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Hereditary breast and ovarian cancer in Andalusian families: a genetic population study.

ABSTRACT: BACKGROUND:The BRCA1/2 mutation profile varies in Spain according to the geographical area studied. The mutational profile of BRCA1/2 in families at risk for hereditary breast and ovarian cancer has not so far been reported in Andalusia (southern Spain). METHODS:We analysed BRCA1/2 germline mutations in 562 high-risk cases with breast and/or ovarian cancer from Andalusian families from 2010 to 2015. RESULTS:Among the 562 cases, 120 (21.4%) carried a germline pathogenic mutation in BRCA1/2; 50 in BRCA1 (41.7%) and 70 in BRCA2 (58.3%). We detected 67 distinct mutations (29 in BRCA1 and 38 in BRCA2), of which 3 in BRCA1 (c.845C?>?A, c.1222_1223delAC, c.2527delA) and 5 in BRCA2 (c.293 T?>?G, c.5558_5559delGT, c.6034delT, c.6650_6654delAAGAT, c.6652delG) had not been previously described. The most frequent mutations in BRCA1 were c.5078_5080delCTG (10%) and c.5123C?>?A (10%), and in BRCA2 they were c.9018C?>?A (14%) and c.5720_5723delCTCT (8%). We identified 5 variants of unknown significance (VUS), all in BRCA2 (c.5836 T?>?C, c.6323G?>?T, c.9501?+?3A?>?T, c.8022_8030delGATAATGGA, c.10186A?>?C). We detected 76 polymorphisms (31 in BRCA1, 45 in BRCA2) not associated with breast cancer risk. CONCLUSIONS:This is the first study reporting the mutational profile of BRCA1/2 in Andalusia. We identified 21.4% of patients harbouring BRCA1/2 mutations, 58.3% of them in BRCA2. We also characterized the clinical data, mutational profile, VUS and haplotype profile.

SUBMITTER: Pajares B

PROVIDER: S-EPMC5994127 | biostudies-literature | 2018 Jun

REPOSITORIES: biostudies-literature

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Hereditary breast and ovarian cancer in Andalusian families: a genetic population study.

Pajares Bella B Porta Javier J Porta Jose María JM Sousa Cristina Fernández-de CF Moreno Ignacio I Porta Daniel D Durán Gema G Vega Tamara T Ortiz Inmaculada I Muriel Carolina C Alba Emilio E Márquez Antonia A

BMC cancer 20180608 1

<h4>Background</h4>The BRCA1/2 mutation profile varies in Spain according to the geographical area studied. The mutational profile of BRCA1/2 in families at risk for hereditary breast and ovarian cancer has not so far been reported in Andalusia (southern Spain).<h4>Methods</h4>We analysed BRCA1/2 germline mutations in 562 high-risk cases with breast and/or ovarian cancer from Andalusian families from 2010 to 2015.<h4>Results</h4>Among the 562 cases, 120 (21.4%) carried a germline pathogenic muta ...[more]

PMID: 29884136

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Project description:BACKGROUND:BRCA1 and BRCA2 mutations explain approximately one-fifth of the inherited susceptibility in high-risk Finnish hereditary breast and ovarian cancer (HBOC) families. EMSY is located in the breast cancer-associated chromosomal region 11q13. The EMSY gene encodes a BRCA2-interacting protein that has been implicated in DNA damage repair and genomic instability. We analysed the role of germline EMSY variation in breast/ovarian cancer predisposition. The present study describes the first EMSY screening in patients with high familial risk for this disease. METHODS:Index individuals from 71 high-risk, BRCA1/2-negative HBOC families were screened for germline EMSY sequence alterations in protein coding regions and exon-intron boundaries using Sanger sequencing and TaqMan assays. The identified variants were further screened in 36 Finnish HBOC patients and 904 controls. Moreover, one novel intronic deletion was screened in a cohort of 404 breast cancer patients unselected for family history. Haplotype block structure and the association of haplotypes with breast/ovarian cancer were analysed using Haploview. The functionality of the identified variants was predicted using Haploreg, RegulomeDB, Human Splicing Finder, and Pathogenic-or-Not-Pipeline 2. RESULTS:Altogether, 12 germline EMSY variants were observed. Two alterations were located in the coding region, five alterations were intronic, and five alterations were located in the 3'untranslated region (UTR). Variant frequencies did not significantly differ between cases and controls. The novel variant, c.2709 + 122delT, was detected in 1 out of 107 (0.9%) breast cancer patients, and the carrier showed a bilateral form of the disease. The deletion was absent in 897 controls (OR = 25.28; P = 0.1) and in 404 breast cancer patients unselected for family history. No haplotype was identified to increase the risk of breast/ovarian cancer. Functional analyses suggested that variants, particularly in the 3'UTR, were located within regulatory elements. The novel deletion was predicted to affect splicing regulatory elements. CONCLUSIONS:These results suggest that the identified EMSY variants are likely neutral at the population level. However, these variants may contribute to breast/ovarian cancer risk in single families. Additional analyses are warranted for rare novel intronic deletions and the 3'UTR variants predicted to have functional roles.

Dataset Information

Hereditary breast and ovarian cancer in Andalusian families: a genetic population study.

Publications

Hereditary breast and ovarian cancer in Andalusian families: a genetic population study.

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