scholarly journals Genetic and clinical landscape of breast cancers with germline BRCA1/2 variants

2020 ◽  
Vol 3 (1) ◽  
Author(s):  
Yukiko Inagaki-Kawata ◽  
Kenichi Yoshida ◽  
Nobuko Kawaguchi-Sakita ◽  
Masahiro Kawashima ◽  
Tomomi Nishimura ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Cancer Susceptibility ◽  
Clonal Selection ◽  
Breast Cancer Susceptibility ◽  
Breast Cancers ◽  
Breast Cancer Patients ◽  
Germline Variants ◽  
Pathogenic Variants ◽  
Cancer Susceptibility Genes ◽  
Tcga Dataset

Abstract The genetic and clinical characteristics of breast tumors with germline variants, including their association with biallelic inactivation through loss-of-heterozygosity (LOH) and second somatic mutations, remain elusive. We analyzed germline variants of 11 breast cancer susceptibility genes for 1,995 Japanese breast cancer patients, and identified 101 (5.1%) pathogenic variants, including 62 BRCA2 and 15 BRCA1 mutations. Genetic analysis of 64 BRCA1/2-mutated tumors including TCGA dataset tumors, revealed an association of biallelic inactivation with more extensive deletions, copy neutral LOH, gain with LOH and younger onset. Strikingly, TP53 and RB1 mutations were frequently observed in BRCA1- (94%) and BRCA2- (9.7%) mutated tumors with biallelic inactivation. Inactivation of TP53 and RB1 together with BRCA1 and BRCA2, respectively, involved LOH of chromosomes 17 and 13. Notably, BRCA1/2 tumors without biallelic inactivation were indistinguishable from those without germline variants. Our study highlights the heterogeneity and unique clonal selection pattern in breast cancers with germline variants.

scholarly journals A systematic review: breast cancer susceptibility genes

2020 ◽  
Vol 218 ◽  
pp. 03039
Author(s):  
ZhiLan Xie
Keyword(s):  
Breast Cancer ◽  
Cancer Susceptibility ◽  
Normal Population ◽  
Breast Cancer Susceptibility ◽  
Breast Cancers ◽  
Breast Cancer Patients ◽  
Cancer Susceptibility Genes ◽  
Cell Life ◽  
Dominant Female ◽  
Cell To Cell Adhesion

Breast cancer is the dominant female cancer and the top cause of cancer deaths in women among the world. The susceptible genes are critical risk factors for both hereditary and sporadic breast cancers. The incidence of carcinoma for carriers with mutated relative genes might increase in comparison with that of the normal population. These genes might be applied in breast cancer populated screening and clinical treatment, in order to improve survival of the breast cancer patients. This study concluded some genes involved in various key elementary processes in cell life, including DNA repair, cell cycle regulation, cell-to-cell adhesion and metabolism, in previous research.

scholarly journals Germline mutations in a clinic-based series of pregnancy associated breast cancer patients

BMC Cancer ◽  
2021 ◽  
Vol 21 (1) ◽  
Author(s):  
Eleni Zografos ◽  
Anna-Maria Korakiti ◽  
Angeliki Andrikopoulou ◽  
Ioannis Rellias ◽  
Constantine Dimitrakakis ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Cancer Susceptibility ◽  
Germline Mutations ◽  
Breast Cancer Susceptibility ◽  
Susceptibility Genes ◽  
Management Approach ◽  
Breast Cancer Patients ◽  
Pathogenic Variants ◽  
Cancer Susceptibility Genes ◽  
Challenging Situation

Abstract Background Pregnancy-associated breast cancer (PABC) defined as breast cancer diagnosed during gestation, lactation or within 1 year after delivery, represents a truly challenging situation with significantly increasing incidence rate. The genomic background of PABC has only recently been addressed while the underlying mechanisms of the disease still remain unknown. This analysis aims to further elucidate the frequency of PABC cases attributable to genetic predisposition and identify specific cancer susceptibility genes characterizing PABC. Methods A comprehensive 94-cancer gene panel was implemented in a cohort of 20 PABC patients treated in our clinic and descriptive correlation was performed among the results and the patients’ clinicopathological data. Results In the present study, 35% of PABC patients tested carried pathogenic mutations in two known cancer predisposition genes (BRCA1 and CHEK2). In total, 30% of the patients carried BRCA1 pathogenic variants. An additional 5% carried pathogenic variants in the CHEK2 gene. Variants of unknown/uncertain significance (VUS) in breast cancer susceptibility genes BRCA2, CHEK2 and BRIP1 were also identified in three different PABC patients (15%). Not all patients carrying germline mutations reported known family history of cancer. Conclusions Genetic testing should be considered as an option for PABC patients since the disease is highly associated with genetic susceptibility among other predisposing factors. Germline mutation identification may further modify PABC management approach and improve the prognostic outcome.

scholarly journals A novel high-throughput assay using mixed genomic DNA for fast screening germline pathogenic variants in breast cancer susceptibility genes

2021 ◽  
Author(s):  
Qiting Wan ◽  
Li Hu ◽  
Lu Yao ◽  
Jiuan Chen ◽  
Jie Sun ◽  
...  
Keyword(s):  
Breast Cancer ◽  
High Throughput ◽  
Genomic Dna ◽  
Cancer Susceptibility ◽  
Breast Cancer Susceptibility ◽  
Susceptibility Genes ◽  
Pathogenic Variants ◽  
Cancer Susceptibility Genes ◽  
Breast Cancer Susceptibility Genes ◽  
High Throughput Assay

The demand for genetic testing for breast cancer susceptibility genes is increasing for both breast cancer patients and healthy individuals. Here we established a novel high-throughput assay to detect germline pathogenic variants in breast cancer susceptibility genes. In general, up 10 to 50 individual genomic DNA samples were mixed together to create a mixed DNA sample and the mixed DNA sample was subjected to a next-generation multigene panel. Germline pathogenic variants in breast cancer susceptibility genes could be found in the mixed DNA sample; next, site-specific Sanger sequencing was performed to identify individuals who carried he pathogenic variant in the mixed samples. We found that the recall and precision rates were 89.9% and 92.9% when twenty individual genomic samples were mixed. Therefore, our new assay can increase an approximately 20-fold of efficacy to identify the pathogenic variants in breast cancer susceptibility genes in individuals when compared with current assay.

scholarly journals Li-Fraumeni syndrome: not a straightforward diagnosis anymore—the interpretation of pathogenic variants of low allele frequency and the differences between germline PVs, mosaicism, and clonal hematopoiesis

2019 ◽  
Vol 21 (1) ◽  
Author(s):  
Felipe Batalini ◽  
Ellie G. Peacock ◽  
Lindsey Stobie ◽  
Alison Robertson ◽  
Judy Garber ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Cancer Patients ◽  
Cancer Susceptibility ◽  
Somatic Mosaicism ◽  
Susceptibility Genes ◽  
Breast Cancer Patients ◽  
Li Fraumeni Syndrome ◽  
Clonal Hematopoiesis ◽  
Pathogenic Variants ◽  
Cancer Susceptibility Genes

Abstract The introduction of next-generation sequencing has resulted in testing multiple genes simultaneously to identify inherited pathogenic variants (PVs) in cancer susceptibility genes. PVs with low minor allele frequencies (MAFs) (< 25–35%) are highlighted on germline genetic test reports. In this review, we focus on the challenges of interpreting PVs with low MAF in breast cancer patients undergoing germline testing and the implications for management. The clinical implications of a germline PV are substantial. For PV carriers in high-penetrance genes like BRCA1, BRCA2, and TP53, prophylactic mastectomy is often recommended and radiation therapy avoided when possible for those with Li-Fraumeni syndrome (LFS). For germline PV carriers in more moderate-risk genes such as PALB2, ATM, and CHEK2, annual breast MRI is recommended and prophylactic mastectomies considered for those with significant family histories. Detection of PVs in cancer susceptibility genes can also lead to recommendations for other prophylactic surgeries (e.g., salpingo-oophorectomy) and increased surveillance for other cancers. Therefore, recognizing when a PV is somatic rather than germline and distinguishing somatic mosaicism from clonal hematopoiesis (CH) is essential. Mutational events that occur at a post-zygotic stage are somatic and will only be present in tissues derived from the mutated cell, characterizing classic mosaicism. Clonal hematopoiesis is a form of mosaicism restricted to the hematopoietic compartment. Among the genes in multi-gene panels used for germline testing of breast cancer patients, the detection of a PV with low MAF occurs most often in TP53, though has been reported in other breast cancer susceptibility genes. Distinguishing a germline TP53 PV (LFS) from a somatic PV (TP53 mosaicism or CH) has enormous implications for breast cancer patients and their relatives. We review how to evaluate a PV with low MAF. The identification of the PV in another tissue confirms mosaicism. Older age, exposure to chemotherapy, radiation, and tobacco are known risk factors for CH, as is the absence of a LFS-related cancer in the setting of a TP53 PV with low MAF. The ability to recognize and understand the implications of somatic PVs, including somatic mosaicism and CH, enables optimal personalized care of breast cancer patients.

scholarly journals Update Breast Cancer 2021 Part 1 – Prevention and Early Stages

2021 ◽  
Author(s):  
Elmar Stickeler ◽  
Bahriye Aktas ◽  
Annika Behrens ◽  
Erik Belleville ◽  
Nina Ditsch ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Cancer Susceptibility ◽  
Checkpoint Inhibitors ◽  
Early Stage ◽  
Pathologic Complete Response ◽  
Neoadjuvant Treatment ◽  
Complete Response ◽  
Breast Cancer Susceptibility ◽  
Breast Cancer Patients ◽  
Cancer Susceptibility Genes

AbstractThis review summarises not only the latest evidence on prevention, but also the current research on the treatment of early-stage breast cancer patients. Recent years have seen a growing body of evidence on the risk of high- and moderate-penetrance breast cancer susceptibility genes. A large international consortium has now been able to further refine the answer to the question of the significance of the so-called panel genes. Moreover, the data on treatment selection regarding endocrine efficacy and the decision for or against chemotherapy have also been advanced markedly. There is also new data on adjuvant CDK4/6 (cyclin-dependent kinase 4/6) inhibitors, which are standard in first-line treatment in patients with metastatic HER2-negative, hormone receptor-positive (HR+) breast cancer. For other therapies such as immune checkpoint inhibitors, which have successfully improved the rate of pathologic complete response (pCR) in neoadjuvant treatment settings for patients with triple-negative breast cancer (TNBC), there is a growing understanding of the quality of life and side effects. This is especially important in situations where patients could possibly be cured without such a regimen.

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