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Breast cancer risk associated with BRCA1/2 variants in the Pakistani population

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Abstract

Background

Majority of the BRCA1 and BRCA2 mutations are associated with the risk of sporadic and familial breast cancer. Since these genes are significant in DNA repair mechanisms, we focused homology-directed DNA repair (HDDR) and BRCA complex.

Methods

We selected BRCA1 variant (rs80356932, 4491C/T) and BRCA2 variant (rs80359182, 319T/C) from the interaction region of BRCA complex and studied in 100 breast cancer patients and 100 controls using tetra-ARMS-PCR.

Results

Here we show that BRCA1 and BRCA2 variants are significantly associated with high breast cancer risk (BRCA1 rs80356932; Genotype T/T OR 8.66, 95% CI 3.16–23.71, p < 0.0001; Allele-T, OR 2.48, 95% CI 1.62–3.81, p < 0.0001 and BRCA2 rs80359182; Genotype C/C OR 4.32, 95% CI 1.95–9.53, p = 0.0001; Allele-C, OR 2.19, 95% CI 1.43–3.34, p = 0.0002). Additionally, bioinformatics analysis showed that BRCA2-tryptophan > arginine substitutions result in altered interaction of BRCA1/PALB2/BRCA2/protein complex and impaired HDDR pathway. We also observed that breast cancer risk was significantly increased in over-weighted and obese women.

Conclusions

Our results indicate that high risk of breast cancer is significantly associated with BRCA1 and BRCA2 variants, and mutations may alter the protein interactions of BRCA complex that results in tumor genesis.

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References

  1. Torre LA, Bray F, Siegel RL, Ferlay J, Lortet-Tieulent J, Jemal A. Global cancer statistics, 2012. CA. 2015;65(2):87–108.

    PubMed  Google Scholar 

  2. Khan RT, Siddique A, Shahid N, Khokher S, Fatima W. Breast cancer risk associated with genes encoding DNA repair MRN complex: a study from Punjab, Pakistan. Breast Cancer. 2018;25(3):350–5. https://doi.org/10.1007/s12282-018-0837-9.

    Article  PubMed  Google Scholar 

  3. Bhurgri Y. Karachi cancer registry data—implications for the national cancer control program of Pakistan. Asian Pac J Cancer Prev. 2004;5(1):77–82.

    PubMed  Google Scholar 

  4. Shaukat U, Ismail M, Mehmood N. Epidemiology, major risk factors and genetic predisposition for breast cancer in the Pakistani population. Asian Pac J Cancer Prev. 2013;14(10):5625–9.

    Article  Google Scholar 

  5. Rosen M, Pishvaian EJ M. Targeting the BRCA1/2 tumor suppressors. Curr Drug Targets. 2014;15(1):17–31.

    Article  CAS  Google Scholar 

  6. Aparicio T, Baer R, Gautier J. DNA double-strand break repair pathway choice and cancer. DNA Repair. 2014;19:169–75.

    Article  CAS  Google Scholar 

  7. Kleibl Z, Kristensen VN. Women at high risk of breast cancer: molecular characteristics, clinical presentation and management. Breast. 2016;28:136–44.

    Article  Google Scholar 

  8. Prodosmo A, Buffone A, Mattioni M, Barnabei A, Persichetti A, De Leo A, Appetecchia M, Nicolussi A, Coppa A, Sciacchitano S. Detection of ATM germline variants by the p53 mitotic centrosomal localization test in BRCA1/2-negative patients with early-onset breast cancer. J Exp Clin Cancer Res. 2016;35(1):135.

    Article  Google Scholar 

  9. Kapoor NS, Curcio LD, Blakemore CA, Bremner AK, McFarland RE, West JG, Banks KC. Multigene panel testing detects equal rates of pathogenic BRCA1/2 mutations and has a higher diagnostic yield compared to limited BRCA1/2 analysis alone in patients at risk for hereditary breast cancer. Ann Surg Oncol. 2015;22(10):3282–8.

    Article  Google Scholar 

  10. Norquist BM, Harrell MI, Brady MF, Walsh T, Lee MK, Gulsuner S, Bernards SS, Casadei S, Yi Q, Burger RA. Inherited mutations in women with ovarian carcinoma. JAMA Oncol. 2016;2(4):482–90.

    Article  Google Scholar 

  11. Prakash R, Zhang Y, Feng W, Jasin M. Homologous recombination and human health: the roles of BRCA1, BRCA2, and associated proteins. Cold Spring Harb Perspect Biol. 2015;7(4):a016600.

    Article  Google Scholar 

  12. Huen MS, Sy SM, Chen J. BRCA1 and its toolbox for the maintenance of genome integrity. Nat Rev Mol Cell Biol. 2010;11(2):138.

    Article  CAS  Google Scholar 

  13. Eroles P. Members of the BRCA1 complexes as new susceptibility genes for breast cancer. Transl Cancer Res. 2013;2(2):103–5.

    CAS  Google Scholar 

  14. Daley JM, Kwon Y, Niu H, Sung P. Focus: 50 years of DNA repair: the Yale symposium reports: investigations of homologous recombination pathways and their regulation. Yale J Biol Med. 2013;86(4):453.

    CAS  PubMed  PubMed Central  Google Scholar 

  15. Shahid T, Soroka J, Kong EH, Malivert L, McIlwraith MJ, Pape T, West SC, Zhang X. Structure and mechanism of action of the BRCA2 breast cancer tumor suppressor. Nat Struct Mol Biol. 2014;21(11):962.

    Article  CAS  Google Scholar 

  16. Holloman WK. Unraveling the mechanism of BRCA2 in homologous recombination. Nat Struct Mol Biol. 2011;18(7):748.

    Article  CAS  Google Scholar 

  17. Liu J, Doty T, Gibson B, Heyer W-D. Human BRCA2 protein promotes RAD51 filament formation on RPA-covered single-stranded DNA. Nat Struct Mol Biol. 2010;17(10):1260.

    Article  CAS  Google Scholar 

  18. Al Abo M, Dejsuphong D, Hirota K, Yonetani Y, Yamazoe M, Kurumizaka H, Takeda S. Compensatory functions and Interdependency of the DNA-binding domain of BRCA2 with the BRCA1–PALB2–BRCA2 complex. Cancer Res. 2014;74(3):797–807.

    Article  CAS  Google Scholar 

  19. Oliver AW, Swift S, Lord CJ, Ashworth A, Pearl LH. Structural basis for recruitment of BRCA2 by PALB2. EMBO Rep. 2009;10(9):990–6.

    Article  CAS  Google Scholar 

  20. Zhang F, Ma J, Wu J, Ye L, Cai H, Xia B, Yu X. PALB2 links BRCA1 and BRCA2 in the DNA-damage response. Curr Biol. 2009;19(6):524–9.

    Article  CAS  Google Scholar 

  21. Park J-Y, Zhang F, Andreassen PR. ALB2: the hub of a network of tumor suppressors involved in DNA damage responses. Biochim Biophys Acta. 2014;1:263–75.

    Google Scholar 

  22. Apostolou P, Fostira F. Hereditary breast cancer: the era of new susceptibility genes. Biomed Res Int. 2013;2013:747318.

    Article  Google Scholar 

  23. Ding YC, Steele L, Kuan C-J, Greilac S, Neuhausen SL. Mutations in BRCA2 and PALB2 in male breast cancer cases from the United States. Breast Cancer Res Treat. 2011;126(3):771–8.

    Article  CAS  Google Scholar 

  24. Elia AE, Elledge SJ. BRCA1 as tumor suppressor: lord without its RING? Breast Cancer Res. 2012;14(2):306.

    Article  CAS  Google Scholar 

  25. Kasparek TR. Humphrey TC DNA double-strand break repair pathways, chromosomal rearrangements and cancer. Semin Cell Dev Biol. 2011;8:886–97.

    Article  Google Scholar 

  26. Kass EM, Jasin M. Collaboration and competition between DNA double-strand break repair pathways. FEBS Lett. 2010;584(17):3703–8.

    Article  CAS  Google Scholar 

  27. Roy R, Chun J, Powell SN. BRCA1 and BRCA2: different roles in a common pathway of genome protection. Nat Rev Cancer. 2012;12(1):68.

    Article  CAS  Google Scholar 

  28. Adank M, van Mil S, Gille J, Waisfisz Q, Meijers-Heijboer H. PALB2 analysis in BRCA2-like families. Breast Cancer Res Treat. 2011;127(2):357–62.

    Article  CAS  Google Scholar 

  29. Lee EY, Muller WJ. Oncogenes and tumor suppressor genes. Cold Spring Harb Perspect Biol. 2010;2(10):a003236.

    Article  CAS  Google Scholar 

  30. Anantha RW, Alcivar AL, Ma J, Cai H, Simhadri S, Ule J, König J, Xia B. Requirement of heterogeneous nuclear ribonucleoprotein C for BRCA gene expression and homologous recombination. PLoS One. 2013;8(4):e61368.

    Article  CAS  Google Scholar 

  31. Ciccia A, Elledge SJ. The DNA damage response: making it safe to play with knives. Mol Cell. 2010;40(2):179–204.

    Article  CAS  Google Scholar 

  32. Kang PCE, Phuah SY, Sivanandan K, Kang IN, Thirthagiri E, Liu JJ, Hassan N, Yoon S-Y, Thong MK, Hui M. Recurrent mutation testing of BRCA1 and BRCA2 in Asian breast cancer patients identify carriers in those with presumed low risk by family history. Breast Cancer Res Treat. 2014;144(3):635–42.

    Article  CAS  Google Scholar 

  33. Xia B, Sheng Q, Nakanishi K, Ohashi A, Wu J, Christ N, Liu X, Jasin M, Couch FJ, Livingston DM. Control of BRCA2 cellular and clinical functions by a nuclear partner, PALB2. Mol Cell. 2006;22(6):719–29.

    Article  CAS  Google Scholar 

  34. Ye S, Dhillon S, Ke X, Collins AR, Day IN. An efficient procedure for genotyping single nucleotide polymorphisms. Nucleic Acids Res. 2001;29(17):e88–8.

    Article  CAS  Google Scholar 

  35. Ikeda N, Miyoshi Y, Yoneda K, Shiba E, Sekihara Y, Kinoshita M, Noguchi S. Frequency of BRCA1 and BRCA2 germline mutations in Japanese breast cancer families. Int J Cancer. 2001;91(1):83–8.

    Article  CAS  Google Scholar 

  36. Rasmussen SA, Overman J, Thomson SA, Colman SD, Abernathy CR, Trimpert RE, Moose R, Virdi G, Roux K, Bauer M. Chromosome 17 loss-of-heterozygosity studies in benign and malignant tumors in neurofibromatosis type 1. Genes Chromosom Cancer. 2000;28(4):425–31.

    Article  CAS  Google Scholar 

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Authors and Affiliations

  1. Department of Microbiology and Molecular Genetics, University of the Punjab, Quaid-e-azam Campus, Lahore, Pakistan

    Saba Abbas, Ayesha Siddique, Rabbia Tariq Khan & Warda Fatima

  2. Department of Environmental Sciences, COMSATS University Islamabad, Vehari Campus, Pakistan

    Naeem Shahid

Authors
  1. Saba Abbas
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  2. Ayesha Siddique
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  3. Naeem Shahid
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  4. Rabbia Tariq Khan
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  5. Warda Fatima
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Corresponding authors

Correspondence to Ayesha Siddique or Warda Fatima.

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The authors declare that they have no conflicts of interest.

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Abbas, S., Siddique, A., Shahid, N. et al. Breast cancer risk associated with BRCA1/2 variants in the Pakistani population. Breast Cancer 26, 365–372 (2019). https://doi.org/10.1007/s12282-018-0932-y

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  • DOI: https://doi.org/10.1007/s12282-018-0932-y

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