Frequency of the ATM IVS10-6T→G variant in Australian multiple-case breast cancer families

Breast Cancer Research

Judy Kirk⁴  Graeme Suthers⁶  Glenice Cheetham²  Kevin Trainor¹  RJ McKinlay Gardner³  Clara L Gaff³  Michael Field⁴  Jennifer Leary⁴  Jane E Visvader⁵  Melody Hiew⁵  Geoffrey J Lindeman⁵ 

[1] Department of Haematology and Genetic Pathology, Flinders Medical Centre, Adelaide, Australia;Molecular Pathology Division, Institute of Medical and Veterinary Science, Adelaide, Australia;Genetic Health Services Victoria, Melbourne, Australia;Familial Cancer Service, Westmead Institute for Cancer Research, University of Sydney, Westmead Hospital, Westmead, Australia;The Walter and Eliza Hall Institute of Medical Research, Melbourne, Australia;Familial Cancer Unit, SA Clinical Genetics Service, Women's and Children's Hospital, North Adelaide, Australia

关键词: IVS10-6T→G;    hereditary predisposition;    breast cancer;    BRCA1;    ATM;   

Others  :  1118740
DOI  :  10.1186/bcr806

 received in 2004-03-15, accepted in 2004-04-29,  发布年份 2004

【 摘 要 】

Background

Germline mutations in the genes BRCA1 and BRCA2 account for only a proportion of hereditary breast cancer, suggesting that additional genes contribute to hereditary breast cancer. Recently a heterozygous variant in the ataxia–telangiectasia mutated (ATM) gene, IVS10-6T→G, was reported by an Australian multiple-case breast cancer family cohort study (the Kathleen Cuningham Foundation Consortium for Research into Familial Breast Cancer) to confer a substantial breast cancer risk. Although this variant can result in a truncated ATM product, its clinical significance as a high-penetrance breast cancer allele or its role as a low-penetrance risk-modifier is controversial.

Methods

We determined the frequency of ATM IVS10-6T→G variants in a cohort of individuals affected by breast and/or ovarian cancer who underwent BRCA1 and BRCA2 genetic testing at four major Australian familial cancer clinics.

Results

Seven of 495 patients (1.4%) were heterozygous for the IVS10-6T→G variant; the carrier rate in unselected Australian women with no family history of breast cancer is reported to be 6 of 725 (0.83%) (P = 0.4). Two of the seven probands also harboured a pathogenic BRCA1 mutation and one patient had a BRCA1 unclassified variant of uncertain significance.

Conclusion

These findings indicate that the ATM IVS10-6T→G variant does not seem to occur at a significantly higher frequency in affected individuals from high-risk families than in the general population. A role for this variant as a low-penetrance allele or as a modifying gene in association with other genes (such as BRCA1) remains possible. Routine testing for ATM IVS10-6T→G is not warranted in mutation screening of affected individuals from high-risk families.

【 授权许可】

   
2004 Lindeman et al.; licensee BioMed Central Ltd. This is an Open Access article: verbatim copying and redistribution of this article are permitted in all media for any purpose, provided this notice is preserved along with the article's original URL.

【 参考文献 】

• [1]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, Birch JM, Lindblom A, Stoppa-Lyonnet D, Bignon Y, Borg A, Hamann U, Haites N, Scott RJ, Maugard CM, Vasen H, Seitz S, Cannon-Albright LA, Schofield A, Zelada-Hedman M, the Breast Cancer Linkage Consortium: 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.
• [2]Antoniou AC, Pharoah PD, McMullan G, Day NE, Ponder BA, Easton D: Evidence for further breast cancer susceptibility genes in addition to BRCA1 and BRCA2 in a population-based study. Genet Epidemiol 2001, 21:1-18.
• [3]Khanna KK, Jackson SP: DNA double-strand breaks: signaling, repair and the cancer connection. Nat Genet 2001, 27:247-254.
• [4]Shiloh Y: ATM and related protein kinases: safeguarding genome integrity. Nat Rev Cancer 2003, 3:155-168.
• [5]Cortez D, Wang Y, Qin J, Elledge SJ: Requirement of ATM-dependent phosphorylation of brca1 in the DNA damage response to double-strand breaks. Science 1999, 286:1162-1166.
• [6]Gatei M, Scott SP, Filippovitch I, Soronika N, Lavin MF, Weber B, Khanna KK: Role for ATM in DNA damage-induced phosphorylation of BRCA1. Cancer Res 2000, 60:3299-3304.
• [7]Savitsky K, Bar-Shira A, Gilad S, Rotman G, Ziv Y, Vanagaite L, Tagle DA, Smith S, Uziel T, Sfez S, Ashkenazi M, Pecker I, Frydman M, Harnik R, Patanjali SR, Simmons A, Clines GA, Sartiel A, Gatti RA, Chessa L, Sanal O, Lavin MF, Jaspers NGJ, Taylor AMR, Arlett CF, Miki T, Weissman SM, Lovett M, Collins FS, Shiloh Y: A single ataxia telangiectasia gene with a product similar to PI-3 kinase. Science 1995, 268:1749-1753.
• [8]Gatti RA, Tward A, Concannon P: Cancer risk in ATM heterozygotes: a model of phenotypic and mechanistic differences between missense and truncating mutations. Mol Genet Metab 1999, 68:419-423.
• [9]Swift M, Reitnauer PJ, Morrell D, Chase CL: Breast and other cancers in families with ataxia-telangiectasia. N Engl J Med 1987, 316:1289-1294.
• [10]Swift M, Morrell D, Massey RB, Chase CL: Incidence of cancer in 161 families affected by ataxia-telangiectasia. N Engl J Med 1991, 325:1831-1836.
• [11]Athma P, Rappaport R, Swift M: Molecular genotyping shows that ataxia-telangiectasia heterozygotes are predisposed to breast cancer. Cancer Genet Cytogenet 1996, 92:130-134.
• [12]Inskip HM, Kinlen LJ, Taylor AM, Woods CG, Arlett CF: Risk of breast cancer and other cancers in heterozygotes for ataxia-telangiectasia. Br J Cancer 1999, 79:1304-1307.
• [13]Janin N, Andrieu N, Ossian K, Lauge A, Croquette MF, Griscelli C, Debre M, Bressac-de-Paillerets B, Aurias A, Stoppa-Lyonnet D: Breast cancer risk in ataxia telangiectasia (AT) heterozygotes: haplotype study in French AT families. Br J Cancer 1999, 80:1042-1045.
• [14]Geoffroy-Perez B, Janin N, Ossian K, Lauge A, Croquette MF, Griscelli C, Debre M, Bressac-de-Paillerets B, Aurias A, Stoppa-Lyonnet D, Andrieu N: Cancer risk in heterozygotes for ataxia-telangiectasia. Int J Cancer 2001, 93:288-293.
• [15]Olsen JH, Hahnemann JM, Borresen-Dale AL, Brondum-Nielsen K, Hammarstrom L, Kleinerman R, Kaariainen H, Lonnqvist T, Sankila R, Seersholm N, Tretli S, Yuen J, Boice JD Jr, Tucker M: Cancer in patients with ataxia-telangiectasia and in their relatives in the nordic countries. J Natl Cancer Inst 2001, 93:121-127.
• [16]Vorechovsky I, Rasio D, Luo L, Monaco C, Hammarstrom L, Webster AD, Zaloudik J, Barbanti-Brodani G, James M, Russo G: The ATM gene and susceptibility to breast cancer: analysis of 38 breast tumors reveals no evidence for mutation. Cancer Res 1996, 56:2726-2732.
• [17]FitzGerald MG, Bean JM, Hegde SR, Unsal H, MacDonald DJ, Harkin DP, Finkelstein DM, Isselbacher KJ, Haber DA: Heterozygous ATM mutations do not contribute to early onset of breast cancer. Nat Genet 1997, 15:307-310.
• [18]Chen J, Birkholtz GG, Lindblom P, Rubio C, Lindblom A: The role of ataxia-telangiectasia heterozygotes in familial breast cancer. Cancer Res 1998, 58:1376-1379.
• [19]Chenevix-Trench G, Spurdle AB, Gatei M, Kelly H, Marsh A, Chen X, Donn K, Cummings M, Nyholt D, Jenkins MA, Scott C, Pupo GM, Dörk T, Bendix R, Kirk J, Tucker K, McCredie MR, Hopper JL, Sambrook J, Mann GJ, Khanna KK: Dominant negative ATM mutations in breast cancer families. J Natl Cancer Inst 2002, 94:205-215.
• [20]Lei H, Pospisilova D, Lindblom A, Vorechovsky I: Re: Dominant negative ATM mutations in breast cancer families. J Natl Cancer Inst 2002, 94:951-952.
• [21]Szabo CI, Schutte M, Broeks A, Houwing-Duistermaat JJ, Thorstenson YR, Durocher F, Oldenburg RA, Wasielewski M, Odefrey F, Thompson D, Floore AN, Kraan J, Klijn JG, van den Ouweland AM, Wagner TM, Devilee P, Simard J, van't Veer LJ, Goldgar DE, Meijers-Heijboer H: Are ATM mutations 7271T→G and IVS10-6T→G really high-risk breast cancer-susceptibility alleles? Cancer Res 2004, 64:840-843.
• [22]Broeks A, Urbanus JH, Floore AN, Dahler EC, Klijn JG, Rutgers EJ, Devilee P, Russell NS, van Leeuwen FE, van't Veer LJ: ATM-heterozygous germline mutations contribute to breast cancer-susceptibility. Am J Hum Genet 2000, 66:494-500.
• [23]Bernstein JL, Bernstein L, Thompson WD, Lynch CF, Malone KE, Teitelbaum SL, Olsen JH, Anton-Culver H, Boice JD, Rosenstein BS, Borresen-Dale AL, Gatti RA, Concannon P, Haile RW: ATM variants 7271T>G and IVS10-6T>G among women with unilateral and bilateral breast cancer. Br J Cancer 2003, 89:1513-1516.
• [24]National Health and Medical Research Council: Clinical Practice Guidelines. Familial aspects of cancer: a guide to clinical practice. [http://www.health.gov.au/nhmrc/publications/synopses/cp67syn.htm] webciteCommonwealth of Australia, Canberra; 1999.
• [25]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: BRCAPRO validation, sensitivity of genetic testing of BRCA1/BRCA2, and prevalence of other breast cancer susceptibility genes. J Clin Oncol 2002, 20:2701-2712.
• [26]Johannsson OT, Idvall I, Anderson C, Borg A, Barkardottir RB, Egilsson V, Olsson H: Tumour biological features of BRCA1-induced breast and ovarian cancer. Eur J Cancer 1997, 33:362-371.
• [27]Armes JE, Trute L, White D, Southey MC, Hammet F, Tesoriero A, Hutchins AM, Dite GS, McCredie MR, Giles GG, Hopper JL, Venter DJ: Distinct molecular pathogeneses of early-onset breast cancers in BRCA1 and BRCA2 mutation carriers: a population-based study. Cancer Res 1999, 59:2011-2017.
• [28]Chenevix-Trench G, Jenkins MA, Khanna KK, Spurdle AB, Marsh A, Chen X, Gatei M, Hobson K, Southey MC, Tesoriero AA, MacAulay P, Karpowicz J, Giles GG, McCredie MRE, Venter DJ, Mann G, Pupo G, Sambrook J, kConFab , Easton DF, Goldgar DE, Antoniou A, Thompson D, Hopper JL: Risk of breast cancer in female carriers of ATM IVS10-6T>G. In The Breast Cancer Linkage Consortium and the International Collaborative Group on Familial Breast and Ovarian Cancer 14th General Meeting: Madrid, Spain 2003, 48.
• [29]Dörk T, Bendix R, Bremer M, Rades D, Klöpper K, Nicke M, Skawran B, Hector A, Yamini P, Steinmann D, Weise S, Stuhrmann M, Karstens JH: Spectrum of ATM gene mutations in a hospital-based series of unselected breast cancer patients. Cancer Res 2001, 61:7608-7615.
• [30]Broeks A, Urbanus JH, de Knijff P, Devilee P, Nicke M, Klöpper K, Dörk T, Floore AN, van't Veer LJ: IVS10-6T>G, an ancient ATM germline mutation linked with breast cancer. Hum Mutat 2003, 21:521-528.
• [31]Foray N, Marot D, Gabriel A, Randrianarison V, Carr AM, Perricaudet M, Ashworth A, Jeggo P: A subset of ATM- and ATR-dependent phosphorylation events requires the BRCA1 protein. EMBO J 2003, 22:2860-2871.
• [32]Sommer SS, Buzin CH, Jung M, Zheng J, Liu Q, Jeong SJ, Moulds J, Nguyen VQ, Feng J, Bennett WP, Dritschilo A: Elevated frequency of ATM gene missense mutations in breast cancer relative to ethnically matched controls. Cancer Genet Cytogenet 2002, 134:25-32.