Breast Cancer Research and Treatment

, Volume 108, Issue 3, pp 399–408 | Cite as

Germline TP53 mutations in BRCA1 and BRCA2 mutation-negative French Canadian breast cancer families

  • Suzanna L. Arcand
  • Christine M. Maugard
  • Parviz Ghadirian
  • André Robidoux
  • Chantal Perret
  • Phil Zhang
  • Eve Fafard
  • Anne-Marie Mes-Masson
  • William D. Foulkes
  • Diane Provencher
  • Steven A. Narod
  • Patricia N. Tonin
Epidemiology
First Online:
Received:
Accepted:

Abstract

About 40% of French Canadian breast and/or ovarian cancer families harbor germline BRCA1 or BRCA1 mutations where common mutations account for about 84% of all mutations identified in cancer families. Within a series of BRCA1 and BRCA2 mutation-negative families, a germline TP53 13398 G>A (Arg213Gln) mutation was identified, which was selected for mutation analysis in this gene because of a family history consistent with Li–Fraumeni syndrome (LFS). Given the founder effects in this population, the 13398 G>A mutation was screened in series of 52 BRCA1 and BRCA2 mutation-negative cancer families, and a mutation-positive family was identified. However, pedigree inspection and expansion of mutation-positive families with the same mutation revealed that they were closely related to each other. To further characterize the contribution of TP53 in cancer families, mutation analysis was performed in the remaining BRCA1 and BRCA2 mutation-negative cancer families. Thirty sequence variants were identified, the majority of which occur in intronic sequences and are not predicted to affect the functionality of TP53. However, the 14538 G>A (Arg290His) mutation was identified in a family which did not exhibit features consistent with LFS or Li–Fraumeni-like (LFL) syndrome. Neither of the TP53 mutations was detected in 381 French Canadian women with breast cancer diagnosed before 50 years of age not selected for family history of cancer. In all, germline TP53 mutations were identified in two of 52 (3.8%) cancer families, suggesting that TP53 is not a major contributor to BRCA1 and BRCA2 mutation-negative breast and/or ovarian cancer families of French Canadian descent.

Keywords

TP53 BRCA1 BRCA2 Breast cancer French Canadian Founder effects 
This is a preview of subscription content, log in to check access.

Notes

Acknowledgments

With thank Marise Roy, Stéphanie Lepage, Manon Deladurantaye, and Myriam Costa for technical support. C.M.M. is a recipient of a chercheur-boursier Fonds de la recherche en santé du Québec (F.R.S.Q.). This work was supported by grants from the Cancer Research Society Inc., to P.N.T., and the Banque de tissus et de données of the Réseau de recherche sur le cancer of the F.R.S.Q. to W.D.F., P.G, C.M.M., A.M. M.-M., D.M.P., and P.N.T.

References

  1. 1.
    Tonin PN, Mes-Masson AM, Futreal PA, Morgan K, Mahon M, Foulkes WD, Cole DE, Provencher D, Ghadirian P, Narod SA (1998) Founder BRCA1 and BRCA2 mutations in French Canadian breast and ovarian cancer families. Am J Hum Genet 63(5):1341–1351PubMedCrossRefGoogle Scholar
  2. 2.
    Oros KK, Ghadirian P, Greenwood CM, Perret C, Shen Z, Paredes Y, Arcand SL, Mes-Masson AM, Narod SA, Foulkes WD et al (2004) Significant proportion of breast and/or ovarian cancer families of French Canadian descent harbor 1 of 5 BRCA1 and BRCA2 mutations. Int J Cancer 112(3):411–419PubMedCrossRefGoogle Scholar
  3. 3.
    Oros KK, Ghadirian P, Maugard CM, Perret C, Paredes Y, Mes-Masson AM, Foulkes WD, Provencher D, Tonin PN (2006) Application of BRCA1 and BRCA2 mutation carrier prediction models in breast and/or ovarian cancer families of French Canadian descent. Clin Genet 70(4):320–329PubMedCrossRefGoogle Scholar
  4. 4.
    Antoniou AC, Durocher F, Smith P, Simard J, Easton DF (2006) BRCA1 and BRCA2 mutation predictions using the BOADICEA and BRCAPRO models and penetrance estimation in high-risk French–Canadian families. Breast Cancer Res 8(1):R3PubMedCrossRefGoogle Scholar
  5. 5.
    Simard J, Dumont M, Moisan AM, Gaborieau V, Vezina H, Durocher F, Chiquette J, Plante M, Avard D, Bessette P et al (2007) Evaluation of BRCA1 and BRCA2 mutation prevalence, risk prediction models and a multi-step testing approach in French–Canadian high-risk breast and ovarian cancer families. J Med Genet 44(2):107–121Google Scholar
  6. 6.
    Manning AP, Abelovich D, Ghadirian P, Lambert JA, Frappier D, Provencher D, Robidoux A, Peretz T, Narod SA, Mes-Masson AM et al (2001) Haplotype analysis of BRCA2 8765delAG mutation carriers in French Canadian and Yemenite Jewish hereditary breast cancer families. Hum Hered 52(2):116–120PubMedCrossRefGoogle Scholar
  7. 7.
    Scriver CR (2001) Human genetics: lessons from Quebec populations. Annu Rev Genomics Hum Genet 2:69–101PubMedCrossRefGoogle Scholar
  8. 8.
    Laberge AM, Michaud J, Richter A, Lemyre E, Lambert M, Brais B, Mitchell GA (2005) Population history and its impact on medical genetics in Quebec. Clin Genet 68(4):287–301PubMedCrossRefGoogle Scholar
  9. 9.
    Vezina H, Durocher F, Dumont M, Houde L, Szabo C, Tranchant M, Chiquette J, Plante M, Laframboise R, Lepine J et al (2005) Molecular and genealogical characterization of the R1443X BRCA1 mutation in high-risk French–Canadian breast/ovarian cancer families. Hum Genet 117(2–3):119–132PubMedCrossRefGoogle Scholar
  10. 10.
    Oros KK, Leblanc G, Arcand SL, Shen Z, Perret C, Mes-Masson AM, Foulkes WD, Ghadiran P, Provencher D, Tonin PN (2006) Haplotype analysis suggest common founders in carriers of the recurrent BRCA2 mutation, 3398delAAAAG, in French Canadian hereditary breast and/ovarian cancer families. BMC Med Genet 7(1):23PubMedCrossRefGoogle Scholar
  11. 11.
    Antoniou AC, Easton DF (2006) Models of genetic susceptibility to breast cancer. Oncogene 25(43):5898–5905PubMedCrossRefGoogle Scholar
  12. 12.
    Li FP, Fraumeni JF Jr, Mulvihill JJ, Blattner WA, Dreyfus MG, Tucker MA, Miller RW (1988) A cancer family syndrome in twenty-four kindreds. Cancer Res 48(18):5358–5362PubMedGoogle Scholar
  13. 13.
    Birch JM, Hartley AL, Tricker KJ, Prosser J, Condie A, Kelsey AM, Harris M, Jones PH, Binchy A, Crowther D et al (1994) Prevalence and diversity of constitutional mutations in the p53 gene among 21 Li-Fraumeni families. Cancer Res 54(5):1298–1304PubMedGoogle Scholar
  14. 14.
    Frebourg T, Barbier N, Yan YX, Garber JE, Dreyfus M, Fraumeni J Jr, Li FP, Friend SH (1995) Germ-line p53 mutations in 15 families with Li-Fraumeni syndrome. Am J Hum Genet 56(3):608–615PubMedGoogle Scholar
  15. 15.
    Varley JM, McGown G, Thorncroft M, Santibanez-Koref MF, Kelsey AM, Tricker KJ, Evans DG, Birch JM (1997) Germ-line mutations of TP53 in Li-Fraumeni families: an extended study of 39 families. Cancer Res 57(15):3245–3252PubMedGoogle Scholar
  16. 16.
    Evans DG, Birch JM, Thorneycroft M, McGown G, Lalloo F, Varley JM (2002) Low rate of TP53 germline mutations in breast cancer/sarcoma families not fulfilling classical criteria for Li-Fraumeni syndrome. J Med Genet 39(12):941–944PubMedCrossRefGoogle Scholar
  17. 17.
    Olivier M, Goldgar DE, Sodha N, Ohgaki H, Kleihues P, Hainaut P, Eeles RA (2003) Li-Fraumeni and related syndromes: correlation between tumor type, family structure, and TP53 genotype. Cancer Res 63(20):6643–6650PubMedGoogle Scholar
  18. 18.
    Strong LC, Stine M, Norsted TL (1987) Cancer in survivors of childhood soft tissue sarcoma and their relatives. J Natl Cancer Inst 79(6):1213–1220PubMedGoogle Scholar
  19. 19.
    Garber JE, Burke EM, Lavally BL, Billett AL, Sallan SE, Scott RM, Kupsky W, Li FP (1990) Choroid plexus tumors in the breast cancer-sarcoma syndrome. Cancer 66(12):2658–2660PubMedCrossRefGoogle Scholar
  20. 20.
    Hartley AL, Birch JM, Tricker K, Wallace SA, Kelsey AM, Harris M, Jones PH (1993) Wilms’ tumor in the Li-Fraumeni cancer family syndrome. Cancer Genet Cytogenet 67(2):133–135PubMedCrossRefGoogle Scholar
  21. 21.
    Eeles RA, Bartkova J, Lane DP, Bartek J (1993) The role of TP53 in breast cancer development. Cancer Surv 18:57–75PubMedGoogle Scholar
  22. 22.
    Eeles RA (1995) Germline mutations in the TP53 gene. Cancer Surv 25:101–124PubMedGoogle Scholar
  23. 23.
    Malkin D, Li FP, Strong LC, Fraumeni JF Jr, Nelson CE, Kim DH, Kassel J, Gryka MA, Bischoff FZ, Tainsky MA et al (1990) Germ line p53 mutations in a familial syndrome of breast cancer, sarcomas, and other neoplasms. Science 250(4985):1233–1238PubMedCrossRefGoogle Scholar
  24. 24.
    Garber JE, Goldstein AM, Kantor AF, Dreyfus MG, Fraumeni JF Jr, Li FP (1991) Follow-up study of twenty-four families with Li-Fraumeni syndrome. Cancer Res 51(22):6094–6097PubMedGoogle Scholar
  25. 25.
    Prosser J, Elder PA, Condie A, MacFadyen I, Steel CM, Evans HJ (1991) Mutations in p53 do not account for heritable breast cancer: a study in five affected families. Br J Cancer 63(2):181–184PubMedGoogle Scholar
  26. 26.
    Borresen AL, Andersen TI, Garber J, Barbier-Piraux N, Thorlacius S, Eyfjord J, Ottestad L, Smith-Sorensen B, Hovig E, Malkin D et al (1992) Screening for germ line TP53 mutations in breast cancer patients. Cancer Res 52(11):3234–3236PubMedGoogle Scholar
  27. 27.
    Warren W, Eeles RA, Ponder BA, Easton DF, Averill D, Ponder MA, Anderson K, Evans AM, DeMars R, Love R et al (1992) No evidence for germline mutations in exons 5–9 of the p53 gene in 25 breast cancer families. Oncogene 7(5):1043–1046PubMedGoogle Scholar
  28. 28.
    Jolly KW, Malkin D, Douglass EC, Brown TF, Sinclair AE, Look AT (1994) Splice-site mutation of the p53 gene in a family with hereditary breast-ovarian cancer. Oncogene 9(1):97–102PubMedGoogle Scholar
  29. 29.
    Sun XF, Johannsson O, Hakansson S, Sellberg G, Nordenskjold B, Olsson H, Borg A (1996) A novel p53 germline alteration identified in a late onset breast cancer kindred. Oncogene 13(2):407–411PubMedGoogle Scholar
  30. 30.
    Rapakko K, Allinen M, Syrjakoski K, Vahteristo P, Huusko P, Vahakangas K, Eerola H, Kainu T, Kallioniemi OP, Nevanlinna H et al (2001) Germline TP53 alterations in Finnish breast cancer families are rare and occur at conserved mutation-prone sites. Br J Cancer 84(1):116–119PubMedCrossRefGoogle Scholar
  31. 31.
    Martin AM, Kanetsky PA, Amirimani B, Colligon TA, Athanasiadis G, Shih HA, Gerrero MR, Calzone K, Rebbeck TR, Weber BL (2003) Germline TP53 mutations in breast cancer families with multiple primary cancers: is TP53 a modifier of BRCA1? J Med Genet 40(4):e34PubMedCrossRefGoogle Scholar
  32. 32.
    Walsh T, Casadei S, Coats KH, Swisher E, Stray SM, Higgins J, Roach KC, Mandell J, Lee MK, Ciernikova S et al (2006) Spectrum of mutations in BRCA1, BRCA2, CHEK2, and TP53 in families at high risk of breast cancer. Jama 295(12):1379–1388PubMedCrossRefGoogle Scholar
  33. 33.
    Ye S, Dhillon S, Ke X, Collins AR, Day IN (2001) An efficient procedure for genotyping single nucleotide polymorphisms. Nucleic Acids Res 29(17):E88–8PubMedCrossRefGoogle Scholar
  34. 34.
    Lehman TA, Haffty BG, Carbone CJ, Bishop LR, Gumbs AA, Krishnan S, Shields PG, Modali R, Turner BC (2000) Elevated frequency and functional activity of a specific germ-line p53 intron mutation in familial breast cancer. Cancer Res 60(4):1062–1069PubMedGoogle Scholar
  35. 35.
    Balz V, Prisack HB, Bier H, Bojar H (2002) Analysis of BRCA1, TP53, and TSG101 germline mutations in German breast and/or ovarian cancer families. Cancer Genet Cytogenet 138(2):120–127PubMedCrossRefGoogle Scholar
  36. 36.
    Bendig I, Mohr N, Kramer F, Weber BH (2004) Identification of novel TP53 mutations in familial and sporadic cancer cases of German and Swiss origin. Cancer Genet Cytogenet 154(1):22–26PubMedCrossRefGoogle Scholar
  37. 37.
    Lalloo F, Varley J, Moran A, Ellis D, O’Dair L, Pharoah P, Antoniou A, Hartley R, Shenton A, Seal S et al (2006) BRCA1, BRCA2 and TP53 mutations in very early-onset breast cancer with associated risks to relatives. Eur J Cancer 42(8):1143–1150PubMedCrossRefGoogle Scholar
  38. 38.
    Ruijs MW, Verhoef S, Wigbout G, Pruntel R, Floore AN, de Jong D, van TVLJ Menko FH (2006) Late-onset common cancers in a kindred with an Arg213Gln TP53 germline mutation. Fam Cancer 5(2):169–174PubMedCrossRefGoogle Scholar
  39. 39.
    Quesnel S, Verselis S, Portwine C, Garber J, White M, Feunteun J, Malkin D, Li FP (1999) p53 compound heterozygosity in a severely affected child with Li-Fraumeni syndrome. Oncogene 18(27):3970–3978PubMedCrossRefGoogle Scholar
  40. 40.
    Durocher F, Labrie Y, Soucy P, Sinilnikova O, Labuda D, Bessette P, Chiquette J, Laframboise R, Lepine J, Lesperance B et al (2006) Mutation analysis and characterization of ATR sequence variants in breast cancer cases from high-risk French Canadian breast/ovarian cancer families. BMC Cancer 6:230PubMedCrossRefGoogle Scholar
  41. 41.
    Tischkowitz M, Xia B, Sabbghian N, Reis-Filho JS, Hamel N, Li G, van Beers EK, li L, Khalil T, Quenneville LA, Omeroglu A, Poll A, Lepage P, Wong N, Nederlof PM, Ashworth A, Tonin PN, Narod SA, Livingston DM, Foulkes WD (2007) Analysis of PALB2/FANCN-associated breast cancer families. PNAS 104(16):6788–6793PubMedCrossRefGoogle Scholar
  42. 42.
    Rahman N, Seal S, Thompson D, Kelly P, Renwick A, Elliott A, Reid S, Spanova K, Barfoot R, Chagtai T et al (2007) PALB2, which encodes a BRCA2-interacting protein, is a breast cancer susceptibility gene. Nat Genet 39(2):165–167PubMedCrossRefGoogle Scholar

Copyright information

© Springer Science+Business Media, LLC 2007

Authors and Affiliations

  • Suzanna L. Arcand
    • 1
  • Christine M. Maugard
    • 2
    • 3
  • Parviz Ghadirian
    • 4
  • André Robidoux
    • 5
  • Chantal Perret
    • 6
  • Phil Zhang
    • 7
  • Eve Fafard
    • 4
  • Anne-Marie Mes-Masson
    • 3
    • 6
  • William D. Foulkes
    • 1
    • 8
    • 9
    • 10
  • Diane Provencher
    • 6
    • 11
  • Steven A. Narod
    • 7
  • Patricia N. Tonin
    • 1
    • 8
    • 10
    • 12
  1. 1.The Research Institute of the McGill University Health CentreMontrealCanada
  2. 2.Service de Médecine GéniqueCentre Hospitalier de l’Université de Montréal (CHUM)MontrealCanada
  3. 3.Département de médecineUniversité de MontréalMontrealCanada
  4. 4.Epidemiology Research Unit, Research CentreCHUM—Hôtel-DieuMontrealCanada
  5. 5.Department of SurgeryCHUM—Hôtel-DieuMontrealCanada
  6. 6.Centre de Recherche du Centre Hospitalier de l’Université de Montréal/Institut du Cancer de MontréalHôpital Notre-DameMontrealCanada
  7. 7.Women’s College Research InstituteWomen’s College Hospital and University of TorontoTorontoCanada
  8. 8.Program in Cancer Genetics, Departments of Oncology and Human GeneticsMcGill UniversityMontrealCanada
  9. 9.Department of Medical GeneticsSir Mortimer B. Davis-Jewish General HospitalMontrealCanada
  10. 10.Departments of Medicine and Human GeneticsMcGill UniversityMontrealCanada
  11. 11.Département d’obstétrique gynécologie, Division de gynécologie oncologiqueUniversité de MontréalMontrealCanada
  12. 12.Medical GeneticsMontreal General HospitalMontrealCanada

Personalised recommendations