Exome sequencing study of Russian breast cancer patients suggests a predisposing role for USP39
| Autor: | Evgeny N. Suspitsin, Peter Schürmann, Ilya V. Bizin, Maria O. Anisimova, Darya Prokofyeva, Aigul R. Venina, Elza Khusnutdinova, Tatiana N. Sokolova, Natalia Bogdanova, Ashok K. Varma, Evgeny N. Imyanitov, Maria A. Mantseva, Ekaterina Sh Kuligina, Andrey V. Koloskov, Syed K. Hasan, Ana Marija Milanović, Svetlana N. Aleksakhina, Anna P. Sokolenko, Marina Bermisheva, Daria D. Krylova, Kirill A. Zagorodnev, Thilo Dörk, Valeria I. Ni, Alexandr A. Romanko, Elena I Anisimova |
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| Rok vydání: | 2019 |
| Předmět: |
0301 basic medicine
Cancer Research Genotype Breast Neoplasms Biology Germline Russia 03 medical and health sciences 0302 clinical medicine Breast cancer Germline mutation Exome Sequencing Biomarkers Tumor Odds Ratio medicine Humans Genetic Predisposition to Disease Gene CHEK2 Alleles Genetic Association Studies Germ-Line Mutation Exome sequencing Genetics Alternative splicing Case-control study Computational Biology Reproducibility of Results medicine.disease Alternative Splicing 030104 developmental biology Oncology 030220 oncology & carcinogenesis Female Ubiquitin-Specific Proteases |
| Zdroj: | Breast Cancer Research and Treatment. 179:731-742 |
| ISSN: | 1573-7217 0167-6806 |
| Popis: | Germline variants in known breast cancer (BC) predisposing genes explain less than half of hereditary BC cases. This study aimed to identify missing genetic determinants of BC. Whole exome sequencing (WES) of lymphocyte DNA was performed for 49 Russian patients with clinical signs of genetic BC predisposition, who lacked Slavic founder mutations in BRCA1, BRCA2, CHEK2, and NBS1 genes. Bioinformatic analysis of WES data was allowed to compile a list of 229 candidate mutations. 79 of these mutations were subjected to a three-stage case–control analysis. The initial two stages, which involved up to 797 high-risk BC patients, 1504 consecutive BC cases, and 1081 healthy women, indicated a potentially BC-predisposing role for 6 candidates, i.e., USP39 c.*208G > C, PZP p.Arg680Ter, LEPREL1 p.Pro636Ser, SLIT3 p.Arg154Cys, CREB3 p.Lys157Glu, and ING1 p.Pro319Leu. USP39 c.*208G > C was strongly associated with triple-negative breast tumors (p = 0.0001). In the third replication stage, we genotyped the truncating variant of PZP (rs145240281) and the potential splice variant of USP39 (rs112653307) in three independent cohorts of Russian, Byelorussian, and German ancestry, comprising a total of 3216 cases and 2525 controls. The data obtained for USP39 rs112653307 supported the association identified in the initial stages (the combined OR 1.72, p = 0.035). This study suggests the role of a rare splicing variant in BC susceptibility. USP39 encodes an ubiquitin-specific peptidase that regulates cancer-relevant tumor suppressors including CHEK2. Further epidemiological and functional studies involving these gene variants are warranted. |
| Databáze: | OpenAIRE |
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