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Ataxia-telangiectasia (AT) is a rare autosomal recessive disorder, characterized by progressive neuronal degeneration, immunological deficiency, radio-sensitivity and an increased risk of cancer. Although several studies have confirmed that AT heterozygosis increases the risk of breast cancer (BC), we do not know how exogenous factors affect this risk. We performed an epidemiological study on the cancer risks associated with AT heterozygosis in France and explored the variation in BC risk according to environmental factors, such as reproductive factors and exposure to ionizing radiation. Information on the amount of ionizing radiation received by an individual in their lifetime and on their reproductive life was collected from the living relatives of 34 AT children (175 female relatives). Consistent with previous reports and with our previous estimate on the entire retrospective cohort, we found that the risk of developing BC is 3.6-fold higher among ATM heterozygous women. An increased risk was associated with an early age at menarche, a late age at first childbirth, nulliparity, premenopausal status and increasing periods of breast cell mitotic activity (BCMA) prior to the first childbirth. Age at menarche, age at 1st childbirth and BCMA seemed to have a stronger effect in ATM heterozygotes than in non-ATM heterozygotes. However, the tests were not all statistically significant (only age at 1st childbirth). Surprisingly, the risk of BC decreased when the chest or breasts were irradiated. It is difficult to interpret the data because of the small sample size, but further investigations should provide a biological explanation for the variation in BC risk associated with exogenous factors according to ATM heterozygosis status.

Ataxia-telangiectasia (AT) is a rare autosomal recessive disorder, characterized by progressive neuronal degeneration, immunological deficiency, radio-sensitivity and an increased risk of cancer. Although several studies have confirmed that AT heterozygosis increases the risk of breast cancer (BC), we do not know how exogenous factors affect this risk. We performed an epidemiological study on the cancer risks associated with AT heterozygosis in France and explored the variation in BC risk according to environmental factors, such as reproductive factors and exposure to ionizing radiation. Information on the amount of ionizing radiation received by an individual in their lifetime and on their reproductive life was collected from the living relatives of 34 AT children (175 female relatives). Consistent with previous reports and with our previous estimate on the entire retrospective cohort, we found that the risk of developing BC is 3.6-fold higher among ATM heterozygous women. An increased risk was associated with an early age at menarche, a late age at first childbirth, nulliparity, premenopausal status and increasing periods of breast cell mitotic activity (BCMA) prior to the first childbirth. Age at menarche, age at 1st childbirth and BCMA seemed to have a stronger effect in ATM heterozygotes than in non-ATM heterozygotes. However, the tests were not all statistically significant (only age at 1st childbirth). Surprisingly, the risk of BC decreased when the chest or breasts were irradiated. It is difficult to interpret the data because of the small sample size, but further investigations should provide a biological explanation for the variation in BC risk associated with exogenous factors according to ATM heterozygosis status.

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.