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Risk of Pancreatic Cancer Associated With Germline ATM Pathogenic Variants


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In a multicenter cohort study reported in JAMA Oncology, Hsu et al found that among pancreatic cancer kindreds, individuals with germline ATM pathogenic variants had a sixfold increased risk of developing pancreatic cancer vs noncarriers of pathogenic variants.

Study Details

The study involved data from pancreatic cancer family registries in the United States, including pedigree data from 130 pancreatic cancer kindreds with a germline ATM pathogenic variant. The 130 families (95% White) comprised 2,227 family members with complete records, including familial relationships, pancreatic cancer diagnosis, ATM status (pathogenic variant carrier, noncarrier, or untyped), proband status, and age. The family members had a mean age of 58 years, and 1,096 (49%) were women.

Key Findings

Among the 2,227 family members, 155 had positive results for a germline ATM pathogenic variant, 16 had a negative result, and the remainder did not have a test result.

Among the 130 families and 2,227 members, 217 individuals had pancreatic cancer, with 78 families having 1, 34 families having 2, and 18 families having 3 or more affected members. The average age at diagnosis was 64 years (range = 31–98 years).

The estimated cumulative risk of pancreatic cancer among individuals with a germline pathogenic ATM variant vs that in noncarriers was 0.08% vs 0.01% by age 30, 0.30% vs 0.05% by age 40, 1.08% vs 0.17% by age 50, 3.03% vs 0.47% by age 60, 6.25% vs 0.99% by age 70, and 9.53% vs 1.53% by age 80 years. Overall, the relative risk of pancreatic cancer was 6.5 (95% confidence interval = 4.5–9.5) in ATM variant carriers vs noncarriers.

In a broader pedigree analysis among 3,361 members of the 130 families that included members with missing data, pancreatic cancer was diagnosed in 108 (4.18%) of 2,580 with unknown pathogenic variant status and known pancreatic cancer status.

The investigators concluded, “This multicenter cohort study found that individuals with a germline pathogenic ATM variant 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.”

Alison P. Klein, PhD, MHS, of the Department of Oncology, Pathology, and Medicine, Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University, is the corresponding author for the JAMA Oncology article.

Disclosure: The study was supported by the National Cancer Institute, Bowen-Chapman Family Research Fund, Fonds de Recherche du Québec, and others. For full disclosures of the study authors, visit jamanetwork.com.


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