Cancer risk in heterozygotes for ataxia-telangiectasia

Abstract

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. Key words: ataxia-telangiectasia; heterozygosity; cancer risk; family study; breast cancerAtaxia-telangiectasia (AT), which is caused by mutations in the ATM (AT-mutated) gene, is a rare autosomal recessive disorder, characterized by progressive neuronal degeneration, immunological deficiency, radiosensitivity and an increased risk of cancer. Most cancers in patients with AT are lymphoid-type. 1,2 Epidemiological studies in AT families have suggested that AT heterozygotes may have increased cancer risk, especially for breast cancer, 3-11 and possibly increased risk of ischemic heart disease. 12 Combined analysis of the available data in 1994 led to an estimate of 3.9 for the increased breast-cancer risk in women. 13 Although an increased risk of developing all cancers has often been found, little is known about increased risk at particular sites, except for breast cancer. 14 Despite suggestions, there is no evidence that the incidence of ovarian, lung, gastric, pancreatic, basal-cell, colon, cervical or biliary system cancers; leukemias; or lymphomas is increased in AT families. 4,11,15 Although homozygotes are rare, 1 in 40...

Increased risk of breast cancer among female relatives of patients with ataxia-telangiectasia: a causal relationship?

“…Olsen et al mentioned that their findings were consistent with our study showing that the risk for breast cancer among female relatives seems to be restricted to the subgroup of obligate carriers (Geoffroy-Perez et al, 2001). They also mentioned that mutation carrier testing among families may bias the estimates by selective testing of survivors and/or relatives affected by cancer.…”

Breast and other cancers in 1445 blood relatives of 75 Nordic patients with ataxia telangiectasia

“…There is no good explanation for the observed difference between the two sexes in the US study, and there is no support in our study for a substantially increased risk for cancers among male relatives. In a separate analysis of the incidence of cancers at sites other than the breast, the French study obtained an overall RR of 0.9 for both sexes combined on the basis of 93 observations (Geoffroy-Perez et al, 2001). Liver was the only site for which there was a significant increase in risk, on the basis of six observed and 1.5 expected cases; sex-specific risks were, however, not given.…”

“…Several studies, however, have estimated carriers to be at three-to five-fold increased risk for developing breast cancer (Swift et al, 1991;Athma et al, 1996;Inskip et al, 1999;Janin et al, 1999;Geoffroy-Perez et al, 2001;Olsen et al, 2001) and perhaps other cancers. With calculated mutation carrier frequencies in the general population in the order of 0.5 -1% for ATM gene mutations, ATM heterozygosity might be responsible for a sizeable proportion of breast cancers in the (female) population (Easton, 1994).…”

ATM and breast cancer susceptibility

“…Subsequent studies have provided inconclusive and/or inconsistent data about whether/which additional cancers are associated with ATM heterozygosity (Geoffroy-Perez et al, 2001;Olsen et al, 2001;Thompson et al, 2005b). Further, larger studies will be required to investigate the role of ATM in susceptibility to cancers other than breast cancer.…”