Skip to main content

Advertisement

SpringerLink
Log in

Deleterious RAD51C germline mutations rarely predispose to breast and ovarian cancer in Pakistan

  • Epidemiology
  • Published:
Breast Cancer Research and Treatment Aims and scope Submit manuscript

Abstract

RAD51C plays a key role in homologous recombination-mediated DNA repair and maintenance of genomic stability. Biallelic RAD51C mutations cause Fanconi anemia, and monoallelic mutations predispose women to breast and ovarian cancer. Genetic variability of RAD51C and its impact in Asian populations have been poorly studied. Here, we report the results of comprehensive mutational screening of the RAD51C gene in 348 BRCA1/2-negative breast and/or ovarian cancer patients from Pakistan. Mutation analysis of the complete RAD51C-coding region was performed using denaturing high-performance liquid chromatography analysis, followed by DNA sequencing of variant fragments. Three novel protein-truncating mutations, c.204T>A, c.225T>G, and c.701C>G, were identified. c.204T>A was found in one out of 22 (4.5 %) early-onset (≤45 years of age) ovarian cancer patients and c.225T>G in one out of 119 (0.8 %) patients from breast cancer only families. c.701C>G was found in a 60-year-old control with no family history of breast/ovarian cancer. Furthermore, three novel in silico-predicted potentially functional mutations, a missense mutation, c.873T>G, a variant in 5′UTR, c.1-34T>G, and a recurrent intronic variant, c.965+21A>G, were identified. The missense mutation was observed in a patient with bilateral breast cancer from a breast and ovarian cancer family (HBOC), the 5′UTR variant was noted in an early-onset breast cancer patient, and the intronic variant in one early-onset breast cancer patient and one ovarian cancer patient from a HBOC family. Five of the six mutations described were not detected in 400 healthy controls. These findings suggest that RAD51C plays a marginal role in breast and ovarian cancer predisposition in Pakistan. Reliable estimation of the clinical implications of carrying a deleterious RAD51C mutation will require identification of additional mutation-positive patients/families.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1

Similar content being viewed by others

References

  1. Howlett NG, Taniguchi T, Olson S, Cox B, Waisfisz Q, De Die-Smulders C, Persky N, Grompe M, Joenje H, Pals G, Ikeda H, Fox EA, D’Andrea AD (2002) Biallelic inactivation of BRCA2 in Fanconi anemia. Science 297(5581):606–609

    Article  CAS  PubMed  Google Scholar 

  2. Xia B, Dorsman JC, Ameziane N, de Vries Y, Rooimans MA, Sheng Q, Pals G, Errami A, Gluckman E, Llera J, Wang W, Livingston DM, Joenje H, de Winter JP (2007) Fanconi anemia is associated with a defect in the BRCA2 partner PALB2. Nat Genet 39(2):159–161

    Article  CAS  PubMed  Google Scholar 

  3. Levran O, Attwooll C, Henry RT, Milton KL, Neveling K, Rio P, Batish SD, Kalb R, Velleuer E, Barral S, Ott J, Petrini J, Schindler D, Hanenberg H, Auerbach AD (2005) The BRCA1-interacting helicase BRIP1 is deficient in Fanconi anemia. Nat Genet 37(9):931–933

    Article  CAS  PubMed  Google Scholar 

  4. Vaz F, Hanenberg H, Schuster B, Barker K, Wiek C, Erven V, Neveling K, Endt D, Kesterton I, Autore F, Fraternali F, Freund M, Hartmann L, Grimwade D, Roberts RG, Schaal H, Mohammed S, Rahman N, Schindler D, Mathew CG (2010) Mutation of the RAD51C gene in a Fanconi anemia-like disorder. Nat Genet 42(5):406–409

    Article  CAS  PubMed  Google Scholar 

  5. Meindl A, Hellebrand H, Wiek C, Erven V, Wappenschmidt B, Niederacher D, Freund M, Lichtner P, Hartmann L, Schaal H, Ramser J, Honisch E, Kubisch C, Wichmann HE, Kast K, Deissler H, Engel C, Muller-Myhsok B, Neveling K, Kiechle M, Mathew CG, Schindler D, Schmutzler RK, Hanenberg H (2010) Germline mutations in breast and ovarian cancer pedigrees establish RAD51C as a human cancer susceptibility gene. Nat Genet 42(5):410–414

    Article  CAS  PubMed  Google Scholar 

  6. Akbari MR, Tonin P, Foulkes WD, Ghadirian P, Tischkowitz M, Narod SA (2010) RAD51C germline mutations in breast and ovarian cancer patients. Breast Cancer Res 12(4):404–405

    Article  PubMed Central  PubMed  Google Scholar 

  7. De Leeneer K, Van BM, De BS, Swietek N, Schietecatte P, Sabbaghian N, Van den EJ, Willocx S, Storm K, Blaumeiser B, van Asperen CJ, Wijnen JT, Leunen K, Legius E, Michils G, Matthijs G, Blok MJ, Gomez-Garcia E, De PA, Tischkowitz M, Poppe B, Claes K (2012) Evaluation of RAD51C as cancer susceptibility gene in a large breast-ovarian cancer patient population referred for genetic testing. Breast Cancer Res Treat 133(1):393–398

    Article  CAS  PubMed  Google Scholar 

  8. Lu W, Wang X, Lin H, Lindor NM, Couch FJ (2012) Mutation screening of RAD51C in high-risk breast and ovarian cancer families. Fam Cancer 11(3):381–385

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  9. Zheng Y, Zhang J, Hope K, Niu Q, Huo D, Olopade OI (2010) Screening RAD51C nucleotide alterations in patients with a family history of breast and ovarian cancer. Breast Cancer Res Treat 124(3):857–861

    Article  CAS  PubMed  Google Scholar 

  10. Wong MW, Nordfors C, Mossman D, Pecenpetelovska G, Very-Kiejda KA, Talseth-Palmer B, Bowden NA, Scott RJ (2011) BRIP1, PALB2, and RAD51C mutation analysis reveals their relative importance as genetic susceptibility factors for breast cancer. Breast Cancer Res Treat 127(3):853–859

    Article  CAS  PubMed  Google Scholar 

  11. Kushnir A, Laitman Y, Shimon SP, Berger R, Friedman E (2012) Germline mutations in RAD51C in Jewish high cancer risk families. Breast Cancer Res Treat 136(3):869–874

    Article  CAS  PubMed  Google Scholar 

  12. Osorio A, Endt D, Fernandez F, Eirich K, de la Hoya M, Schmutzler R, Caldes T, Meindl A, Schindler D, Benitez J (2012) Predominance of pathogenic missense variants in the RAD51C gene occurring in breast and ovarian cancer families. Hum Mol Genet 21(13):2889–2898

    Article  CAS  PubMed  Google Scholar 

  13. Romero A, Perez-Segura P, Tosar A, Garcia-Saenz JA, Az-Rubio E, Caldes T, de la Hoya M (2011) A HRM-based screening method detects RAD51C germ-line deleterious mutations in Spanish breast and ovarian cancer families. Breast Cancer Res Treat 129(3):939–946

    Article  CAS  PubMed  Google Scholar 

  14. Loveday C, Turnbull C, Ruark E, Xicola RM, Ramsay E, Hughes D, Warren-Perry M, Snape K, Eccles D, Evans DG, Gore M, Renwick A, Seal S, Antoniou AC, Rahman N (2012) Germline RAD51C mutations confer susceptibility to ovarian cancer. Nat Genet 44(5):475–476

    Article  CAS  PubMed  Google Scholar 

  15. Thompson ER, Boyle SE, Johnson J, Ryland GL, Sawyer S, Choong DYH, kConFab, Chenevix-Trench G, Trainer AH, Lindeman GJ, Mitchell G, James PA, Campbell IG (2012) Analysis of RAD51C germline mutations in high-risk breast and ovarian cancer families and ovarian cancer patients. Hum Mutat 33(1):95–99

    Article  CAS  PubMed  Google Scholar 

  16. Coulet F, Fajac A, Colas C, Eyries M, Dion-Miniere A, Rouzier R, Uzan S, Lefranc JP, Carbonnel M, Cornelis F, Cortez A, Soubrier F (2013) Germline RAD51C mutations in ovarian cancer susceptibility. Clin Genet 83(4):332–336

    Article  CAS  PubMed  Google Scholar 

  17. Vuorela M, Pylkas K, Hartikainen JM, Sundfeldt K, Lindblom A, von Wachenfeldt WA, Haanpaa M, Puistola U, Rosengren A, Anttila M, Kosma VM, Mannermaa A, Winqvist R (2011) Further evidence for the contribution of the RAD51C gene in hereditary breast and ovarian cancer susceptibility. Breast Cancer Res Treat 130(3):1003–1010

    Article  CAS  PubMed  Google Scholar 

  18. Pelttari LM, Heikkinen T, Thompson D, Kallioniemi A, Schleutker J, Holli K, Blomqvist C, Aittomaki K, Butzow R, Nevanlinna H (2011) RAD51C is a susceptibility gene for ovarian cancer. Hum Mol Genet 20(16):3278–3288

    Article  CAS  PubMed  Google Scholar 

  19. Pang Z, Yao L, Zhang J, Ouyang T, Li J, Wang T, Fan Z, Fan T, Lin B, Xie Y (2011) RAD51C germline mutations in Chinese women with familial breast cancer. Breast Cancer Res Treat 129(3):1019–1020

    Article  PubMed  Google Scholar 

  20. Rashid MU, Zaidi A, Torres D, Sultan F, Benner A, Naqvi B, Shakoori AR, Seidel-Renkert A, Farooq H, Narod S, Amin A, Hamann U (2006) Prevalence of BRCA1 and BRCA2 mutations in Pakistani breast and ovarian cancer patients. Int J Cancer 119(12):2832–2839

    Article  CAS  PubMed  Google Scholar 

  21. Rashid MU, Gull S, Asghar K, Muhammad N, Amin A, Hamann U (2012) Prevalence of TP53 germ line mutations in young Pakistani breast cancer patients. Fam Cancer 11(2):307–311

    Article  CAS  PubMed  Google Scholar 

  22. Rashid MU, Muhammad N, Faisal S, Amin A, Hamann U (2013) Constitutional CHEK2 mutations are infrequent in early-onset and familial breast/ovarian cancer patients from Pakistan. BMC Cancer 13(6):312–318

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  23. Silvestri V, Rizzolo P, Falchetti M, Zanna I, Masala G, Palli D, Ottini L (2011) Mutation screening of RAD51C in male breast cancer patients. Breast Cancer Res 13(1):404–405

    Article  PubMed Central  PubMed  Google Scholar 

  24. Schnurbein G, Hauke J, Wappenschmidt B, Weber-Lassalle N, Engert S, Hellebrand H, Garbes L, Becker A, Neidhardt G, Rhiem K, Meindl A, Schmutzler RK, Hahnen E (2013) RAD51C deletion screening identifies a recurrent gross deletion in breast cancer and ovarian cancer families. Breast Cancer Res 15(6):R120

    Article  PubMed Central  PubMed  Google Scholar 

  25. Petitjean A, Mathe E, Kato S, Ishioka C, Tavtigian SV, Hainaut P, Olivier M (2007) Impact of mutant p53 functional properties on TP53 mutation patterns and tumor phenotype: lessons from recent developments in the IARC TP53 database. Hum Mutat 28(6):622–629

    Article  CAS  PubMed  Google Scholar 

  26. Chan PA, Duraisamy S, Miller PJ, Newell JA, McBride C, Bond JP, Raevaara T, Ollila S, Nystrom M, Grimm AJ, Christodoulou J, Oetting WS, Greenblatt MS (2007) Interpreting missense variants: comparing computational methods in human disease genes CDKN2A, MLH1, MSH2, MECP2, and tyrosinase (TYR). Hum Mutat 28(7):683–693

    Article  CAS  PubMed  Google Scholar 

  27. Usmani K, Khanum A, Afzal H, Ahmad N (1996) Breast carcinoma in Pakistani women. J Environ Pathol Toxicol Oncol 15(2–4):251–253

    CAS  PubMed  Google Scholar 

  28. Bhurgri Y, Kayani N, Faridi N, Pervez S, Usman A, Bhurgri H, Malik J, Bashir I, Bhurgri A, Hasan SH, Zaidi SH (2007) Patho-epidemiology of breast cancer in Karachi ‘1995–1997’. Asian Pac J Cancer Prev 8(2):215–220

    PubMed  Google Scholar 

  29. Kakarala M, Rozek L, Cote M, Liyanage S, Brenner DE (2010) Breast cancer histology and receptor status characterization in Asian Indian and Pakistani women in the U.S—a SEER analysis. BMC Cancer 10:191

    Article  PubMed Central  PubMed  Google Scholar 

  30. Moran MS, Gonsalves L, Goss DM, Ma S (2011) Breast cancers in U.S. residing Indian-Pakistani versus non-Hispanic White women: comparative analysis of clinical-pathologic features, treatment, and survival. Breast Cancer Res Treat 128(2):543–551

    Article  PubMed Central  PubMed  Google Scholar 

  31. Scheckenbach K, Baldus SE, Balz V, Freund M, Pakropa P, Sproll C, Schafer KL, Wagenmann M, Schipper J, Hanenberg H (2014) RAD51C—a new human cancer susceptibility gene for sporadic squamous cell carcinoma of the head and neck (HNSCC). Oral Oncol 50(3):196–199

    Article  CAS  PubMed  Google Scholar 

  32. Clague J, Wilhoite G, Adamson A, Bailis A, Weitzel JN, Neuhausen SL (2011) RAD51C germline mutations in breast and ovarian cancer cases from high-risk families. PLoS ONE 6(9):e25632

    Article  CAS  PubMed Central  PubMed  Google Scholar 

Download references

Acknowledgments

We are grateful to all family members for their participation in this study. This study was supported by the Shaukat Khanum Memorial Cancer Hospital and Research Centre and the German Cancer Research Center.

Conflict of interest

The authors declare that they have no conflicts of interest.

Author information

Authors and Affiliations

  1. Shaukat Khanum Memorial Cancer Hospital and Research Centre (SKMCH & RC), Lahore, Pakistan

    Muhammad U. Rashid, Noor Muhammad & Saima Faisal

  2. German Cancer Research Center (DKFZ), Molecular Genetics of Breast Cancer, Im Neuenheimer Feld 580, 69120, Heidelberg, Germany

    Muhammad U. Rashid & Ute Hamann

  3. Carolinas Medical Center, Levine Cancer Institute, Charlotte, USA

    Asim Amin

Authors
  1. Muhammad U. Rashid
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Noor Muhammad
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Saima Faisal
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Asim Amin
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Ute Hamann
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Ute Hamann.

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Rashid, M.U., Muhammad, N., Faisal, S. et al. Deleterious RAD51C germline mutations rarely predispose to breast and ovarian cancer in Pakistan. Breast Cancer Res Treat 145, 775–784 (2014). https://doi.org/10.1007/s10549-014-2972-0

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s10549-014-2972-0

Keywords

Search

Navigation