Cancer risks for ATM variant heterozygotes

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.

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.

An increased risk of breast and pancreatic cancers was observed for PV/PPV heterozygotes, and HRs were similar in the 3 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 to 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.

Our findings will help in the clinical management of families in which an ATM PV/PPV segregates.