Whole exome sequencing of breast cancer (TNBC) cases from India: association of MSH6 and BRIP1 variants with TNBC risk and oxidative DNA damage

• Published in: Molecular biology reports 2018-10, Vol.45 (5), p.1413-1419
• Main Authors: Aravind Kumar, M., Naushad, Shaik Mohammad, Narasimgu, Narasimhulu, Nagaraju Naik, S., Kadali, Srilatha, Shanker, Uday, Lakshmi Narasu, M.
• Format: Article
• Language: English
• Subjects: Aged; Animal Anatomy; Animal Biochemistry; Biomedical and Life Sciences; BRCA1 protein; BRCA1 Protein - genetics; Breast cancer; Cell cycle; Deoxyribonucleic acid; Detoxification; DNA; DNA Damage; DNA Repair; DNA sequencing; DNA-Binding Proteins - genetics; DNA-Binding Proteins - metabolism; ErbB-2 protein; Fanconi Anemia Complementation Group Proteins - genetics; Fanconi Anemia Complementation Group Proteins - metabolism; Female; Gelatinase B; Gene Frequency; Genetic Association Studies; Genetic Predisposition to Disease; Genomes; Histology; Humans; Life Sciences; Metastases; Middle Aged; Mismatch repair; Morphology; MSH6 protein; Nucleotide excision repair; Original Article; Oxidative Stress - genetics; Polymorphism, Single Nucleotide; Pruning; Receptor, ErbB-2 - genetics; Receptor, ErbB-2 - metabolism; Risk Factors; RNA Helicases - genetics; RNA Helicases - metabolism; Triple Negative Breast Neoplasms - genetics; Whole Exome Sequencing - methods; Xeroderma Pigmentosum Group D Protein - genetics; Xeroderma Pigmentosum Group D Protein - metabolism
• ISSN: 0301-4851; 1573-4978
• DOI: 10.1007/s11033-018-4307-4

Whole exome sequencing in triple negative breast cancer cases (n = 8) and targeted sequencing in healthy controls (n = 48) revealed BRIP1 rs552752779 (MAF: 75% vs. 6.25%, OR 45.00, 95% CI 9.43–243.32), ERBB2 rs527779103 (MAF: 62.5% vs. 7.29%, OR 21.19, 95% CI 5.11–94.32), ERCC2 rs121913016 (MAF: 56.25% vs. 7.29%, OR 16.34, 95% CI 4.02–70.41), MSH6 rs2020912 (MAF: 56.25% vs. 1.04%, OR 122.13, 95% CI 12.29–2985.48) as risk factors for triple negative breast cancer. Construction of classification and regression tree followed by smart pruning identified MSH6 and BRIP1 variants as the major determinants of TNBC (Triple Negative Breast Cancer) risk. Except for ERBB2, all other genes regulate DNA repair and chromosomal integrity. In TNBC cases, two likely pathogenic variations i.e. NCOR1 rs562300336 and PIM1 rs746748226 were observed at frequencies of 18.75% and 12.5%, respectively. Among the 24 variants of unknown significance, MMP9 rs199676062, SYNE1 rs368709678, AURKA rs373550419, ABCC4 rs11568694 have variant allele frequency ≥ 62.5%. These genes regulate metastasis, nuclear modeling, cell cycle and cellular detoxification, respectively. To conclude, aberrations in DNA mismatch repair, nucleotide excision repair or BRCA1 associated genome surveillance mechanism contribute towards triple negative breast cancer.