Familial Cancer

, Volume 12, Issue 4, pp 587–595 | Cite as

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

  • Zhi L. Teo
  • Sarah D. Sawyer
  • Paul A. James
  • Gillian Mitchell
  • Alison H. Trainer
  • Geoffrey J. Lindeman
  • Kylie Shackleton
  • Linda Cicciarelli
  • Melissa C. Southey
Letter to the Editor

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.

Keywords

PALB2 Hereditary breast cancer Familial cancer centre BRCA1 and BRCA2 mutation negative 

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. 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 PubMedCrossRefGoogle Scholar
  2. 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):448–457PubMedCrossRefGoogle Scholar
  3. 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):263–267PubMedCrossRefGoogle Scholar
  4. 4.
    Houlston RS, McCarter E, Parbhoo S, Scurr JH, Slack J (1992) Family history and risk of breast-cancer. J Med Genet 29(3):154–157PubMedCrossRefGoogle Scholar
  5. 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):365–371PubMedCrossRefGoogle Scholar
  6. 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):89–92PubMedGoogle Scholar
  7. 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):735–738PubMedCrossRefGoogle Scholar
  8. 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):454–462PubMedCrossRefGoogle Scholar
  9. 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):1389–1399CrossRefGoogle Scholar
  10. 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 PubMedCrossRefGoogle Scholar
  11. 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 PubMedCrossRefGoogle Scholar
  12. 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):420–431PubMedCrossRefGoogle Scholar
  13. 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):873–875PubMedCrossRefGoogle Scholar
  14. 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 PubMedCrossRefGoogle Scholar
  15. 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 PubMedCrossRefGoogle Scholar
  16. 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):165–167PubMedCrossRefGoogle Scholar
  17. 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 PubMedCrossRefGoogle Scholar
  18. 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 PubMedCrossRefGoogle Scholar
  19. 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):208PubMedCrossRefGoogle Scholar
  20. 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):R109PubMedCrossRefGoogle Scholar
  21. 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):1117–1130PubMedCrossRefGoogle Scholar
  22. 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 OncolGoogle Scholar
  23. 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):2701–2712PubMedCrossRefGoogle Scholar
  24. 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. 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 PubMedCrossRefGoogle Scholar
  26. 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 PubMedCrossRefGoogle Scholar
  27. 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 PubMedCrossRefGoogle Scholar
  28. 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 PubMedCrossRefGoogle Scholar
  29. 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

Copyright information

© Springer Science+Business Media Dordrecht 2013

Authors and Affiliations

  • Zhi L. Teo
    • 1
  • Sarah D. Sawyer
    • 2
  • Paul A. James
    • 2
    • 3
  • Gillian Mitchell
    • 2
    • 3
  • Alison H. Trainer
    • 2
    • 4
  • Geoffrey J. Lindeman
    • 4
    • 5
    • 6
  • Kylie Shackleton
    • 4
  • Linda Cicciarelli
    • 2
  • Melissa C. Southey
    • 1
  1. 1.Genetic Epidemiology Laboratory, Department of PathologyThe University of MelbourneMelbourneAustralia
  2. 2.Familial Cancer CentreThe Peter MacCallum Cancer CentreEast MelbourneAustralia
  3. 3.The Sir Peter MacCallum Department of OncologyThe University of MelbourneMelbourneAustralia
  4. 4.Familial Cancer CentreThe Royal Melbourne HospitalParkvilleAustralia
  5. 5.The Walter and Eliza Hall Institute of Medical ResearchParkvilleAustralia
  6. 6.The Department of MedicineThe University of MelbourneMelbourneAustralia

Personalised recommendations