Germline EMSY sequence alterations in hereditary breast cancer and ovarian cancer families

BMC Cancer

Research Article

Minna Kankuri-Tammilehto¹  Satu-Leena Laasanen²  Anne Kallioniemi³  Riikka Nurminen⁴  Kirsi M. Määttä⁴  Johanna Schleutker⁵ 

[1] Department of Clinical Genetics, Turku University Hospital, Kiinamyllynkatu 4-8, FI-20521, Turku, Finland;Department of Pediatrics, Genetics Outpatient Clinic, and Department of Dermatology, Tampere UniversityHospital, PO BOX 2000, FI-33521, Tampere, Finland;Department of Dermatology, Tampere University Hospital, PO BOX 2000, FI-33521, Tampere, Finland;Institute of Biosciences and Medical Technology - BioMediTech, University of Tampere, Lääkärinkatu 1, FI-33520, Tampere, Finland;Institute of Biosciences and Medical Technology - BioMediTech, University of Tampere, Lääkärinkatu 1, FI-33520, Tampere, Finland;Fimlab Laboratories, Tampere University Hospital, Biokatu 4, FI-33520, Tampere, Finland;Institute of Biosciences and Medical Technology - BioMediTech, University of Tampere, Lääkärinkatu 1, FI-33520, Tampere, Finland;Fimlab Laboratories, Tampere University Hospital, Biokatu 4, FI-33520, Tampere, Finland;Institute of Biomedicine, University of Turku, Kiinamyllynkatu 10, FI-20014, Turku, Finland;Department of Medical Genetics, Turku University Hospital, Kiinamyllynkatu 10, FI-20521, Turku, Finland;

关键词: Breast cancer;    Ovarian cancer;    Germline;    EMSY;   

DOI  :  10.1186/s12885-017-3488-x

 received in 2016-08-30, accepted in 2017-07-17,  发布年份 2017

来源: Springer

【 摘 要 】

BackgroundBRCA1 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.MethodsIndex 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.ResultsAltogether, 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.ConclusionsThese 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.

【 授权许可】

CC BY   
© The Author(s). 2017