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Identifying sequence variants contributing to hereditary breast and ovarian cancer in BRCA1 and BRCA2 negative breast and ovarian cancer patients.

ABSTRACT: Families with breast and ovarian cancer are often tested for disease associated sequence variants in BRCA1 and BRCA2. Pathogenic sequence variants (PVs) in these two genes are known to increase breast and ovarian cancer risks in females. However, in most families no PVs are detected in these two genes. Currently, several studies have identified other genes involved in hereditary breast and ovarian cancer (HBOC). To identify genetic risk factors for breast and ovarian cancer in a Norwegian HBOC cohort, 101 breast and/or ovarian cancer patients negative for PVs and variants of unknown clinical significance (VUS) in BRCA1/2 were screened for PVs in 94 genes using next-generation sequencing. Sixteen genes were closely scrutinized. Nine different deleterious germline PVs/likely pathogenic variants (LPVs) were identified in seven genes in 12 patients: three in ATM, and one in CHEK2, ERCC5, FANCM, RAD51C, TP53 and WRN. Additionally, 32 different VUSs were identified and these require further characterization. For carriers of PV/LPV in many of these genes, there are no national clinical management programs in Norway. The diversity of genetic risk factors possibly involved in cancer development show the necessity for more knowledge to improve the clinical follow-up of this genetically diverse patient group.

SUBMITTER: Jarhelle E

PROVIDER: S-EPMC6934654 | biostudies-literature | 2019 Dec

REPOSITORIES: biostudies-literature

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Identifying sequence variants contributing to hereditary breast and ovarian cancer in BRCA1 and BRCA2 negative breast and ovarian cancer patients.

Jarhelle Elisabeth E Riise Stensland Hilde Monica Frostad HMF Hansen Geir Åsmund Myge GÅM Skarsfjord Siri S Jonsrud Christoffer C Ingebrigtsen Monica M Strømsvik Nina N Van Ghelue Marijke M

Scientific reports 20191227 1

Families with breast and ovarian cancer are often tested for disease associated sequence variants in BRCA1 and BRCA2. Pathogenic sequence variants (PVs) in these two genes are known to increase breast and ovarian cancer risks in females. However, in most families no PVs are detected in these two genes. Currently, several studies have identified other genes involved in hereditary breast and ovarian cancer (HBOC). To identify genetic risk factors for breast and ovarian cancer in a Norwegian HBOC c ...[more]

PMID: 31882575

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Project description:BACKGROUND: BRCA1 and BRCA2 germline mutations predispose heterozygous carriers to hereditary breast/ovarian cancer. However, unclassified variants (UVs) (variants with unknown clinical significance) and missense polymorphisms in BRCA1 and BRCA2 genes pose a problem in genetic counseling, as their impact on risk of breast and ovarian cancer is still unclear. The objective of our study was to identify UVs and missense polymorphisms in Algerian breast/ovarian cancer patients and relatives tested previously for BRCA1 and BRCA2 genes germline mutations analysis. METHODS: We analyzed 101 DNA samples from 79 breast/ovarian cancer families. The approach used is based on BRCA1 and BRCA2 sequence variants screening by SSCP or High-Resolution Melting (HRM) curve analysis followed by direct sequencing. In silico analyses have been performed using different bioinformatics programs to individualize genetics variations that can disrupt the BRCA1 and BRCA2 genes function. RESULTS: Among 80 UVs and polymorphisms detected in BRCA1/2 genes (33 BRCA1 and 47 BRCA2), 31 were new UVs (10 BRCA1 and 21 BRCA2), 7 were rare UVs (4 BRCA1 and 3 BRCA2) and 42 were polymorphic variants (19 BRCA1 and 23 BRCA2). Moreover, 8 new missense UVs identified in this study: two BRCA1 (c.4066C>A/p.Gln1356Lys, c.4901G>T/p.Arg1634Met) located respectively in exons 11 and 16, and six BRCA2 (c.1099G>A/p.Asp367Asn, c.2636C>A/p.Ser879Tyr, c.3868T>A/p.Cys1290Ser, c.5428G>T/p.Val1810Phe, c.6346C>G/p.His2116Asp and c.9256G>A/p.Gly3086Arg) located respectively in exons 10, 11 and 24, show a damaging PSIC score yielded by PolyPhen2 program and could be pathogenic. In addition, 5 new BRCA} missense UVs out of six that were found to be damaging by PolyPhen2 program, also were deleterious according to SIFT program. The rare BRCA1 UV c.5332G>A/p.Asp1778Asn was found here for the first time in co-occurrence in trans with the deleterious BRCA1 mutation c.798_799delTT/p.Ser267LysfsX19 in young breast cancer patient. Moreover, 10 new identified intronic variants with unknown clinical significance (3 BRCA1 and 7 BRCA2) in the present study, could be considered as benign, because GeneSplicer, SpliceSiteFinder and MaxEntScan prediction programs show no splice site alteration for these variants. Several missense polymorphisms of BRCA1 c.2612C>T/p.Pro871Leu, c.3548A>G/p.Lys1183Arg, c.4837A>G/p.Ser1613Gly and BRCA2 c.865A>C/p.Asn289His, c.1114A>C/p.Asn372His, c.2971A>G/p.Asn991Asp, c.7150C>A/p.Gly2384Lys have been identified with high frequency in patients who were tested negative for BRCA1 and BRCA2 mutations. These missense polymorphisms could have a role as susceptibility breast cancer markers in Algerian breast/ovarian cancer families where pathological BRCA1 and BRCA2 mutations were not present. CONCLUSIONS: For the first time, UVs and missense polymorphisms in BRCA1 and BRCA2 genes have been identified in Algerian breast/ovarian cancer families. Evaluation of breast/ovarian cancer risk induced by the eight new missense UVs and common polymorphisms detected in our present work is on going in a larger study.

Project description:BACKGROUND: The prevalence of BRCA1 and BRCA2 mutations in Spain is heterogeneous and varies according to geographical origin of studied families. The contribution of these mutations to hereditary breast and ovarian cancer has not been previously investigated in Asturian populations (Northern Spain). METHODS: In the present work, 256 unrelated high-risk probands with breast and/or ovarian cancer from families living in Asturias were analyzed for the presence of a BRCA1 or BRCA2 gene mutation from October 2007 to May 2012. The entire coding sequences and each intron/exon boundaries of BRCA1/2 genes were screened both by direct sequencing and Multiplex Ligation-dependent Probe Amplification (MLPA). RESULTS: A total of 59 families (23%) were found to carry a pathogenic germ line mutation, 39 in BRCA1 and 20 in BRCA2. Twenty nine additional families (12%) carried an unknown significance variant. We detected 28 distinct pathogenic mutations (16 in BRCA1 and 12 in BRCA2), of which 3 mutations in BRCA1 (c.1674delA, c.1965C>A and c.2900_2901dupCT) and 5 in BRCA2 (c.262_263delCT, c.2095C>T, c.3263dupC, c.4030_4035delinsC, c.8042_8043delCA) had not been previously described.The novel mutations c.2900_2901dupCT in BRCA1 and c.4030_4035delinsC in BRCA2 occurred in 8 and 6 families respectively and clustered in two separated small geographically isolated areas suggesting a founder effect. These 2 mutations, together with the Galician BRCA1 mutation c.211A>G (9 families), and the common BRCA1 mutation c.3331_3334delCAAG (6 families), account for approximately 50% of all affected families. By contrast, very frequent mutations in other Spanish series such as the BRCA1 Ashkenazi founder mutation c.68_69delAG, was found in only one family. CONCLUSIONS: In this study we report the BRCA1 and BRCA2 spectrum of mutations and their geographical distribution in Asturias, which largely differ from other areas of Spain. Our findings may help design a first step recurrent mutation panel for screening high-risk breast and/or ovarian cancer families from this specific area.

Dataset Information

Identifying sequence variants contributing to hereditary breast and ovarian cancer in BRCA1 and BRCA2 negative breast and ovarian cancer patients.

Publications

Identifying sequence variants contributing to hereditary breast and ovarian cancer in BRCA1 and BRCA2 negative breast and ovarian cancer patients.

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