Risk of Pancreatic Cancer among Individuals with Pathogenic Variants in the ATM Gene

Fang Chi Hsu, Nicholas J. Roberts, Erica Childs, Nancy Porter, Kari G. Rabe, Ayelet Borgida, Chinedu Ukaegbu, Michael G. Goggins, Ralph H. Hruban, George Zogopoulos, Sapna Syngal, Steven Gallinger, Gloria M. Petersen, Alison P. Klein

Research output: Contribution to journalArticlepeer-review


Importance: Pathogenic germline variants in the ATM gene 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 ATM variants has not been well estimated. Objective: To estimate age-specific penetrance of pancreatic cancer in individuals with a pathogenic variant in the ATM gene. 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 germline ATM variant. 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, ATM status, proband status, and age), of which 155 individuals had positive results for an ATM pathogenic 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 pathogenic ATM variant 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) in ATM variant carriers compared with noncarriers. Conclusions and Relevance: 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..

Original languageEnglish (US)
Pages (from-to)1664-1668
Number of pages5
JournalJAMA Oncology
Issue number11
StatePublished - Nov 2021

ASJC Scopus subject areas

  • Oncology
  • Cancer Research


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