Cancer risks for ATM variant heterozygotes.

PURPOSE: Cancer risks of individuals heterozygous for an ATM pathogenic or predicted pathogenic variant (PV/PPV) remain imprecise to guide optimal clinical management. Therefore, we aimed to estimate these risks in different family settings. METHODS: Data were collected on 141 ataxia-telangiectasia families, 398 Hereditary Breast and Ovarian Cancer families and 96 families with a history of pancreatic cancer enrolled in French nation-wide epidemiological studies CoF-AT2, TUMOSPEC or GENESIS. Hazard ratios (HR) and cumulative risks were estimated using a modified segregation analysis method. RESULTS: An increased risk of breast and pancreatic cancers was observed for PV/PPV heterozygotes, and HRs were similar in the three family sets. When combined, HR were 4.0 (95%CI:2.9-5.6) for female breast cancer, 6.6 (95%CI:3.6-12.1) for female pancreatic cancer, and 2.8 (95%CI:1.4-5.5) for male pancreatic cancer. In birth cohort 1960-1969, female heterozygotes had a cumulative risk of breast cancer of 9.9% (95%CI:7.1%-13%) by age 50, and of 40% (95%CI:31%-51%) by age 80. Their risk of pancreatic cancer by age 80 was 8.1% (95%CI:4.3%-14%). The risk of male pancreatic cancer by age 80 was 5.1% (95%CI:2.4%-9.3%). No increased risk of ovarian and prostate cancers was observed. CONCLUSION: Our findings will help in the clinical management of families where an ATM PV/PPV segregates.