The pathology of familial breast cancer: The pathology of familial breast cancer How do the functions of BRCA1 and BRCA2 relate to breast tumour pathology?

BRCA1 and BRCA2 as important DNA repair genes have been thoroughly investigated in abundant studies. The potential relationships of BRCA1/2 pathogenic variants between multicancers have been verified in Caucasians but few in Chinese. In this study, we performed a two-stage study to screen BRCA1/2 pathogenic variants or variants of uncertain significance (VUS) with 7580 cancer cases and 4874 cancer-free controls, consisting of a discovery stage with 70 familial breast cancer cases and a subsequent validation stage with 7510 cases (3217 breast cancer, 1133 cervical cancer, 2044 hepatocellular carcinoma, and 1116 colorectal cancer). 48 variants were obtained from 70 familial breast cancer cases after BRCA1/2 exon detection, and finally, 20 pathogenic variants or VUS were selected for subsequent validation. Four recurrent variants in sporadic cases (BRCA1 c.4801A>T, BRCA1 c.3257del, BRCA1 c.440del, and BRCA2 c.7409dup) were identified and three of them were labeled Class 5 by ENIGMA. Two variants (BRCA1 c.3257del and c.440del) were specific in breast cancer cases, while BRCA2 c.7409dup and c.4307T>C were detected in two hepatocellular carcinoma patients and the BRCA1 c.4801A>T variant in one cervical cancer patient, respectively. Moreover, BRCA1 c.3257del was the most frequent variant observed in Chinese sporadic breast cancer and showed increased proliferation of BRCA1c.3257del-overexpressing triple-negative breast cancer cell lines (MDA-MB-231) in vitro. In addition to the known founder deleterious mutations, our findings highlight that the recurrently pathogenic variants in breast cancer cases could be taken as candidate genetic screening loci for a more efficient genetic screening of the Chinese population.

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A multi-institutional study of the prevalence of BRCA1 and BRCA2 large genomic rearrangements in familial breast cancer patients

BMC Cancer ◽

10.1186/1471-2407-14-645 ◽

2014 ◽

Vol 14 (1) ◽

Cited By ~ 16

Author(s):

Moon-Woo Seong ◽

◽

Sung Im Cho ◽

Kyu Hyung Kim ◽

Il Yong Chung ◽

...

Keyword(s):

Breast Cancer ◽

Cancer Patients ◽

Familial Breast Cancer ◽

Genomic Rearrangements ◽

Breast Cancer Patients ◽

Brca1 And Brca2 ◽

Large Genomic Rearrangements

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A case of familial breast cancer with double heterozygosity for BRCA1 and BRCA2 genes

Breast Cancer ◽

10.1007/s12282-012-0432-4 ◽

2012 ◽

Vol 22 (5) ◽

pp. 557-561 ◽

Cited By ~ 5

Author(s):

Tadashi Nomizu ◽

Masami Matsuzaki ◽

Naoto Katagata ◽

Yusuke Kobayashi ◽

Takeshi Sakuma ◽

...

Keyword(s):

Breast Cancer ◽

Familial Breast Cancer ◽

Brca1 And Brca2 ◽

Brca1 And Brca2 Genes ◽

Double Heterozygosity

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CHEK2*1100delC Genotyping for Clinical Assessment of Breast Cancer Risk: Meta-Analyses of 26,000 Patient Cases and 27,000 Controls

Journal of Clinical Oncology ◽

10.1200/jco.2007.12.5922 ◽

2008 ◽

Vol 26 (4) ◽

pp. 542-548 ◽

Cited By ~ 189

Author(s):

Maren Weischer ◽

Stig Egil Bojesen ◽

Christina Ellervik ◽

Anne Tybjærg-Hansen ◽

Børge Grønne Nordestgaard

Keyword(s):

Breast Cancer ◽

Early Onset ◽

Familial Breast Cancer ◽

Brca2 Mutation ◽

Mutation Screening ◽

Cumulative Risk ◽

Brca1 And Brca2 ◽

Chek2 1100Delc ◽

Increased Risk ◽

Meta Analyses

Purpose CHEK2*1100delC heterozygosity may be associated with an increased risk of breast cancer; however, it is unclear whether the evidence is sufficient to recommend genotyping in clinical practice. Patients and Methods We identified studies on CHEK2*1100delC heterozygosity and the risk of unselected, early-onset, and familial breast cancer through comprehensive, computer-based searches of PubMed, EMBASE, and Web of Science. Aggregated risk estimates were compared with previous estimates for BRCA1 and BRCA2 mutation heterozygotes. Results By using fixed-effect models for CHEK2*1100delC heterozygotes versus noncarriers, we found aggregated odds ratios of 2.7 (95% CI, 2.1 to 3.4) for unselected breast cancer, 2.6 (95% CI, 1.3 to 5.5) for early-onset breast cancer, and 4.8 (95% CI, 3.3 to 7.2) for familial breast cancer. For familial breast cancer, this corresponds to a cumulative risk of breast cancer at age 70 years in CHEK2*1100delC heterozygotes of 37% (95% CI, 26% to 56%), which compares with similar previous estimates of 57% (95% CI, 47% to 66%) for BRCA1 mutation heterozygotes and 49% (95% CI, 40% to 57%) for BRCA2 mutation heterozygotes. Conclusion These meta-analyses emphasize that CHEK2*1100delC is an important breast cancer–predisposing gene, which increases the risk three- to five-fold. Because the cumulative risk of breast cancer at age 70 years among familial patient cases for CHEK2*1100delC heterozygotes is almost as high as that for BRCA1 and BRCA2 mutation heterozygotes, genotyping for CHEK2*1100delC should be considered together with BRCA1 and BRCA2 mutation screening in women with a family history of breast cancer.

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Etiology of familial breast cancer with undetected BRCA1 and BRCA2 mutations: clinical implications

Cellular Oncology ◽

10.1007/s13402-013-0158-0 ◽

2013 ◽

Vol 37 (1) ◽

pp. 1-8 ◽

Cited By ~ 10

Author(s):

Eugenia Yiannakopoulou

Keyword(s):

Breast Cancer ◽

Familial Breast Cancer ◽

Clinical Implications ◽

Brca1 And Brca2 ◽

Brca2 Mutations ◽

Brca1 And Brca2 Mutations

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BRCA1 and BRCA2 genes mutations among high risk breast cancer patients in Jordan

Scientific Reports ◽

10.1038/s41598-020-74250-2 ◽

2020 ◽

Vol 10 (1) ◽

Author(s):

Munir Abu-Helalah ◽

Belal Azab ◽

Rasmi Mubaidin ◽

Dema Ali ◽

Hanan Jafar ◽

...

Keyword(s):

Breast Cancer ◽

Cancer Patients ◽

Familial Breast Cancer ◽

Cancer Surveillance ◽

Breast Cancer Patients ◽

Brca1 And Brca2 ◽

Genetic Profiling ◽

Delay In Diagnosis ◽

Jordanian Population ◽

Pathogenic Mutations

Abstract Familial breast cancer is estimated to account for 15–20% of all cases of breast cancer. Surveillance for familial breast cancer is well-established world-wide. However, this service does not exist in Jordan, due to the scarcity of information with regard to the genetic profiling of these patients, and therefore lack of recommendations for policy-makers. As such, patients with very strong family history of breast or ovarian cancers are not screened routinely; leading to preventable delay in diagnosis. Whole coding sequencing for BCRA1/BCRA2 using next-generation sequencing (NGS)/Ion PGM System was performed. Sanger sequencing were then used to confirm the pathogenic variants detected by NGS. In this study, 192 breast cancer patients (and 8 ovarian cancer cases) were included. The prevalence of recurrent pathogenic mutations was 14.5%, while the prevalence of newly detected mutations was 3.5%. Two novel pathogenic mutations were identified in BRCA2 genes. The common mutations in the Ashkenazi population used for screening may not apply in the Jordanian population, as previously reported mutations were not prevalent, and other new mutations were identified. These data will aid to establish a specific screening test for BRCA 1/BRCA2 in the Jordanian population.

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