Cancer risk in heterozygotes for ataxia-telangiectasia
Béatrice Geoffroy-Perez
U521 INSERM, Institut Gustave Roussy, Villejuif, France
Search for more papers by this authorAnthony Laugé
Laboratoire de pathologie moléculaire des cancers, Unité de Génétique Oncologique, Institut Curie, Paris, France
Search for more papers by this authorMarie-Françoise Croquette
Centre Hospitalier Feron-Vrau, Lille, France
Search for more papers by this authorClaude Griscelli
Service d'Immuno-Hematologie pédiatrique, Hôpital des Enfants Malades, Paris, France
Search for more papers by this authorMarianne Debré
Service d'Immuno-Hematologie pédiatrique, Hôpital des Enfants Malades, Paris, France
Search for more papers by this authorBrigitte Bressac-de-Paillerets
Institut Gustave Roussy, Villejuif, France
Search for more papers by this authorAlain Aurias
Laboratoire de pathologie moléculaire des cancers, Unité de Génétique Oncologique, Institut Curie, Paris, France
Search for more papers by this authorDominique Stoppa-Lyonnet
Laboratoire de pathologie moléculaire des cancers, Unité de Génétique Oncologique, Institut Curie, Paris, France
Search for more papers by this authorCorresponding Author
Nadine Andrieu
U521 INSERM, Institut Gustave Roussy, Villejuif, France
Fax: +33-1-42-11-53-15
U521 INSERM, Institut Gustave Roussy, 39 rue Camille Desmoulins, 94805 Villejuif Cedex, FranceSearch for more papers by this authorBéatrice Geoffroy-Perez
U521 INSERM, Institut Gustave Roussy, Villejuif, France
Search for more papers by this authorAnthony Laugé
Laboratoire de pathologie moléculaire des cancers, Unité de Génétique Oncologique, Institut Curie, Paris, France
Search for more papers by this authorMarie-Françoise Croquette
Centre Hospitalier Feron-Vrau, Lille, France
Search for more papers by this authorClaude Griscelli
Service d'Immuno-Hematologie pédiatrique, Hôpital des Enfants Malades, Paris, France
Search for more papers by this authorMarianne Debré
Service d'Immuno-Hematologie pédiatrique, Hôpital des Enfants Malades, Paris, France
Search for more papers by this authorBrigitte Bressac-de-Paillerets
Institut Gustave Roussy, Villejuif, France
Search for more papers by this authorAlain Aurias
Laboratoire de pathologie moléculaire des cancers, Unité de Génétique Oncologique, Institut Curie, Paris, France
Search for more papers by this authorDominique Stoppa-Lyonnet
Laboratoire de pathologie moléculaire des cancers, Unité de Génétique Oncologique, Institut Curie, Paris, France
Search for more papers by this authorCorresponding Author
Nadine Andrieu
U521 INSERM, Institut Gustave Roussy, Villejuif, France
Fax: +33-1-42-11-53-15
U521 INSERM, Institut Gustave Roussy, 39 rue Camille Desmoulins, 94805 Villejuif Cedex, FranceSearch for more papers by this authorAbstract
Epidemiological studies have suggested that ataxia-telangiectasia (AT) heterozygotes have a predisposition to cancer, especially breast cancer in women. Now, haplotyping can identify heterozygotes for AT mutation (ATM) in AT families, allowing the risk of cancer associated with ATM heterozygosity status to be better assessed. We report a family study of AT patients, in which we estimated the risk of cancer according to ATM heterozygosity status. We analyzed demographic characteristics and occurrence of cancer in 1,423 relatives of AT patients. Haplotyping was performed in living relatives. The probability of being heterozygotes for ATM was calculated for deceased relatives. The risk of developing cancer was estimated in the cohort of relatives, and expected numbers of cancer cases were calculated from French age period-specific incidence rates. The number of cancers at all sites in the total population of relatives was not higher than expected. However, significant heterogeneity was found according to ATM heterozygosity status. This is mainly due to the increased risk of breast cancer previously observed in obligate heterozygotes. In obligate heterozygotes, relative risk (RR) was non-significantly increased for thyroid cancer, leukemia and liver cancer. Risks of ovarian, lung, pancreatic, kidney, stomach and colorectal cancers were non-significantly increased in the group with 0.5 probability of being heterozygotes. The RR was not significantly increased for any site of cancer, except for breast. Therefore, there is no evidence that specific screening of relatives of AT patients would be justified at particular sites other than the breast. However, the amplitude of the risk of breast cancer estimated in heterozygous women does not appear to justify a separate screening program from that already available to women with a first-degree relative affected by breast cancer. © 2001 Wiley-Liss, Inc.
REFERENCES
- 1 Taylor A. Ataxia-telangiectasia genes and predisportion lo leukemia, lymphoma and breast cancer. Br J Cancer 1992; 66: 5–9,
- 2 Khanna KK. Cancer risk and the ATM gene: a continuing debate. J Natl Cancer Inst 2000; 92: 795–802.
- 3 Swift M, Reitnauer PJ, Morrell D, Chase CL. Breast and other cancers in families with ataxia-telangiectasia. N Engl J Med 1987; 316: 1289–94.
- 4 Swift M, Morrell D, Massey RB, Chase CL. Incidence of cancer in 161 families affected by ataxia-telangiectasia [see comments]. N Engl J Med 1991; 325: 1831–6.
- 5 Pippard EC, Hall AJ, Barker DJ, Bridges BA. Cancer in homozygotes and heterozygotes of ataxia-telangiectasia and xeroderma pigmentosum in Britain. Cancer Res 1988; 48: 2929–32.
- 6 Morrell D, Chase CL, Swift M. Cancers in 44 families with ataxia-telangiectasia. Cancer Genet Cytogenet 1990; 50: 119–23.
- 7 Børresen AL, Andersen TI, Tretli S, Heiberg A, Moller P. Breast cancer and other cancers in Norwegian families with ataxia-telangiectasia. Genes Chromosomes Cancer 1990; 2: 339–40.
- 8 Athma P, Rappaport R, Swift M. Molecular genotyping shows that ataxia-telangiectasia heterozygotes are predisposed to breast cancer. Cancer Genet Cytogenet 1996; 92: 130–4.
- 9 Stankovic T, Kidd AM, Sutcliffe A, McGuire GM, Robinson P, Weber P, et al. ATM mutations and phenotypes in ataxia-telangiectasia families in the British isles: expression of mutant ATM and the risk of leukemia, lymphoma, and breast cancer. Am J Hum Genet 1998; 62: 334–45.
- 10 Janin N, Andrieu N, Ossian K, Lauge A, Croquette MF, Griscelli C, et al. Breast cancer risk in ataxia telangiectasia (AT) heterozygotes: haplotype study in French AT families. Br J Cancer 1999; 80: 1042–5.
- 11 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: 1304–7.
- 12 Su Y, Swift M. Mortality rates among carriers of ataxia-telangiectasia mutant alleles. Ann Intern Med 2000; 133: 770–8.
- 13 Easton DF. Cancer risks in A-T heterozygotes. Int J Radiat Biol 1994; 66: S177–82.
- 14 Angele S, Hall J. The ATM gene and breast cancer: is it really a risk factor? Mutat Res 2000; 462: 167–78.
- 15 Swift M, Sholman L, Perry M, Chase C. Malignant neoplasms in the families of patients with ataxia-telangiectasia. Cancer Res 1976; 36: 209–15.
- 16 Swift M, Morrell D, Cromartie E, Chamberlin AR, Skolnick MH, Bishop DT. The incidence and gene frequency of ataxia-telangiectasia in the United States. Am J Hum Genet 1986; 39: 573–83.
- 17 Savitsky K, Bar-Shira A, Gilad S, Rotman G, Ziv Y, Vanagaite L, et al. A single ataxia telangiectasia gene with a product similar to PI-3 kinase [see comments]. Science 1995; 268: 1749–53.
- 18 Stewart GS, Maser RS, Stankovic T, Bressan DA, Kaplan MI, Jaspers NG, et al. The DNA double-strand break repair gene hMRE11 is mutated in individuals with an ataxia-telangiectasia-like disorder. Cell 1999; 99: 577–87.
- 19 Gatti RA, Berkel I, Boder E, Braedt G, Charmley P, Concannon P, et al. Localization of an ataxia-telangiectasia gene to chromosome 11q22-23. Nature 1988; 336: 577–80.
- 20
Laake K,
Odegard A,
Andersen TI,
Bukholm IK,
Karesen R,
Nesland JM, et al.
Loss of heterozygosity at 11q23.1 in breast carcinomas: indication for involvement of a gene distal and close to ATM.
Genes Chromosomes Cancer
1997; 18:
175–80.
10.1002/(SICI)1098-2264(199703)18:3<175::AID-GCC4>3.0.CO;2-Z CAS PubMed Web of Science® Google Scholar
- 21 Benhamou E, Laplanche A, Wartelle M, Gignoux M, Ménégoz F, Robillard J, et al. Incidence des cancers en France 1978–1982. Statistiques de santé. Paris: INSERM, 1990.
- 22 De Vathaire F, Koscielny S, Rezvani A, Laplanche A, Estève J, Ferlay J. Estimation de l'incidence des cancers en France 1983–1987. Statistiques de santé. Paris: INSERM, 1996.
- 23 Ménégoz F, Chérié-Challine L. Le cancer en France: incidence et mortalité. Paris: Ministère de l'emploi et de la solidarité, 1999.
- 24 Coleman M, Douglas A, Hermon C, Peto J. Cohort study analysis with a FORTRAN computer program. Int J Epidemiol 1986; 15: 134–7.
- 25 Breslow NE, Day NE. The design and analysis of cohort studies. In: W Dawis. Statistical methods in cancer research. Lyon: IARC, 1987.
- 26 Swift M, Chase CL, Morrell D. Cancer predisposition of ataxia-telangiectasia heterozygotes. Cancer Genet Cytogenet 1990; 46: 21–7.
- 27 FitzGerald MG, Bean JM, Hegde SR, Unsal H, MacDonald DJ, Harkin DP, et al. Heterozygous ATM mutations do not contribute to early onset of breast cancer [see comments]. Nat Genet 1997; 15: 307–10.
- 28 Broeks A, Urbanus JH, Floore AN, Dahler EC, Klijn JG, Rutgers EJ, et al. ATM-heterozygous germline mutations contribute to breast cancer susceptibility. Am J Hum Genet 2000; 66: 494–500.
- 29 Glanz K, Grove J, Le Marchand L, Gotay C. Underreporting of family history of colon cancer: correlates and implications. Cancer Epidemiol Biomarkers Prev 1999; 8: 635–9.
- 30 Aitken J, Bain C, Ward M, Siskind V, MacLennan R. How accurate is self-reported family history of colorectal cancer? Am J Epidemiol 1995; 141: 863–71.
- 31 Stilgenbauer S, Schaffner C, Litterst A, Liebisch P, Gilad S, Bar-Shira A, et al. Biallelic mutations in the ATM gene in T-prolymphocytic leukemia. Nat Med 1997; 3: 1155–9.
- 32 Vorechovsky I, Luo L, Dyer MJ, Catovsky D, Amlot PL, Yaxley JC, et al. Clustering of missense mutations in the ataxia-telangiectasia gene in a sporadic T-cell leukaemia. Nat Genet 1997; 17: 96–9.
- 33 Stoppa-Lyonnet D, Soulier J, Lauge A, Dastot H, Garand R, Sigaux F, et al. Inactivation of the ATM gene in T-cell prolymphocytic leukemias. Blood 1998; 91: 3920–6.
- 34 Stoppa-Lyonnet D, Lauge A, Sigaux F, Stern MH. No germline ATM mutation in a series of 1 6T-cell prolymphocytic leukemias [letter, comment]. Blood 2000; 96: 374–6.
- 35 Parkin DM, Pisani P, Ferlay J. Estimates of the worldwide incidence of eighteen major cancers in 1985. Int J Cancer 1993; 54: 594–606.
- 36 Scully R, Livingston DM. In search of the tumor-suppressor functions of BRCA1 and BRCA2. Nature 2000; 408: 429–32.
- 37 Krieger N. Exposure, susceptibility and breast cancer risk: a hypothesis regarding exogenous carcinogens, breast tissue development, and social gradients, including black/white differences, in breast cancer incidence. Breast Cancer Res Treat 1989; 13: 205–23.
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