Risk of Pancreatic Cancer Among Individuals With Pathogenic Variants in the ATM Gene

Importance

Pathogenic germline variants in theATMgene have been associated with pancreatic cancer risk. Although genetic testing identifies these variants in approximately 1% to 3% of unselected patients with pancreatic cancer, the lifetime risk of pancreatic cancer among individuals with pathogenic ATMvariants has not been well estimated.

Objective

To estimate age-specific penetrance of pancreatic cancer in individuals with a pathogenic variant in theATMgene.

Design, Setting, and Participants

This was a multicenter cohort study of pancreatic cancer family registries in the US and Canada using pedigree data from 130 pancreatic cancer kindreds with a pathogenic germlineATMvariant. Data analyses were performed from January 2020 to February 2021.

Main Outcomes and Measures

Observational age-specific risk of pancreatic cancer. Penetrance was estimated using modified segregation analysis.

Results

The study population of 130 families (123 [95%] White families) comprised 2227 family members (mean age [SD], 58 [22] years; 1096 [49%] women) with complete records (ie, including familial relationships, pancreatic cancer diagnosis,ATMstatus, proband status, and age), of which 155 individuals had positive results for anATMpathogenic variant, 16 had a negative result, and the remainder did not have a test result. In these 130 families, 217 individuals had pancreatic cancer: 78 families had 1 such member; 34 families had 2 such members; and 18 families had 3 or more members with pancreatic cancer. The average (range) age at diagnosis was 64 (31-98) years. The cumulative risk of pancreatic cancer among individuals with a germline pathogenicATMvariant was estimated to be 1.1% (95% CI, 0.8%-1.3%) by age 50 years; 6.3% (95% CI, 3.9%-8.7%) by age 70 years; and 9.5% (95% CI, 5.0%-14.0%) by age 80 years. Overall, the relative risk of pancreatic cancer was 6.5 (95% CI, 4.5-9.5) inATMvariant carriers compared with noncarriers.

Conclusions and Relevance

This multicenter cohort study found that individuals with a germline pathogenicATMvariant were at an increased lifetime risk of pancreatic cancer. These risk estimates can help guide decision-making when evaluating the risks and benefits of enhanced early detection surveillance.