Germline TP53 mutational spectrum in French Canadians with breast cancer

BMC Medical Genetics

Patricia N Tonin⁴  Steven A Narod¹  William D Foulkes⁴  Diane Provencher²  Anne-Marie Mes-Masson³  Mohammed R Akbari¹  Suzanna L Arcand⁵ 

[1] Women’s College Research Institute, Women’s College Hospital, and University of Toronto, Toronto, Ontario, Canada;Division de gynécologie oncologique Université de Montréal, Montreal, Quebec, Canada;Centre de recherche du Centre hospitalier de l’Université de Montréal et Institut du cancer de Montréal, Montreal, Quebec, Canada;Program in Cancer Genetics, Departments of Oncology, Human Genetics and Medicine, McGill University, Quebec, Canada;Cancer Research Program, The Research Institute of the McGill University Health Centre, 1001 Decarie Boulevard, E02.6217, Montreal H4A 3J1, Quebec, Canada

关键词: BRCA2;    BRCA1;    Founders;    French Canadian;    Hereditary breast cancer;    Breast cancer;    TP53;   

Others  :  1177678
DOI  :  10.1186/s12881-015-0169-y

 received in 2014-07-28, accepted in 2015-03-27,  发布年份 2015

【 摘 要 】

Background

Specific germline mutations in the hereditary breast-ovarian cancer susceptibility (HBC/HBOC) genes, BRCA1, BRCA2 and PALB2, have been shown to recur in French Canadians of Quebec, Canada, and this has been attributed to common ancestors. Germline TP53 mutation carriers are known to segregate in Li-Fraumeni syndrome families, which feature young age of onset breast cancer. We have reported rare TP53 mutation carriers in French Canadian HBC families, though none recurred possibly due to the limited number of cancer families investigated. Here we describe TP53 germline mutations found in French Canadian cancer families provided from hereditary cancer clinics; investigate 37 new BRCA1 and BRCA2 mutation-negative HBC/HBOC families for the TP53 mutations; and assess the frequency of TP53 mutations in a 1235 French Canadian breast cancer cases not selected for family history of cancer.

Methods

TP53 mutation-positive pedigrees from French Canadian cancer families were provided from local hereditary cancer clinics. Bidirectional Sanger sequencing of all protein encoding exons of TP53 was performed using peripheral blood lymphocyte DNA from breast/ovarian cancer probands from 37 HBC/HBOC families of French Canadian descent. Targeted bidirectional Sanger sequencing assay of regions containing the identified TP53 mutations was performed on 1235 French Canadian breast cancer cases not selected for family history cancer.

Results

Five new TP53 mutations were identified in six pedigrees from hereditary cancer clinics. No deleterious mutations were identified in cancer probands from 37 HBC/HBOC families. A targeted mutation screen of the 1235 breast cancer cases identified a c.844C>T [p.Arg282Trp] mutation carrier. This mutation was also found among the six mutation-positive cancer families provided by the local hereditary cancer clinics. The targeted screen also uncovered a new TP53 mutation, c.685T>C [p.Cys229Arg] that was found in two breast cancer cases. All TP53 mutation carriers were among the 656 women with breast cancer diagnosed less than 50 years of age.

Conclusions

In all six new TP53 mutations were identified in French Canadians, where two each occurred in independently ascertained cases/families. Although all newly identified breast cancer mutation carriers reported a family history of cancer, none were consistent with features of Li-Fraumeni syndrome families.

【 授权许可】

   
2015 Arcand et al.; licensee BioMed Central.

【 图 表 】

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【 参考文献 】

• [1]Lalloo F, Evans DG: Familial breast cancer. Clin Genet 2012, 82(2):105-14.
• [2]PDQ® Genetics of Breast and Ovarian Cancer [http://www.cancer.gov/cancertopics/pdq/genetics/breast-and-ovarian/HealthProfessional]
• [3]Li-Fraumeni Syndrome [http://www.ncbi.nlm.nih.gov/books/NBK1311/]
• [4]Evans DG, Birch JM, Ramsden RT, Sharif S, Baser ME: Malignant transformation and new primary tumours after therapeutic radiation for benign disease: substantial risks in certain tumour prone syndromes. J Med Genet 2006, 43(4):289-94.
• [5]Mai PL, Malkin D, Garber JE, Schiffman JD, Weitzel JN, Strong LC, et al.: Li-Fraumeni syndrome: report of a clinical research workshop and creation of a research consortium. Canc Genet 2012, 205(10):479-87.
• [6]Saslow D, Boetes C, Burke W, Harms S, Leach MO, Lehman CD, et al.: American Cancer Society guidelines for breast screening with MRI as an adjunct to mammography. CA Cancer J Clin 2007, 57(2):75-89.
• [7]McCuaig JM, Armel SR, Novokmet A, Ginsburg OM, Demsky R, Narod SA, et al.: Routine TP53 testing for breast cancer under age 30: ready for prime time? Fam Cancer 2012, 11(4):607-13.
• [8]Evans DG, Moran A, Hartley R, Dawson J, Bulman B, Knox F, et al.: Long-term outcomes of breast cancer in women aged 30 years or younger, based on family history, pathology and BRCA1/BRCA2/TP53 status. Br J Cancer 2010, 102(7):1091-8.
• [9]Daly MB, Pilarski R, Axilbund JE, Buys SS, Crawford B, Friedman S, et al.: Genetic/familial high-risk assessment: breast and ovarian, version 1.2014. J Natl Compr Canc Netw 2014, 12(9):1326-38.
• [10]Arcand SL, Maugard CM, Ghadirian P, Robidoux A, Perret C, Zhang P, et al.: Germline TP53 mutations in BRCA1 and BRCA2 mutation-negative French Canadian breast cancer families. Breast Cancer Res Treat 2008, 108(3):399-408.
• [11]Tonin PN, Mes-Masson AM, Futreal PA, Morgan K, Mahon M, Foulkes WD, et al.: Founder BRCA1 and BRCA2 mutations in French Canadian breast and ovarian cancer families. Am J Hum Genet 1998, 63(5):1341-51.
• [12]Oros KK, Ghadirian P, Greenwood CM, Perret C, Shen Z, Paredes Y, et al.: Significant proportion of breast and/or ovarian cancer families of French Canadian descent harbor 1 of 5 BRCA1 and BRCA2 mutations. Int J Cancer 2004, 112(3):411-9.
• [13]Foulkes WD, Ghadirian P, Akbari MR, Hamel N, Giroux S, Sabbaghian N, et al.: Identification of a novel truncating PALB2 mutation and analysis of its contribution to early-onset breast cancer in French-Canadian women. Breast Cancer Res 2007, 9(6):R83. BioMed Central Full Text
• [14]Ghadirian P, Robidoux A, Zhang P, Royer R, Akbari M, Zhang S, et al.: The contribution of founder mutations to early-onset breast cancer in French-Canadian women. Clin Genet 2009, 76(5):421-6.
• [15]Wagner J, Portwine C, Rabin K, Leclerc JM, Narod SA, Malkin D: High frequency of germline p53 mutations in childhood adrenocortical cancer. J Natl Cancer Inst 1994, 86(22):1707-10.
• [16]Cavallone L, Arcand SL, Maugard CM, Nolet S, Gaboury LA, Mes-Masson AM, et al.: Comprehensive BRCA1 and BRCA2 mutation analyses and review of French Canadian families with at least three cases of breast cancer. Fam Cancer 2010, 9(4):507-17.
• [17]Ghadirian P, Robidoux A, Nassif E, Martin G, Potvin C, Patocskai E, et al.: Screening for BRCA1 and BRCA2 mutations among French-Canadian breast cancer cases attending an outpatient clinic in Montreal. Clin Genet 2014, 85(1):31-5.
• [18]Wojnarowicz PM, Oros KK, Quinn MC, Arcand SL, Gambaro K, Madore J, et al.: The genomic landscape of TP53 and p53 annotated high grade ovarian serous carcinomas from a defined founder population associated with patient outcome. PLoS One 2012., 7(9) Article ID e45484
• [19]Petitjean A, Mathe E, Kato S, Ishioka C, Tavtigian SV, Hainaut P, et al.: Impact of mutant p53 functional properties on TP53 mutation patterns and tumor phenotype: lessons from recent developments in the IARC TP53 database. Hum Mutat 2007, 28(6):622-9.
• [20]Chompret A, Brugieres L, Ronsin M, Gardes M, Dessarps-Freichey F, Abel A, et al.: P53 germline mutations in childhood cancers and cancer risk for carrier individuals. Br J Cancer 2000, 82(12):1932-7.
• [21]Hwang SJ, Lozano G, Amos CI, Strong LC: Germline p53 mutations in a cohort with childhood sarcoma: sex differences in cancer risk. Am J Hum Genet 2003, 72(4):975-83.
• [22]Dumont P, Leu JI, Della Pietra AC 3rd, George DL, Murphy M: The codon 72 polymorphic variants of p53 have markedly different apoptotic potential. Nat Genet 2003, 33(3):357-65.
• [23]Osorio A, Martinez-Delgado B, Pollan M, Cuadros M, Urioste M, Torrenteras C, et al.: A haplotype containing the p53 polymorphisms Ins16bp and Arg72Pro modifies cancer risk in BRCA2 mutation carriers. Hum Mutat 2006, 27(3):242-8.
• [24]Novokmet A, Baskin B, Ray P, Malkin D. Li-Fraumeni syndrome: retesting archival DNA samples identifies previously unrecognized germline p53 mutations (Abstract Number 1214T). In: 12th International Congress of Human Genetics/61st Annual Meeting of The American Society of Human Genetics: October 13, 2011 2011 [http://www.ichg2011.org].
• [25]Schmidt MK, Reincke S, Broeks A, Braaf LM, Hogervorst FB, Tollenaar RA, et al.: Do MDM2 SNP309 and TP53 R72P interact in breast cancer susceptibility? A large pooled series from the breast cancer association consortium. Cancer Res 2007, 67(19):9584-90.
• [26]Sinilnikova OM, Antoniou AC, Simard J, Healey S, Leone M, Sinnett D, et al.: The TP53 Arg72Pro and MDM2 309G > T polymorphisms are not associated with breast cancer risk in BRCA1 and BRCA2 mutation carriers. Br J Cancer 2009, 101(8):1456-60.
• [27]Cote S, Arcand SL, Royer R, Nolet S, Mes-Masson AM, Ghadirian P, et al.: The BRCA2 c.9004G > A (E2002K) [corrected] variant is likely pathogenic and recurs in breast and/or ovarian cancer families of French Canadian descent. Breast Cancer Res Treat 2012, 131(1):333-40.
• [28]Guidugli L, Pankratz VS, Singh N, Thompson J, Erding CA, Engel C, et al.: A classification model for BRCA2 DNA binding domain missense variants based on homology-directed repair activity. Cancer Res 2013, 73(1):265-75.
• [29]Laberge AM, Michaud J, Richter A, Lemyre E, Lambert M, Brais B, et al.: Population history and its impact on medical genetics in Quebec. Clin Genet 2005, 68(4):287-301.
• [30]Achatz MI, Olivier M, Le Calvez F, Martel-Planche G, Lopes A, Rossi BM, et al.: The TP53 mutation, R337H, is associated with Li-Fraumeni and Li-Fraumeni-like syndromes in Brazilian families. Cancer Lett 2007, 245(1–2):96-102.
• [31]Garritano S, Gemignani F, Palmero EI, Olivier M, Martel-Planche G, Le Calvez-Kelm F, et al.: Detailed haplotype analysis at the TP53 locus in p.R337H mutation carriers in the population of Southern Brazil: evidence for a founder effect. Hum Mutat 2010, 31(2):143-50.