 gene mutations) or hormonal (imbalance between estrogen and androgen levels), have been implicated in male breast cancer pathophysiology. Male-to-female (MtF) transsexualism is a condition that generally involves cross-sex hormone therapy. Anti-androgens and estrogens are used to mimic the female hormonal environment and induce the cross-sex secondary characteristics. In certain situations, the change in the hormonal milieu can be disadvantageous and favor the development of hormone-dependent pathologies, such as cancer. We report a case of a MtF transgender patient who developed breast cancer after 7 years of cross-sex hormonal therapy. The patient was found to be BRCA2 positive, and suffered recurrent disease. The patient was unaware of being a member of an established BRCA2 mutation-positive kindred. This represents the first case of a BRCA2 mutation predisposing to breast cancer in a MtF transgender patient.
35
Goelen, Guido, Adelheid Rigo, Maryse Bonduelle, and Jacques De Grève. "Moral Concerns of Different Types of Patients in Clinical BRCA1/2 Gene Mutation Testing." Journal of Clinical Oncology 17, no. 5 (May 1999): 1595. http://dx.doi.org/10.1200/jco.1999.17.5.1595.
Full textAbstract:
PURPOSE: Implementing predictive genetic testing for a severe and common chronic disease such as breast cancer may raise unique ethical problems. Here we report on moral concerns experienced by patients in the setting of genetic counseling based on BRCA1/2 gene testing. PATIENTS AND METHODS: Patients were members of breast or breast/ovarian cancer families in a consecutive series of 100 families who received counseling at a familial cancer clinic. The patients' moral concerns were identified using the grounded theory approach in the qualitative analysis of verbal transcripts of 45 counseling sessions. Included were sessions with patients who had breast and ovarian cancer, as well as their male and female relatives, before and after the specific BRCA1/2 gene mutation was identified in the family, and before and after those who opted for mutation analysis were informed of their carrier status. RESULTS: There is an association of BRCA1/2 gene mutation carrier status and specific topics of moral concern. The moral preoccupations of patients with breast and ovarian cancer (probable carriers) related to their being instrumental in the detection of the specific mutation segregating in the family. The preoccupations of possible carriers concerned their own offspring. Individuals who tested positive (proven carriers) were concerned with issues of confidentiality. Patients who tested negative (proven noncarriers) were concerned with helping siblings and other relatives. CONCLUSION: Knowledge of the moral concerns of subjects in the study sample may help health care providers be aware of the moral concerns of their own patients. This report may also contribute to the debate on predictive testing for familial adult-onset diseases from the patient's perspective.
36
Hart, Lowell L., Kai Treuner, Li Ma, Jenna Wong, Catherine A. Schnabel, and James Andrew Reeves. "Integration of molecular cancer classification and next-generation sequencing to identify metastatic patients eligible for PARP inhibitors." Journal of Clinical Oncology 39, no. 15_suppl (May 20, 2021): e15080-e15080. http://dx.doi.org/10.1200/jco.2021.39.15_suppl.e15080.
Full textAbstract:
e15080 Background: Olaparib, rucaparib, and niraparib are 3 poly-ADP-ribose polymerase inhibitors (PARPi) approved by the FDA for ovarian, breast, pancreatic, prostate, fallopian tube and peritoneal cancers with BRCA mutations. Several ongoing clinical trials aim to determine the efficacy of PARPi in various other cancer types, including specific cancer subtypes, such as clear cell renal cell carcinoma and cholangiocarcinoma either as monotherapy or combination therapy; however, eligibility for PARPi therapy requires the identification of the primary tumor type and confirmation of BRCA mutation. The 92-gene assay (CancerTYPE ID) is a validated gene expression classifier of 50 tumor types and subtypes for metastatic patients with unknown or uncertain diagnoses. Multimodal biomarker testing, including next-generation sequencing (NGS), enables identification of actionable biomarkers to guide targeted therapy selection. In the current study, a database of metastatic cases that integrates tumor type with biomarker analysis was characterized to identify those eligible for PARPi treatment. Methods: MOSAIC (Molecular Synergy to Advance Individualized Cancer Care) is an IRB-approved, de-identified database of cases submitted for CancerTYPE ID testing with tissue-guided multimodal biomarker testing by NGS, including tumor mutational burden (TMB) fluorescent in situ hybridization (FISH), and microsatellite instability (MSI), and immunohistochemistry (IHC) (NeoTYPE profiles, Neogenomics). For the current study, metastatic cancers classified as ovarian, breast, pancreatic, or prostate were identified in the database, followed by NGS analysis to detect mutations in BRCA1 or BRCA2. Results: The current analysis included 2151 CancerTYPE ID cases, from which 71 ovarian, 47 breast, 12 pancreatic and 15 prostate cancer cases were identified. Out of 46 cases of ovarian cancer with molecular biomarker results, NGS identified 7 (15.3%) cases with BRCA1 mutation and 4 (8.7%) cases with BRCA2 mutation. Additionally, 4 (10.5%) cases with BRCA1 mutation and 1 (2.6%) case with BRCA2 mutation out of 38 cases of breast cancer with BRCA results were detected. No cases of prostate cancer or pancreatic cancer with mutations in BRCA1 or BRCA2 were detected. Conclusions: These findings in metastatic patients demonstrate the clinical utility of tumor type identification combined with molecular biomarker profiling, leading to additional options for patients with advanced disease. Specifically, analysis of the MOSAIC database identified a subset of patients with metastatic cancers eligible for PARPi therapy based on tumor type and BRCA mutation status. As new and approved PARPi are evaluated for efficacy in additional tumor types, patients can be identified that may be eligible for these targeted cancer drugs.
37
Kim, Yong-Chan, Sae-Young Won, and Byung-Hoon Jeong. "Identification of Prion Disease-Related Somatic Mutations in the Prion Protein Gene (PRNP) in Cancer Patients." Cells 9, no. 6 (June 17, 2020): 1480. http://dx.doi.org/10.3390/cells9061480.
Full textAbstract:
Prion diseases are caused by misfolded prion protein (PrPSc) and are accompanied by spongiform vacuolation of brain lesions. Approximately three centuries have passed since prion diseases were first discovered around the world; however, the exact role of certain factors affecting the causative agent of prion diseases is still debatable. In recent studies, somatic mutations were assumed to be cause of several diseases. Thus, we postulated that genetically unstable cancer tissue may cause somatic mutations in the prion protein gene (PRNP), which could trigger the onset of prion diseases. To identify somatic mutations in the PRNP gene in cancer tissues, we analyzed somatic mutations in the PRNP gene in cancer patients using the Cancer Genome Atlas (TCGA) database. In addition, to evaluate whether the somatic mutations in the PRNP gene in cancer patients had a damaging effect, we performed in silico analysis using PolyPhen-2, PANTHER, PROVEAN, and AMYCO. We identified a total of 48 somatic mutations in the PRNP gene, including 8 somatic mutations that are known pathogenic mutations of prion diseases. We identified significantly different distributions among the types of cancer, the mutation counts, and the ages of diagnosis between the total cancer patient population and cancer patients carrying somatic mutations in the PRNP gene. Strikingly, although invasive breast carcinoma and glioblastoma accounted for a high percentage of the total cancer patient population (9.9% and 5.4%, respectively), somatic mutations in the PRNP gene have not been identified in these two cancer types. We suggested the possibility that somatic mutations of the PRNP gene in glioblastoma can be masked by a diagnosis of prion disease. In addition, we found four aggregation-prone somatic mutations, these being L125F, E146Q, R151C, and K204N. To the best of our knowledge, this is the first specific analysis of the somatic mutations in the PRNP gene in cancer patients.
38
Ni, Ying, Spencer Seballos, Shireen Ganapathi, Danielle Gurin, Benjamin Fletcher, Joanne Ngeow, Rebecca Nagy, et al. "Germline and somatic SDHx alterations in apparently sporadic differentiated thyroid cancer." Endocrine-Related Cancer 22, no. 2 (January 5, 2015): 121–30. http://dx.doi.org/10.1530/erc-14-0537.
Full textAbstract:
Along with breast and endometrial cancers, thyroid cancer is a major component cancer in Cowden syndrome (CS). Germline variants in SDHB/C/D (SDHx) genes account for subsets of CS/CS-like cases, conferring a higher risk of breast and thyroid cancers over those with only germline PTEN mutations. To investigate whether SDHx alterations at both germline and somatic levels occur in apparently sporadic breast cancer and differentiated thyroid cancer (DTC), we analyzed SDHx genes in the following four groups: i) 48 individuals with sporadic invasive breast adenocarcinoma for germline mutation; ii) 48 (expanded to 241) DTC for germline mutation; iii) 37 pairs DTC tumor-normal tissues for germline and somatic mutation and mRNA expression levels; and iv) data from 476 patients in the Cancer Genome Atlas thyroid carcinoma dataset for validation. No germline SDHx variant was found in a pilot series of 48 breast cancer cases. As germline SDHx variants were found in our pilot of 48 thyroid cancer cases, we expanded to three series of DTC comprising a total 754 cases, and found 48 (6%) with germline SDHx variants (P<0.001 compared with 0/350 controls). In 513 tumors, we found 27 (5%) with large somatic duplications within chromosome 1 encompassing SDHC. Both papillary and follicular thyroid tumors showed consistent loss of SDHC/D gene expression (P<0.001), which is associated with earlier disease onset and higher pathological-TNM stage. Therefore, we conclude that both germline and somatic SDHx mutations/variants occur in sporadic DTC but are very rare in sporadic breast cancer, and overall loss of SDHx gene expression is a signature of DTC.
39
Watson, Patrice, Rita Lieberman, Carrie Snyder, Vanessa J. Clark, Henry T. Lynch, and Jeffrey T. Holt. "Detecting BRCA2 Protein Truncation in Tissue Biopsies to Identify Breast Cancers That Arise in BRCA2 Gene Mutation Carriers." Journal of Clinical Oncology 27, no. 24 (August 20, 2009): 3894–900. http://dx.doi.org/10.1200/jco.2008.20.5211.
Full textAbstract:
Purpose Mutations in the BRCA2 gene are dominantly inherited but cause cancers when the wild-type allele has loss of heterozygosity (LOH) within the cancer. Because most disease-associated BRCA2 mutations are protein-truncating mutations, a test for truncated BRCA2 proteins should identify most BRCA2 hereditary cancers. Methods We have developed a tissue truncation test to identify truncated BRCA2 proteins in breast cancer tissue biopsies in vivo that does not use amplification or genetic manipulations. N-terminal and C-terminal antibodies are used to visualize protein truncation by demonstrating that the beginning of the protein is present but the end (ie, terminus) is absent. Results A quantitative C-terminal immunostaining score or a C-terminal to N-terminal truncation ratio correctly classified 20 of 21 breast cancers arising in BRCA2 mutation carriers and 57 of 58 cancers arising outside the context of a multiple-case breast cancer family. This represents a sensitivity of 95% and a specificity of 98%. Because of the presence of C-terminal BRCA2 protein and atypical clinical features of the misclassified cancer in a BRCA2 mutation carrier, we performed polymerase chain reaction and sequence analyses on this cancer. The results showed continued presence of the BRCA2 wild-type allele in the cancer, which indicated that intact BRCA2 protein was present in this cancer. Conclusion This immunohistochemistry-based test (which takes only 4 hours) appears to identify BRCA2 hereditary cancer with high accuracy. The test also appears to diagnose the biochemical loss of BRCA2 protein in cancers (ie, BRCA2-mutant genotype), which will usually but not always agree with the presence of a germline BRCA2 mutation found by susceptibility testing by DNA sequencing of blood samples.
40
Guttery, David S., Karen Page, Allison Hills, Laura Woodley, Stephanie D. Marchese, Basma Rghebi, Robert K. Hastings, et al. "Noninvasive Detection of Activating Estrogen Receptor 1 (ESR1) Mutations in Estrogen Receptor–Positive Metastatic Breast Cancer." Clinical Chemistry 61, no. 7 (July 1, 2015): 974–82. http://dx.doi.org/10.1373/clinchem.2015.238717.
Full textAbstract:
Abstract BACKGROUND Activating mutations in the estrogen receptor 1 (ESR1) gene are acquired on treatment and can drive resistance to endocrine therapy. Because of the spatial and temporal limitations of needle core biopsies, our goal was to develop a highly sensitive, less invasive method of detecting activating ESR1 mutations via circulating cell-free DNA (cfDNA) and tumor cells as a “liquid biopsy.” METHODS We developed a targeted 23-amplicon next-generation sequencing (NGS) panel for detection of hot-spot mutations in ESR1, phosphatidylinositol-4,5-bisphosphate 3-kinase, catalytic subunit alpha (PIK3CA), tumor protein p53 (TP53), fibroblast growth factor receptor 1 (FGFR1), and fibroblast growth factor receptor 2 (FGFR2) in 48 patients with estrogen receptor-α–positive metastatic breast cancer who were receiving systemic therapy. Selected mutations were validated using droplet digital PCR (ddPCR). RESULTS Nine baseline cfDNA samples had an ESR1 mutation. NGS detected 3 activating mutations in ESR1, and 3 hot-spot mutations in PIK3CA, and 3 in TP53 in baseline cfDNA, and the ESR1 p.D538G mutation in 1 matched circulating tumor cell sample. ddPCR analysis was more sensitive than NGS and identified 6 additional baseline cfDNA samples with the ESR1 p.D538G mutation at a frequency of <1%. In serial blood samples from 11 patients, 4 showed changes in cfDNA, 2 with emergence of a mutation in ESR1. We also detected a low frequency ESR1 mutation (1.3%) in cfDNA of 1 primary patient who was thought to have metastatic disease but was clear by scans. CONCLUSIONS Early identification of ESR1 mutations by liquid biopsy might allow for cessation of ineffective endocrine therapies and switching to other treatments, without the need for tissue biopsy and before the emergence of metastatic disease.
41
Gorodetska, I. V., S. V. Serga, E. O. Stakhovsky, O. A. Kononenko, O. E. Stakhovsky, M. V. Pikul, S. V. Demydov, and I. A. Kozeretska. "Mutation 6174delT in the BRCA2 gene in men with prostate cancer in Ukraine." Faktori eksperimental'noi evolucii organizmiv 23 (September 9, 2018): 182–85. http://dx.doi.org/10.7124/feeo.v23.1011.
Full textAbstract:
Aim. Mutations in BRCA1/2 genes are known to increase the risk of human breast cancer, pancreatic cancer and prostate cancer. In Ukraine only mutations in woman BRCA1/2 were studied, thus the situation with these diseases related to disturbance of these genes in Ukrainian men remains poorly explored. 6174delT is a frameshift mutation and is results in stop of transcription and translation of the functional protein BRCA2. Methods. Genomic DNA was purified from peripheral blood.We performed PCR analysis of 116 DNA from men with prostate cancer in order to detect presence of mutation in BRCA2 gene (6174delT). To detect the mutation by mutagenically separated PCR, we used two PCR reactions. The first reaction used one general primer and one primer specific to the mutation, and the second reaction was with one general primer and one primer specific to the wild type allele. Results. Among screened samples no mutations in the BRCA2 gene were found in prostate cancer patients. Conclusions. Our results suggest that the incidence of this event is not more than 0.9% among men with prostate cancer inUkraine.
Keywords: mutation, 6174delT, BRCA2, prostate cancer, Ukraine.
42
Brankovic-Magic, Mirjana, Jelena Dobricic, Radmila Jankovic, Irene Konstantopoulou, Drakoulis Yannoukakos, and Sinisa Radulovic. "Identifying and testing for hereditary susceptibility to breast/ovarian cancer in Serbia: Where are we now?" Archive of Oncology 14, no. 3-4 (2006): 131–35. http://dx.doi.org/10.2298/aoo0604131b.
Full textAbstract:
About 90% of all breast cancers can be considered as sporadic, without inherited gene alteration. The rest of breast cancers (about 5 to 10%) are considered hereditary, most commonly caused by alterations of BRCA1/2 tumor suppressor genes. Lifetime risks for breast and ovarian cancers are increased among BRCA1/2 mutation carriers - 4 to 8 and 10 to 20 fold higher respectively. Due to the small proportion of hereditary form of disease, as well as to the high cost, BRCA testing is not screening test for general population. It is addressed to selected part of population that fit to recommended criteria. Full coding region sequencing of both genes is "gold standard" for detection of BRCA mutation. Concerning BRCA testing in Serbia, complete or partial sequencing of BRCA1/2 coding region was performed in 60 samples. The presence of 4 BRCA1 known mutations, previously detected elsewhere, has been shown: 185delAG, C61G, 3447del4 and 5382insC (detected twice). In BRCA1 gene, exon 16, an unclassified variant M1652I was found. Polymorphic variants in BRCA1 (8 polymorphisms) and BRCA2 (5 polymorphisms) genes were also detected. The majority of found BRCA1 and BRCA2 polymorphic variants are the missense ones and their influence on breast/ovarian cancer risk in our population has to be proved. Identification of BRCA mutations carriers and establishment of spectra and frequency of BRCA mutations should enable introduction of BRCA1/2 testing into the clinical practice of Serbia. .
43
Kirichek, Svetlana, Andrey Kirichek, and Daniil Korabelnikov. "Identification of BRCA- and CHEK2-related breast cancer and ovarian cancer in women in outpatient oncology clinical practice." Russian Medical and Social Journal 1, no. 1 (July 1, 2019): 22–30. http://dx.doi.org/10.35571/rmsj.2019.1.002.
Full textAbstract:
Introduction. Currently breast cancer is considered a heterogeneous disease and spectrum of several biological subtypes. Ovarian cancer is also characterized by a variety of molecular genetic alterations. Both diseases remain the leading specific causes of death in age group 40-49 and 50-59 for females.
Objective: to evaluate the frequency of mutations in the genes BRCA1/2 and CHEK2 in patients with breast cancer and patients with ovarian cancer, as well as in women with benign neoplasms of the mammary glands, and to analyze their clinical and morphological correlations with the disease characteristics in the routine clinical practice of an outpatient oncologist.
Patients and Methods: Seventy-six women were included in the present analysis. All of them were observed by the oncologist in Consultative and diagnostic center of Burdenko Main Military Clinical Hospital (Moscow) between January 2016 and May 2019, and were divided in three groups: patients with breast cancer (n=20), patients with ovarian cancer (n=17) and control group of women with benign neoplasms of the mammary glands (fibrocystic mastopathy in 29, breast fibroadenoma in 11), with no history of any oncological disease. One patient has metachronous malignant neoplasms of independent (primary) multiple sites: breast and ovarian cancer. All women were genotyped for pathogenic germline mutations 185delAG, 300T>C (Cyse61Gly), 2080delA, 3819delGTAAA, 3875delGTCT, 4153delA, 5382InsC in the gene BRCA1, mutation 6174delT in the gene BRCA2 and mutations IVS2+1G>A, I157T and IVS2+1G>A in the gene CHEK2 by polymerase chain reaction real-time using a set “OncoGenetics” (LLC «Research and Production Company DNA-Technology», Russia, registration certificate № 2010/08415).
Results: Pathogenic germline BRCA1 mutations were identified in 4 (20%) patients with breast cancer, 3 (17,6%) patients with ovarian cancer and 1 (2,5%) women with breast fibroadenoma. Pathogenic germline CHEK2 mutations were identified in 3 (15%) patients with breast cancer, all cases were represented by the I157T mutation. In the control group carriers of BRCA1 or BRCA2 mutations (n=2) were associated with early onset development of breast fibroadenoma in the age before 30 years. The risk of BRCA or CHEK2 mutated genes was significant higher in patients with breast cancer (45%, HR 9.0, 95% CI: 2.14 - 37.8) compared with the control group of women with benign breast tumors (5%, p <0.001). The risk of BRCA or CHEK2 mutations was also higher in patients with ovarian cancer (17.6%, HR 3.53, 95% CI: 0.65 – 19.26) compared with the control group (5%), but the difference did not reach significance (p=0.151).
Genotyping BRCA and CHEK2 results were correlated (r = 0.423) with a family history: mutations were more often detected in women with a family history of cancer (42.9% versus 7.3%, p = 0.001).
Women with identified mutations showed an increased risk of early onset cancer development before the age of 50 years (69.2%, HR 4.33, 95% CI: 1.64 - 11.36, p = 0.003) compared with wild-type carriers BRCA and CHEK2 genes (16%).
The only case of primary multiple metachronous malignant tumors of the breast and ovaries, as well as cases of bilateral breast cancer lesions were detected only among carriers of BRCA1/2 mutations.
The prevalence of aggressive high grade cancer was higher in patients with BRCA and CHEK2 mutations (63.6%, HR 2.45, 95% CI: 0.87 - 6.90) than in patients with wild type genes (47.1 %), however, the difference did not reach significance (p = 0.141).
Conclusions: Our results have shown the relevance and value of identifying for BRCA- and CHEK2-related breast cancer and ovarian cancer in women in everyday clinical practice. The vast majority of cases of breast and ovarian cancer among carriers of BRCA1/2 and CHEK2 mutations are found in the working and reproductive age of women and are associated with unfavorable disease characteristics - high grade and lower survival.
44
Sant'Ana, Rosane Oliveira, Isabelle Joyce de Lima Silva-Fernandes, Maria Claudia dos Santos Luciano, Paulo Goberlanio de Barros Silva, and Marcos Venício Alves Lima. "Pathological complete response (pCR) after neoadjuvant chemotherapy (NAC) for advanced breast cancer patients with high risk for Hereditary Breast and Ovarian Cancer Syndrome (HBOC)." Journal of Clinical Oncology 38, no. 15_suppl (May 20, 2020): e13549-e13549. http://dx.doi.org/10.1200/jco.2020.38.15_suppl.e13549.
Full textAbstract:
e13549 Background: Local Advanced Breast Cancer (LABC) is associated with high risk of death. NAC is a safe and effective approach for these populations. pCR is a proven prognostic factor in several studies of NAC. HBOC is associated to high risk of breast cancer usually in young age and especially for BRCA1 mutations with a basal phenotype. The aim of this study was to evaluate the influence of BRCA mutational status on frequence of pCR. Methods: this is part of a retrospective, observational study of prevalence of HBOC among patients admitted for cancer therapy in our institution. Since August, 2018 over 300 pte suspected for HBOC (by NCCN criteria) have been screened for NGS with a 31-gene painel. Statistical analysis performed Person X2/Fisher and logistic regression ( p< 0.05; SPSS 20.0). Results: Most pte were women (80%), with median age of 38y (22-72y), most tumors were (80%) stage III, Luminal B (23%) and TNBC (36%). Pathogenic mutations were identified in 34%(n = 28) of the sample ( BRCA1 50%, BRCA2 16.7%, PALB2 16.7%, follow by TP53, PMS2, XRCC2, MUTYH, BARD1 and ATM with 2.8% each).The majority of patients had more than 1 NCCN criteria: age < 45y (83%), family member with BC < 50y (24%) or TNBC (33%) the most common. TNBC tumors had stronger association with germline mutation ( p< 0.001). Regarding response rate there were 13 stable disease (SD), 5 progressive disease (PD), 43 pCR and 39 pathological partial response (pPR). There were no differences in pRC among mutated or no mutated pte, p= 0,170. However, among mutated TNBC there were strong correlation with more pCR, p< 0,006. There was no difference on pCR rate related to mutation status (BRCA vs Non-BRCA), p = 0,84. Conclusions: the present study corroborates other data about the impact of germline mutation status over pCR after NAC for LABC, except for mutated TNBC population, whose seems to be more NAC sensitive.
45
Rebbeck, Timothy R., Tara Friebel, Henry T. Lynch, Susan L. Neuhausen, Laura van ’t Veer, Judy E. Garber, Gareth R. Evans, et al. "Bilateral Prophylactic Mastectomy Reduces Breast Cancer Risk in BRCA1 and BRCA2 Mutation Carriers: The PROSE Study Group." Journal of Clinical Oncology 22, no. 6 (March 15, 2004): 1055–62. http://dx.doi.org/10.1200/jco.2004.04.188.
Full textAbstract:
Purpose Data on the efficacy of bilateral prophylactic mastectomy for breast cancer risk reduction in women with BRCA1 and BRCA2 (BRCA1/2) mutations are limited, despite the clinical use of this risk-management strategy. Thus, we estimated the degree of breast cancer risk reduction after surgery in women who carry these mutations. Patients and Methods Four hundred eighty-three women with disease-associated germline BRCA1/2 mutations were studied for the occurrence of breast cancer. Cases were mutation carriers who underwent bilateral prophylactic mastectomy and who were followed prospectively from the time of their center ascertainment and their surgery, with analyses performed for both follow-up periods. Controls were BRCA1/2 mutation carriers with no history of bilateral prophylactic mastectomy matched to cases on gene, center, and year of birth. Both cases and controls were excluded for previous or concurrent diagnosis of breast cancer. Analyses were adjusted for duration of endogenous ovarian hormone exposure, including age at bilateral prophylactic oophorectomy if applicable. Results Breast cancer was diagnosed in two (1.9%) of 105 women who had bilateral prophylactic mastectomy and in 184 (48.7%) of 378 matched controls who did not have the procedure, with a mean follow-up of 6.4 years. Bilateral prophylactic mastectomy reduced the risk of breast cancer by approximately 95% in women with prior or concurrent bilateral prophylactic oophorectomy and by approximately 90% in women with intact ovaries. Conclusion Bilateral prophylactic mastectomy reduces the risk of breast cancer in women with BRCA1/2 mutations by approximately 90%.
46
Saleen Salam Abdulhadi and Abbas Abdullah Mohammed. "Sequencing and structure analysis of UBC gene for breast and lung cancer." International Journal of Research in Pharmaceutical Sciences 10, no. 3 (July 12, 2019): 1640–45. http://dx.doi.org/10.26452/ijrps.v10i3.1329.
Full textAbstract:
In the present study, sequencing approach has been adopted for exploring the genetic alteration of sequences for the ubiquitin gene (UBC) in patients of breast and lung cancer and comparing the results with a normal sequence that obtained from NCBI. The aim of this study was to detect for genetic alterations of UBC gene in the breast and lung cancer patients then compare with healthy control subjects, to investigate the association between the mutations at the intron region of the UBC gene and cancer disease, 40 blood samples were examined from patients with breast and lung cancer aged ranged from (17-65) years, were collected at Al-Amal Hospital of cancer in Baghdad province/Iraq, the period of collecting samples were from October/2018 to January/2019. While twenty-two blood samples from healthy control subjects were collected at ages ranged from(19-59). After DNA extraction, the PCR primer was designed to amplify the region in the UBC gene (part of exon 1 and the whole intron). Here we report the polymorphism of the intron sequence of the UBC gene in Iraqi population as the results of sequencing the PCR amplified products showed three different transition mutation G→A, C→T, T→C in patients with breast cancer were also appeared in healthy control subjects. While nine transition mutations appeared in lung cancer patients, at different locations of the sequence were detected by BLAST tool.
47
Abdalwahid, Shadan Mohammed Jihad, Sami Ismael, and Shahab Wahhab Kareem. "Pre-Cancer Diagnosis via TP53 Gene Mutations Applied Ensemble Algorithms." Technium BioChemMed 2, no. 4 (September 9, 2021): 9–16. http://dx.doi.org/10.47577/biochemmed.v2i4.4654.
Full textAbstract:
According to current study, individuals with cancer who have a gene mutation have a bad prognosis. Young women with breast cancer had a poorer prognosis than older women, although it is unknown if the p53 gene mutation contributed to this. Due in part to the devastation of cancer, the appropriate technology may help cancer sufferers in regaining their lives. Researchers seek for mutations in cancer-causing gene sequences in order to identify the precancerous stage. While genetic testing may be used to forecast some kinds of cancer, there is presently no effective technique for identifying all cancers caused by TP53 gene mutations. It is one of the most often discovered genetic anomalies in human cancer is a malfunction in the action of the protein P53. As a consequence, the Universal Mutation Database is used to identify gene mutations (UMDCell-line2010).
The issue is that, although many basic databases (for example, Excel format databases) exist that include datasets of TP53 gene mutations associated with disease (cancer), this huge database is incapable of detecting cancer. Thus, the purpose the objective of this study is to create an approach for data mining that utilizes a neural network to ascertain the pre-cancerous state. To begin, bioinformatics techniques such as BLAST, CLUSTALW, and NCBI were used to determine whether or not there were any malignant mutations; second, the proposed method was carried out in two stages: to begin, bioinformatics techniques such as BLAST, CLUSTALW, and NCBI were used to determine whether or not there were any malignant mutations; and third, the proposed method was carried out in two stages: to begin, bioinformatics techniques such as To begin, bioinformatics tools such as BLAST and CLUSTAL
Vote Algorithms were utilized to classify pre-cancer by malignant mutations in the disease's early stages. The writers teach and evaluate their subjects using a variety of situations, including cross validation and percentages. This page contains a review of the algorithms discussed before.
48
Ferreira-Gonzalez, Andrea. "Plasma PIK3CA Mutation Testing in Advanced Breast Cancer Patients for Personalized Medicine: A Value Proposition." Journal of Applied Laboratory Medicine 5, no. 5 (September 1, 2020): 1076–89. http://dx.doi.org/10.1093/jalm/jfaa117.
Full textAbstract:
Abstract Background Even though endocrine therapy is often initially successful in treating advanced breast cancer, most patients inevitably face disease progression. In advanced hormone receptor–positive (HR+) breast cancer, activation of the PI3K downstream pathway is a critical feature of the mechanism of endocrine resistance. A significant recent advance in treating HR+ advanced breast cancer has been the recent introduction of PI3K inhibitor (PI3Ki) for the treatment of patients with HR+, HER2-negative (HER2−) advanced or metastatic breast cancer that harbors PIK3CA mutations. A value proposition concept was applied to assess the potential benefits of cell-free tumor DNA (ctDNA) testing to identify patients who might respond to PI3Ki treatment. Content By applying the framework of the value proposition to >35 publications, in addition to recommendations from professional organizations, it was evident that robust clinical evidence exists to support the role of ctDNA PIK3CA mutation evaluation in identifying patients with advanced breast cancer who could benefit from PI3Ki treatment. Summary Detection of PIK3CA gene mutations in HR+HER2− advanced breast cancer patients allows for the identification of patients who might benefit from more effective personalized treatment with molecularly targeted drugs.
49
Bull, Shelley B., Hilmi Ozcelik, Dushanthi Pinnaduwage, Martin E. Blackstein, Donald A. J. Sutherland, Kathleen I. Pritchard, Anjela T. Tzontcheva, et al. "The Combination of p53 Mutation and neu/erbB-2 Amplification Is Associated With Poor Survival in Node-Negative Breast Cancer." Journal of Clinical Oncology 22, no. 1 (January 1, 2004): 86–96. http://dx.doi.org/10.1200/jco.2004.09.128.
Full textAbstract:
Purpose Increases in neu/erbB-2 have been implicated in breast cancer prognosis, but do not predict all recurrences. On the basis of evidence that p53 mutation is involved in the development of human neoplasia, we examined the prognostic value of p53 alterations in combination with neu/erbB-2 amplification. Patients and Methods A consecutive series of women were observed for recurrence and death (median follow-up of 85 months) and tumors from 543 individuals were analyzed for p53 mutation status and neu/erbB-2 amplification. Exons 4 through 10 of the p53 gene were analyzed by single-stranded conformational polymorphism and mutations were confirmed by DNA sequencing. The association of p53 mutation status and neu/erbB-2 amplification with risk of recurrence and death was examined in survival analyses with traditional and histologic markers as prognostic factors. Results p53 mutations occurred in 24.5% of the axillary node-negative breast carcinomas. Mutations were more frequent in carcinomas with neu/erbB-2 amplification: 38.9% compared with only 20.9% in those without neu/erbB-2 amplification. We found elevated risks of disease recurrence and overall mortality in patients with both p53 mutation and neu/erbB-2 amplification in their tumor compared with patients with neither or only one of the alterations. This increase persisted with adjustment for other prognostic factors (relative risk, 2.32; P = .002 for recurrence; relative risk, 2.22; P = .004 for death). Conclusion Evaluation of tumors for p53 mutations may be beneficial to identify women at higher risk of disease recurrence and death when the tumor has neu/erbB-2 amplification, but in the absence of neu/erbB-2 amplification, the presence of p53 mutation may not provide additional independent prognostic information.
50
Frank, Tom S. "Laboratory Determination of Hereditary Susceptibility to Breast and Ovarian Cancer." Archives of Pathology & Laboratory Medicine 123, no. 11 (November 1, 1999): 1023–26. http://dx.doi.org/10.5858/1999-123-1023-ldohst.
Full textAbstract:
Abstract Inherited mutations in the genes BRCA1 and BRCA2 are associated with a significantly increased risk of breast cancer, particularly before the age of 50 years, as well as an increased risk of ovarian cancer. Patients with early-onset breast cancer or ovarian cancer at any age with a family history of either disease are at higher risk of carrying a mutation in BRCA1 or BRCA2. Laboratory analysis of these genes can determine whether a patient has inherited an increased risk of breast and ovarian cancer. In the absence of a mutation that has been previously identified in a family member, most tests for hereditary breast-ovarian cancer risk analyze the entire coding sequences of BRCA1 and BRCA2. The gene sequencing process itself can be automated, but the data must be interpreted by an individual with training in molecular diagnostics. Management options generally available to individuals with hereditary susceptibility to breast and ovarian cancer include heightened surveillance, prophylactic surgery, and chemoprevention. The use of genetic techniques to identify women with increased risk of cancer demonstrates the application of recent advances in the understanding of the genetic basis of malignancy to laboratory medicine and clinical care.