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BMC Cancer
Published in: BMC Cancer 1/2008

Open Access 01-12-2008 | Research article

Haplotype analysis of TP53 polymorphisms, Arg72Pro and Ins16, in BRCA1 and BRCA2 mutation carriers of French Canadian descent

Authors: Luca Cavallone, Suzanna L Arcand, Christine Maugard, Parviz Ghadirian, Anne-Marie Mes-Masson, Diane Provencher, Patricia N Tonin

Published in: BMC Cancer | Issue 1/2008

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Abstract

Background

The TP53 polymorphisms Arg72Pro (Ex4+199 G>C) and Ins16 (IVS3+24 ins16) have been proposed to modify risk of breast cancer associated with germline BRCA1 and BRCA2 mutations. Allele frequencies of these polymorphisms were investigated to determine if they modify risk in BRCA mutation carriers in breast cancer cases drawn from French Canadian cancer families, a population shown to exhibit strong founder effects.

Methods

The frequencies of the TP53 alleles, genotypes and haplotypes of 157 index breast cancer cases comprised of 42 BRCA1 mutation carriers, 57 BRCA2 mutation carriers, and 58 BRCA mutation-negative cases, where each case was drawn from independently ascertained families were compared. The effect of TP53 variants on the age of diagnosis was also investigated for these groups. The TP53 polymorphisms were also investigated in 112 women of French Canadian descent with no personal history of cancer.

Results

The BRCA mutation-positive groups had the highest frequency of homozygous carriers of the 72Pro allele compared with mutation-negative group. The TP53 polymorphisms exhibited linkage disequilibrium (p < 0.001), where the 72Arg and Ins16minus alleles occurred in strong disequilibrium. The highest frequency of carriers of Ins16minus-72Arg haplotype occurred in the BRCA mutation-negative groups. The BRCA1 mutation carriers homozygous for the 72Pro allele had the youngest ages of diagnosis of breast cancer. However none of these observations were statistically significant. In contrast, the BRCA2 mutation carriers homozygous for the 72Pro allele had a significantly older age of diagnosis of breast cancer (p = 0.018). Moreover, in this group, the mean age of diagnosis of breast cancer in carriers of the Ins16minus-72Arg haplotype was significantly younger than that of the individuals who did not this carry this haplotype (p = 0.009).

Conclusion

We observed no significant association of breast cancer risk with TP53 genetic variants based on BRCA1/2 mutation carrier status. Although the small sample size did not permit analysis of all possible haplotypes, we observed that BRCA2 mutation carriers harboring the Ins16minus-72Arg haplotype had a significantly younger mean age of diagnosis of breast cancer. These observations suggest that investigations in a larger French Canadian sample are warranted to further elucidate the effects of TP53 variants on age of diagnosis of breast cancer among BRCA1 and BRCA2 mutation carriers.
Appendix
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Literature
1.
Tonin PN, Mes-Masson AM, Futreal PA, Morgan K, Mahon M, Foulkes WD, Cole DE, Provencher D, Ghadirian P, Narod SA: Founder BRCA1 and BRCA2 mutations in French Canadian breast and ovarian cancer families. Am J Hum Genet. 1998, 63: 1341-1351. 10.1086/302099.CrossRefPubMedPubMedCentral
2.
Oros KK, Ghadirian P, Greenwood CM, Perret C, Shen Z, Paredes Y, Arcand SL, Mes-Masson AM, Narod SA, Foulkes WD, Provencher D, Tonin PN: 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: 411-419. 10.1002/ijc.20406.CrossRefPubMed
3.
Oros KK, Leblanc G, Arcand SL, Shen Z, Perret C, Mes-Masson AM, Foulkes WD, Ghadirian P, Provencher D, Tonin PN: 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. 2006, 7: 23-10.1186/1471-2350-7-23.CrossRefPubMedPubMedCentral
4.
Antoniou AC, Durocher F, Smith P, Simard J, Easton DF: BRCA1 and BRCA2 mutation predictions using the BOADICEA and BRCAPRO models and penetrance estimation in high-risk French-Canadian families. Breast Cancer Res. 2006, 8: R3-10.1186/bcr1365.CrossRefPubMed
5.
Simard J, Dumont M, Moisan AM, Gaborieau V, Malouin H, Durocher F, Chiquette J, Plante M, Avard D, Bessette P, Brousseau C, Dorval M, Godard B, Houde L, Joly Y, Lajoie MA, Leblanc G, Lepine J, Lesperance B, Vezina H, Parboosingh J, Pichette R, Provencher L, Rheaume J, Sinnett D, Samson C, Simard JC, Tranchant M, Voyer P, Easton D, Tavtigian SV, Knoppers BM, Laframboise R, Bridge P, Goldgar D: Evaluation of BRCA1 and BRCA2 mutation prevalence, risk prediction models and a multistep testing approach in French-Canadian families with high risk of breast and ovarian cancer. J Med Genet. 2007, 44: 107-121. 10.1136/jmg.2006.044388.CrossRefPubMed
6.
Manning AP, Abelovich D, Ghadirian P, Lambert JA, Frappier D, Provencher D, Robidoux A, Peretz T, Narod SA, Mes-Masson AM, Foulkes WD, Wang T, Morgan K, Fujiwara TM, Tonin PN: Haplotype analysis of BRCA2 8765delAG mutation carriers in French Canadian and Yemenite Jewish hereditary breast cancer families. Hum Hered. 2001, 52: 116-120. 10.1159/000053364.CrossRefPubMed
7.
Scriver CR: Human genetics: lessons from Quebec populations. Annu Rev Genomics Hum Genet. 2001, 2: 69-101. 10.1146/annurev.genom.2.1.69.CrossRefPubMed
8.
Laberge AM, Michaud J, Richter A, Lemyre E, Lambert M, Brais B, Mitchell GA: Population history and its impact on medical genetics in Quebec. Clin Genet. 2005, 68: 287-301. 10.1111/j.1399-0004.2005.00497.x.CrossRefPubMed
9.
Vezina H, Durocher F, Dumont M, Houde L, Szabo C, Tranchant M, Chiquette J, Plante M, Laframboise R, Lepine J, Nevanlinna H, Stoppa-Lyonnet D, Goldgar D, Bridge P, Simard J: Molecular and genealogical characterization of the R1443X BRCA1 mutation in high-risk French-Canadian breast/ovarian cancer families. Hum Genet. 2005, 117: 119-132. 10.1007/s00439-005-1297-9.CrossRefPubMed
10.
Ford D, Easton DF, Stratton M, Narod S, Goldgar D, Devilee P, Bishop DT, Weber B, Lenoir G, Chang-Claude J, Sobol H, Teare MD, Struewing J, Arason A, Scherneck S, Peto J, Rebbeck TR, Tonin P, Neuhausen S, Barkardottir R, Eyfjord J, Lynch H, Ponder BA, Gayther SA, Zelada-Hedman M, .: Genetic heterogeneity and penetrance analysis of the BRCA1 and BRCA2 genes in breast cancer families. The Breast Cancer Linkage Consortium. Am J Hum Genet. 1998, 62: 676-689. 10.1086/301749.CrossRefPubMedPubMedCentral
11.
Easton DF, Ford D, Bishop DT: Breast and ovarian cancer incidence in BRCA1-mutation carriers. Breast Cancer Linkage Consortium. Am J Hum Genet. 1995, 56: 265-271.CrossRefPubMedPubMedCentral
12.
Antoniou AC, Easton DF: Polygenic inheritance of breast cancer: Implications for design of association studies. Genet Epidemiol. 2003, 25: 190-202. 10.1002/gepi.10261.CrossRefPubMed
13.
Simchoni S, Friedman E, Kaufman B, Gershoni-Baruch R, Orr-Urtreger A, Kedar-Barnes I, Shiri-Sverdlov R, Dagan E, Tsabari S, Shohat M, Catane R, King MC, Lahad A, Levy-Lahad E: Familial clustering of site-specific cancer risks associated with BRCA1 and BRCA2 mutations in the Ashkenazi Jewish population. Proc Natl Acad Sci U S A. 2006, 103: 3770-3774. 10.1073/pnas.0511301103.CrossRefPubMedPubMedCentral
14.
Narod SA: Modifiers of risk of hereditary breast cancer. Oncogene. 2006, 25: 5832-5836. 10.1038/sj.onc.1209870.CrossRefPubMed
15.
Phelan CM, Rebbeck TR, Weber BL, Devilee P, Ruttledge MH, Lynch HT, Lenoir GM, Stratton MR, Easton DF, Ponder BA, Cannon-Albright L, Larsson C, Goldgar DE, Narod SA: Ovarian cancer risk in BRCA1 carriers is modified by the HRAS1 variable number of tandem repeat (VNTR) locus. Nat Genet. 1996, 12: 309-311. 10.1038/ng0396-309.CrossRefPubMed
16.
Rebbeck TR, Kantoff PW, Krithivas K, Neuhausen S, Blackwood MA, Godwin AK, Daly MB, Narod SA, Garber JE, Lynch HT, Weber BL, Brown M: Modification of BRCA1-associated breast cancer risk by the polymorphic androgen-receptor CAG repeat. Am J Hum Genet. 1999, 64: 1371-1377. 10.1086/302366.CrossRefPubMedPubMedCentral
17.
Levy-Lahad E, Lahad A, Eisenberg S, Dagan E, Paperna T, Kasinetz L, Catane R, Kaufman B, Beller U, Renbaum P, Gershoni-Baruch R: A single nucleotide polymorphism in the RAD51 gene modifies cancer risk in BRCA2 but not BRCA1 carriers. Proc Natl Acad Sci U S A. 2001, 98: 3232-3236. 10.1073/pnas.051624098.CrossRefPubMedPubMedCentral
18.
Rebbeck TR, Wang Y, Kantoff PW, Krithivas K, Neuhausen SL, Godwin AK, Daly MB, Narod SA, Brunet JS, Vesprini D, Garber JE, Lynch HT, Weber BL, Brown M: Modification of B. Cancer Res. 2001, 61: 5420-5424.PubMed
19.
Hughes DJ, Ginolhac SM, Coupier I, Barjhoux L, Gaborieau V, Bressac-de-Paillerets B, Chompret A, Bignon YJ, Uhrhammer N, Lasset C, Giraud S, Sobol H, Hardouin A, Berthet P, Peyrat JP, Fournier J, Nogues C, Lidereau R, Muller D, Fricker JP, Longy M, Toulas C, Guimbaud R, Yannoukakos D, Mazoyer S, Lynch HT, Lenoir GM, Goldgar DE, Stoppa-Lyonnet D, Sinilnikova OM: Breast cancer risk in BRCA1 and BRCA2 mutation carriers and polyglutamine repeat length in the AIB1 gene. Int J Cancer. 2005, 117: 230-233. 10.1002/ijc.21176.CrossRefPubMed
20.
Kadouri L, Kote-Jarai Z, Hubert A, Durocher F, Abeliovich D, Glaser B, Hamburger T, Eeles RA, Peretz T: A single-nucleotide polymorphism in the RAD51 gene modifies breast cancer risk in BRCA2 carriers, but not in BRCA1 carriers or noncarriers. Br J Cancer. 2004, 90: 2002-2005. 10.1038/sj.bjc.6601837.CrossRefPubMedPubMedCentral
21.
Spurdle AB, Antoniou AC, Kelemen L, Holland H, Peock S, Cook MR, Smith PL, Greene MH, Simard J, Plourde M, Southey MC, Godwin AK, Beck J, Miron A, Daly MB, Santella RM, Hopper JL, John EM, Andrulis IL, Durocher F, Struewing JP, Easton DF, Chenevix-Trench G: The AIB1 polyglutamine repeat does not modify breast cancer risk in BRCA1 and BRCA2 mutation carriers. Cancer Epidemiol Biomarkers Prev. 2006, 15: 76-79. 10.1158/1055-9965.EPI-05-0709.CrossRefPubMed
22.
Cheung AM, Elia A, Tsao MS, Done S, Wagner KU, Hennighausen L, Hakem R, Mak TW: Brca2 deficiency does not impair mammary epithelium development but promotes mammary adenocarcinoma formation in p53(+/-) mutant mice. Cancer Res. 2004, 64: 1959-1965. 10.1158/0008-5472.CAN-03-2270.CrossRefPubMed
23.
Jonkers J, Meuwissen R, van der GH, Peterse H, van , Berns A: Synergistic tumor suppressor activity of BRCA2 and p53 in a conditional mouse model for breast cancer. Nat Genet. 2001, 29: 418-425. 10.1038/ng747.CrossRefPubMed
24.
Ongusaha PP, Ouchi T, Kim KT, Nytko E, Kwak JC, Duda RB, Deng CX, Lee SW: BRCA1 shifts p53-mediated cellular outcomes towards irreversible growth arrest. Oncogene. 2003, 22: 3749-3758. 10.1038/sj.onc.1206439.CrossRefPubMed
25.
Arcand SL, Maugard CM, Ghadirian P, Robidoux A, Perret C, Zhang P, Fafard E, Mes-Masson AM, Foulkes WD, Provencher D, Narod SA, Tonin PN: Germline TP53 mutations in BRCA1 and BRCA2 mutation-negative French Canadian breast cancer families. Breast Cancer Res Treat. 2007
26.
Sjalander A, Birgander R, Hallmans G, Cajander S, Lenner P, Athlin L, Beckman G, Beckman L: p53 polymorphisms and haplotypes in breast cancer. Carcinogenesis. 1996, 17: 1313-1316. 10.1093/carcin/17.6.1313.CrossRefPubMed
27.
Weston A, Godbold JH: Polymorphisms of H-ras-1 and p53 in breast cancer and lung cancer: a meta-analysis. Environ Health Perspect. 1997, 105 Suppl 4: 919-926. 10.2307/3433304.CrossRefPubMed
28.
Wang-Gohrke S, Rebbeck TR, Besenfelder W, Kreienberg R, Runnebaum IB: p53 germline polymorphisms are associated with an increased risk for breast cancer in German women. Anticancer Res. 1998, 18: 2095-2099.PubMed
29.
Papadakis EN, Dokianakis DN, Spandidos DA: p53 codon 72 polymorphism as a risk factor in the development of breast cancer. Mol Cell Biol Res Commun. 2000, 3: 389-392. 10.1006/mcbr.2000.0241.CrossRefPubMed
30.
Wang-Gohrke S, Becher H, Kreienberg R, Runnebaum IB, Chang-Claude J: Intron 3 16 bp duplication polymorphism of p53 is associated with an increased risk for breast cancer by the age of 50 years. Pharmacogenetics. 2002, 12: 269-272. 10.1097/00008571-200204000-00012.CrossRefPubMed
31.
Buyru N, Tigli H, Dalay N: P53 codon 72 polymorphism in breast cancer. Oncol Rep. 2003, 10: 711-714.PubMed
32.
Huang XE, Hamajima N, Katsuda N, Matsuo K, Hirose K, Mizutani M, Iwata H, Miura S, Xiang J, Tokudome S, Tajima K: Association of p53 codon Arg72Pro and p73 G4C14-to-A4T14 at exon 2 genetic polymorphisms with the risk of Japanese breast cancer. Breast Cancer. 2003, 10: 307-311.CrossRefPubMed
33.
Suspitsin EN, Buslov KG, Grigoriev MY, Ishutkina JG, Ulibina JM, Gorodinskaya VM, Pozharisski KM, Berstein LM, Hanson KP, Togo AV, Imyanitov EN: Evidence against involvement of p53 polymorphism in breast cancer predisposition. Int J Cancer. 2003, 103: 431-433. 10.1002/ijc.10834.CrossRefPubMed
34.
Kalemi TG, Lambropoulos AF, Gueorguiev M, Chrisafi S, Papazisis KT, Kotsis A: The association of p53 mutations and p53 codon 72, Her 2 codon 655 and MTHFR C677T polymorphisms with breast cancer in Northern Greece. Cancer Lett. 2005, 222: 57-65. 10.1016/j.canlet.2004.11.025.CrossRefPubMed
35.
Noma C, Miyoshi Y, Taguchi T, Tamaki Y, Noguchi S: Association of p53 genetic polymorphism (Arg72Pro) with estrogen receptor positive breast cancer risk in Japanese women. Cancer Lett. 2004, 210: 197-203. 10.1016/j.canlet.2004.03.031.CrossRefPubMed
36.
Ohayon T, Gershoni-Baruch R, Papa MZ, Distelman MT, Eisenberg BS, Friedman E: The R72P P53 mutation is associated with familial breast cancer in Jewish women. Br J Cancer. 2005, 92: 1144-1148. 10.1038/sj.bjc.6602451.CrossRefPubMedPubMedCentral
37.
Tommiska J, Eerola H, Heinonen M, Salonen L, Kaare M, Tallila J, Ristimaki A, von SK, Aittomaki K, Heikkila P, Blomqvist C, Nevanlinna H: Breast cancer patients with p53 Pro72 homozygous genotype have a poorer survival. Clin Cancer Res. 2005, 11: 5098-5103. 10.1158/1078-0432.CCR-05-0173.CrossRefPubMed
38.
Damin AP, Frazzon AP, Damin DC, Roehe A, Hermes V, Zettler C, Alexandre CO: Evidence for an association of TP53 codon 72 polymorphism with breast cancer risk. Cancer Detect Prev. 2006, 30: 523-529. 10.1016/j.cdp.2006.09.007.CrossRefPubMed
39.
Ma H, Hu Z, Zhai X, Wang S, Wang X, Qin J, Chen W, Jin G, Liu J, Gao J, Wang X, Wei Q, Shen H: Joint effects of single nucleotide polymorphisms in P53BP1 and p53 on breast cancer risk in a Chinese population. Carcinogenesis. 2006, 27: 766-771. 10.1093/carcin/bgi295.CrossRefPubMed
40.
Campbell IG, Eccles DM, Dunn B, Davis M, Leake V: p53 polymorphism in ovarian and breast cancer. Lancet. 1996, 347: 393-394. 10.1016/S0140-6736(96)90569-3.CrossRefPubMed
41.
Khaliq S, Hameed A, Khaliq T, Ayub Q, Qamar R, Mohyuddin A, Mazhar K, Qasim-Mehdi S: P53 mutations, polymorphisms, and haplotypes in Pakistani ethnic groups and breast cancer patients. Genet Test. 2000, 4: 23-29. 10.1089/109065700316435.CrossRefPubMed
42.
Wirtenberger M, Frank B, Hemminki K, Klaes R, Schmutzler RK, Wappenschmidt B, Meindl A, Kiechle M, Arnold N, Weber BH, Niederacher D, Bartram CR, Burwinkel B: Interaction of Werner and Bloom syndrome genes with p53 in familial breast cancer. Carcinogenesis. 2006, 27: 1655-1660. 10.1093/carcin/bgi374.CrossRefPubMed
43.
Dumont P, Leu JI, Della PAC, George DL, Murphy M: The codon 72 polymorphic variants of p53 have markedly different apoptotic potential. Nat Genet. 2003, 33: 357-365. 10.1038/ng1093.CrossRefPubMed
44.
Thomas M, Kalita A, Labrecque S, Pim D, Banks L, Matlashewski G: Two polymorphic variants of wild-type p53 differ biochemically and biologically. Mol Cell Biol. 1999, 19: 1092-1100.CrossRefPubMedPubMedCentral
45.
Osorio A, Martinez-Delgado B, Pollan M, Cuadros M, Urioste M, Torrenteras C, Melchor L, Diez O, De La HM, Velasco E, Gonzalez-Sarmiento R, Caldes T, Alonso C, Benitez J: A haplotype containing the p53 polymorphisms Ins16bp and Arg72Pro modifies cancer risk in BRCA2 mutation carriers. Hum Mutat. 2006, 27: 242-248. 10.1002/humu.20283.CrossRefPubMed
46.
Santos AM, Sousa H, Portela C, Pereira D, Pinto D, Catarino R, Rodrigues C, Araujo AP, Lopes C, Medeiros R: TP53 and P21 polymorphisms: response to cisplatinum/paclitaxel-based chemotherapy in ovarian cancer. Biochem Biophys Res Commun. 2006, 340: 256-262.CrossRefPubMed
47.
Martin AM, Kanetsky PA, Amirimani B, Colligon TA, Athanasiadis G, Shih HA, Gerrero MR, Calzone K, Rebbeck TR, Weber BL: Germline TP53 mutations in breast cancer families with multiple primary cancers: is TP53 a modifier of BRCA1?. J Med Genet. 2003, 40: e34-10.1136/jmg.40.4.e34.CrossRefPubMedPubMedCentral
48.
Guo SW, Thompson EA: A Monte Carlo method for combined segregation and linkage analysis. Am J Hum Genet. 1992, 51: 1111-1126.PubMedPubMedCentral
49.
Sherry ST, Ward MH, Kholodov M, Baker J, Phan L, Smigielski EM, Sirotkin K: dbSNP: the NCBI database of genetic variation. Nucleic Acids Res. 2001, 29: 308-311. 10.1093/nar/29.1.308.CrossRefPubMedPubMedCentral
Metadata
Title
Haplotype analysis of TP53 polymorphisms, Arg72Pro and Ins16, in BRCA1 and BRCA2 mutation carriers of French Canadian descent
Authors
Luca Cavallone
Suzanna L Arcand
Christine Maugard
Parviz Ghadirian
Anne-Marie Mes-Masson
Diane Provencher
Patricia N Tonin
Publication date
01-12-2008
Publisher
BioMed Central
Published in
BMC Cancer / Issue 1/2008
Electronic ISSN: 1471-2407
DOI
https://doi.org/10.1186/1471-2407-8-96

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