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The incidence of PALB2 c.3113G>A in women with a strong family history of breast and ovarian cancer attending familial cancer centres in Australia

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Abstract

The familial aggregation of breast cancer has been well-described with approximately 25 % of breast cancers attributable to inherited mutations in currently known breast cancer susceptibility genes. PALB2 c.3113G>A (p.Trp1038*) is a protein-truncating mutation which has been associated with high estimated risk of breast cancer in Australian women (91 %; 95 % CI = 44–100) to age 70 years. This study screened for PALB2 c.3113G>A in germline DNA representing 871 unrelated individuals from “high-risk” breast and/or ovarian cancer families evaluated in the setting of a Familial Cancer Centre in Australia. The PALB2 c.3113G>A mutation was identified in eight of 871 probands (0.92 %) from these families. Median age of diagnosis was 42 years. Five of these eight women had contra-lateral breast cancers. Available data suggests that PALB2 c.3113G>A is a rare mutation with estimated breast cancer risks similar in magnitude to that associated with BRCA2 mutations. Although the proportion of high-risk women carrying this PALB2 mutation is low, research efforts should continue in order to effect its translation into clinical genetic testing practice.

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Abbreviations

FCC:

Familial cancer centre

VFBCC:

Victorian familial breast cancer cohort

WGA:

Whole genome amplified

ER:

Estrogen receptor

PR:

Progesterone receptor

HER2:

Human epidermal growth factor-2

MLPA:

Multiplex ligation-dependent probe amplification

References

  1. Turnbull C, Rahman N (2008) Genetic predisposition to breast cancer: past, present, and future. Annu Rev Genomics Hum Genet 9:321–345. doi:10.1146/annurev.genom.9.081307.164339

    Article  PubMed  CAS  Google Scholar 

  2. Dite GS, Jenkins MA, Southey MC, Hocking JS, Giles GG, McCredie MRE, Venter DJ, Hopper JL (2003) Familial risks, early-onset breast cancer, and BRCA1 and BRCA2 germline mutations. J Natl Cancer Inst 95(6):448–457

    Article  PubMed  CAS  Google Scholar 

  3. Lynch HT, Watson P, Conway T, Fitzsimmons ML, Lynch J (1988) Breast-cancer family history as a risk factor for early onset breast-cancer. Breast Cancer Res Treat 11(3):263–267

    Article  PubMed  CAS  Google Scholar 

  4. Houlston RS, McCarter E, Parbhoo S, Scurr JH, Slack J (1992) Family history and risk of breast-cancer. J Med Genet 29(3):154–157

    Article  PubMed  CAS  Google Scholar 

  5. Colditz GA, Rosner BA, Speizer FE (1996) Risk factors for breast cancer according to family history of breast cancer. J Natl Cancer Inst 88(6):365–371

    Article  PubMed  CAS  Google Scholar 

  6. Frank TS, Deffenbaugh AM, Hulick M, Gumpper K (1999) Hereditary susceptibility to breast cancer: significance of age of onset in family history and contribution of BRCA1 and BRCA2. Dis Markers 15(1–3):89–92

    PubMed  CAS  Google Scholar 

  7. Negri E, Braga C, LaVecchia C, Franceschi S, Parazzini F (1997) Family history of cancer and risk of breast cancer. Int J Cancer 72(5):735–738

    Article  PubMed  CAS  Google Scholar 

  8. Poole CA, Byers T, Calle EE, Bondy J, Fain P, Rodriguez C (1999) Influence of a family history of cancer within and across multiple sites on patterns of cancer mortality risk for women. Am J Epidemiol 149(5):454–462

    Article  PubMed  CAS  Google Scholar 

  9. Beral V, Bull D, Doll R, Peto R, Reeves G (2001) Familial breast cancer: collaborative reanalysis of individual data from 52 epidemiological studies including 58,209 women with breast cancer and 101,986 women without the disease. Lancet 358(9291):1389–1399

    Article  Google Scholar 

  10. Hemminki K, Granstrom C (2003) Familial breast cancer: scope for more susceptibility genes? Breast Cancer Res Treat 82(1):17–22. doi:10.1023/B:BREA.0000003871.38587.8b

    Article  PubMed  CAS  Google Scholar 

  11. Peto J, Collins N, Barfoot R, Seal S, Warren W, Rahman N, Easton DF, Evans C, Deacon J, Stratton MR (1999) Prevalence of BRCA1 and BRCA2 gene mutations in patients with early-onset breast cancer. J Natl Cancer Inst 91(11):943–949. doi:10.1093/jnci/91.11.943

    Article  PubMed  CAS  Google Scholar 

  12. Cui JS, Antoniou AC, Dite GS, Southey MC, Venter DJ, Easton DF, Giles GG, McCredie MRE, Hopper JL (2001) After BRCA1 and BRCA2-what next? Multifactorial segregation analyses of three-generation, population-based Australian families affected by female breast cancer. Am J Hum Genet 68(2):420–431

    Article  PubMed  CAS  Google Scholar 

  13. Renwick A, Thompson D, Seal S, Kelly P, Chagtai T, Ahmed M, North B, Jayatilake H, Barfoot R, Spanova K, McGuffog L, Evans DG, Eccles D, Easton DF, Stratton MR, Rahman N (2006) ATM mutations that cause ataxia-telangiectasia are breast cancer susceptibility alleles. Nat Genet 38(8):873–875

    Article  PubMed  CAS  Google Scholar 

  14. Meijers-Heijboer H, van den Ouweland A, Klijn J, Wasielewski M, de Snoo A, Oldenburg R, Hollestelle A, Houben M, Crepin E, van Veghel-Plandsoen M, Elstrodt F, van Duijn C, Bartels C, Meijers C, Schutte M, McGuffog L, Thompson D, Easton DF, Sodha N, Seal S, Barfoot R, Mangion J, Chang-Claude J, Eccles D, Eeles R, Evans DG, Houlston R, Murday V, Narod S, Peretz T, Peto J, Phelan C, Zhang HX, Szabo C, Devilee P, Goldgar D, Futreal PA, Nathanson KL, Weber BL, Rahman N, Stratton MR (2002) Low-penetrance susceptibility to breast cancer due to CHEK2*1100delC in noncarriers of BRCA1 or BRCA2 mutations. Nat Genet 31(1):55–59. doi:10.1038/ng879

    Article  PubMed  CAS  Google Scholar 

  15. Seal S, Thompson D, Renwick A, Elliott A, Kelly P, Barfoot R, Chagtai T, Jayatilake H, Ahmed M, Spanova K, North B, McGuffog L, Evans DG, Eccles D, Easton DF, Stratton MR, Rahman N (2006) Truncating mutations in the Fanconi anemia J gene BRIP1 are low-penetrance breast cancer susceptibility alleles. Nat Genet 38(11):1239–1241. doi:10.1038/ng1902

    Article  PubMed  CAS  Google Scholar 

  16. Rahman N, Seal S, Thompson D, Kelly P, Renwick A, Elliott A, Reid S, Spanova K, Barfoot R, Chagtai T, Jayatilake H, McGuffog L, Hanks S, Evans DG, Eccles D, Easton DF, Stratton MR (2007) PALB2, which encodes a BRCA2-interacting protein, is a breast cancer susceptibility gene. Nat Genet 39(2):165–167

    Article  PubMed  CAS  Google Scholar 

  17. Sy SMH, Huen MSY, Chen JJ (2009) PALB2 is an integral component of the BRCA complex required for homologous recombination repair. Proc Natl Acad Sci USA 106(17):7155–7160. doi:10.1073/pnas.0811159106

    Article  PubMed  CAS  Google Scholar 

  18. Zhang F, Ma JL, Wu JX, Ye L, Cai H, Xia B, Yu XC (2009) PALB2 Links BRCA1 and BRCA2 in the DNA-Damage Response. Curr Biol 19(6):524–529. doi:10.1016/j.cub.2009.02.018

    Article  PubMed  CAS  Google Scholar 

  19. Byrnes GB, Southey MC, Hopper JL (2008) Are the so-called low penetrance breast cancer genes, ATM, BRIP1, PALB2 and CHEK2, high risk for women with strong family histories? Breast Cancer Res 10(3):208

    Article  PubMed  Google Scholar 

  20. Southey M, Teo Z, Dowty J, Odefrey F, Park D, Tischkowitz M, Sabbaghian N, Apicella C, Byrnes G, Winship I, Baglietto L, Giles G, Goldgar D, Foulkes W, Hopper J, kConFab, the Breast Cancer Family R (2010) A PALB2 mutation associated with high risk of breast cancer. Breast Cancer Res 12(6):R109

    Article  PubMed  CAS  Google Scholar 

  21. Antoniou A, Pharoah PDP, Narod S, Risch HA, Eyfjord JE, Hopper JL, Loman N, Olsson H, Johannsson O, Borg A, Pasini B, Radice P, Manoukian S, Eccles DM, Tang N, Olah E, Anton-Culver H, Warner E, Lubinski J, Gronwald J, Gorski B, Tulinius H, Thorlacius S, Eerola H, Nevanlinna H, Syrjakoski K, Kallioniemi OP, Thompson D, Evans C, Peto J, Lalloo F, Evans DG, Easton DF (2003) Average risks of breast and ovarian cancer associated with BRCA1 or BRCA2 mutations detected in case series unselected for family history: a combined analysis of 22 studies. Am J Hum Genet 72(5):1117–1130

    Article  PubMed  CAS  Google Scholar 

  22. Sawyer S, Mitchell G, McKinley J, Chenevix-Trench G, Beesley J, Chen XQ, Bowtell D, Trainer AH, Harris M, Lindeman GJ, James PA (2012) A role for common genomic variants in the assessment of familial breast cancer. J Clin Oncol

  23. Berry DA, Iversen ES Jr, Gudbjartsson DF, Hiller EH, Garber JE, Peshkin BN, Lerman C, Watson P, Lynch HT, Hilsenbeck SG, Rubinstein WS, Hughes KS, Parmigiani G (2002) BRCAPRO validation, sensitivity of genetic testing of BRCA1/BRCA2, and prevalence of other breast cancer susceptibility genes. J Clin Oncol 20(11):2701–2712

    Article  PubMed  CAS  Google Scholar 

  24. NBOCC (2012) Advice about familial aspects of breast cancer and epithelial ovarian cancer: a guide for health professionals. http://canceraustralia.nbocc.org.au/

  25. Tischkowitz M, Capanu M, Sabbaghian N, Li L, Liang X, Vallee MP, Tavtigian SV, Concannon P, Foulkes WD, Bernstein L, Bernstein JL, Begg CB (2012) Rare germline mutations in PALB2 and breast cancer risk: a population-based study. Hum Mutat 33(4):674–680. doi:10.1002/humu.22022

    Article  PubMed  CAS  Google Scholar 

  26. Elston CW, Ellis IO, Pinder SE (1999) Pathological prognostic factors in breast cancer. Crit Rev Oncol Hematol 31(3):209–223. doi:10.1016/s1040-8428(99)00034-7

    Article  PubMed  CAS  Google Scholar 

  27. Wong MW, Nordfors C, Mossman D, Pecenpetelovska G, Avery-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. doi:10.1007/s10549-011-1443-0

    Article  PubMed  CAS  Google Scholar 

  28. Casadei S, Norquist BM, Walsh T, Stray S, Mandell JB, Lee MK, Stamatoyannopoulos JA, King MC (2011) Contribution of inherited mutations in the BRCA2-Interacting protein PALB2 to familial breast cancer. Cancer Res 71(6):2222–2229. doi:10.1158/0008-5472.can-10-3958

    Article  PubMed  CAS  Google Scholar 

  29. Mann GJ, Thorne H, Balleine RL, Butow PN, Clarke CL, Edkins E, Evans GM, Fereday S, Haan E, Gattas M, Giles GG, Goldblatt J, Hopper JL, Kirk J, Leary JA, Lindeman G, Niedermayr E, Phillips KA, Picken S, Pupo GM, Saunders C, Scott CL, Spurdle AB, Suthers G, Tucker K, Chenevix-Trench G (2006) Analysis of cancer risk and BRCA1 and BRCA2 mutation prevalence in the kConFab familial breast cancer resource. Breast Cancer Res 8 (1):R12. doi: 10.1186/bcr1377

    Google Scholar 

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Acknowledgments

This study was supported by the Victorian Cancer Agency (CTTS07, EOI09-50); the National Health and Medical Research Council (NHMRC) via project grant APP1029974, Senior Research Fellowship (M.C.S.), Dora Lush Postgraduate Scholarship (Z.L.T.), Principal Research Fellowship (G.J.L.) and IRIISS; University of Melbourne, Postgraduate Faculty Research Scholarship (Z.L.T.) and the Victorian Breast Cancer Research Consortium and Operational Infrastructure Support. M.C.S. and G.J.L are Victorian Breast Cancer Research Consortium Group Leaders. We wish to thank A/Prof Ian Campbell and the VBCRC Cancer Genetics Laboratory, Peter MacCallum Cancer Centre for their assistance with the preparation of the DNA samples (Victorian Breast Cancer Research Consortium). We also thank Prof Ingrid Winship for her contribution and critical assessment of the manuscript. The authors gratefully acknowledge the contribution of the staff at the Familial Cancer centres who assisted in the annotation of the families and the staff of the Genetic Epidemiology Laboratory who supported aspects of the bench work.

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The authors declare that they have no conflict of interest.

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Correspondence to Melissa C. Southey.

Additional information

Zhi L. Teo and Sarah D. Sawyer contributed equally to this work.

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Teo, Z.L., Sawyer, S.D., James, P.A. et al. The incidence of PALB2 c.3113G>A in women with a strong family history of breast and ovarian cancer attending familial cancer centres in Australia. Familial Cancer 12, 587–595 (2013). https://doi.org/10.1007/s10689-013-9620-4

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  • DOI: https://doi.org/10.1007/s10689-013-9620-4

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