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

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Abstract

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.

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Abbreviations

TNBC:

Triple negative breast cancer

WES:

Whole exome sequencing

cfDNA:

Cell-free DNA

MAF:

Minor allele frequency

OR:

Odds ratio

dbSNP:

The single nucleotide polymorphism database

MMR:

Miss-match repair

HPLC:

High-performance liquid chromatography

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Authors and Affiliations

  1. Centre for Biotechnology, Institute of Science and Technology, Jawaharlal Nehru Technological University, Hyderabad, 500085, India

    M. Aravind Kumar, Uday Shanker & M. Lakshmi Narasu

  2. Sandor Life Sciences, Road No. 3, Banjara Hills, Hyderabad, 500034, India

    M. Aravind Kumar, Shaik Mohammad Naushad, Narasimhulu Narasimgu, S. Nagaraju Naik & Srilatha Kadali

Authors
  1. M. Aravind Kumar
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  2. Shaik Mohammad Naushad
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  3. Narasimhulu Narasimgu
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  4. S. Nagaraju Naik
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  5. Srilatha Kadali
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  6. Uday Shanker
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  7. M. Lakshmi Narasu
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Correspondence to M. Aravind Kumar.

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Conflict of interest

None of the authors has a financial or other relationship with other people or organizations that may inappropriately influence this work.

Ethical approval

The study protocol was approved by Institutional Ethical committee of This study was approved by The Institutional ethical committee of Sandor Proteomics Pvt Ltd, Hyderabad, India. (EC/SRP/008/2012, Dated 26.6.12.) This study complied with the ethical principles outlined in the Declaration of Helsinki.

Informed consent

Informed consent was obtained from all the study participants (Cases as well as controls) during their enrollment for the study.

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Aravind Kumar, M., Naushad, S.M., Narasimgu, N. et al. Whole exome sequencing of breast cancer (TNBC) cases from India: association of MSH6 and BRIP1 variants with TNBC risk and oxidative DNA damage. Mol Biol Rep 45, 1413–1419 (2018). https://doi.org/10.1007/s11033-018-4307-4

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  • DOI: https://doi.org/10.1007/s11033-018-4307-4

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