Risk of Pancreatic Cancer Among Individuals With Pathogenic Variants in the ATM Gene
Open accessAbstract
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.
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ATM mutations are the second most frequent known cause of germline mutations in PDAC after BRCA2 and confer a comparable lifetime increased risk of PDAC in carriers.
“Mutations of ATM are the second most frequent known cause of germline mutations in PDAC, after BRCA2, conferring a comparable lifetime increased risk of PDAC in mutation carriers91.”
From Pancreatic cancer: Advances and challenges (2023) · cites this paper as [91]
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- Authors
- Hsu, F.-C., Roberts, N. J., Childs, E., Porter, N., Rabe, K. G., Borgida, A., Ukaegbu, C., Goggins, M. G., Hruban, R. H., Zogopoulos, G., Syngal, S., Gallinger, S., Petersen, G. M., & Klein, A. P.
- Affiliations
- Johns Hopkins University (US)
- Mayo Clinic (US)
- University of Toronto (CA)
- Institut du cancer Rosalind & Morris Goodman (CA)
- Brigham and Women's Hospital (US)
- Divison of General Surgery, University of Toronto, Toronto, Ontario, Canada
- Corresponding author
- Klein, Alison P.
- ORCID
- Venue
- JAMA Oncology
- Publisher
- American Medical Association (AMA)
- Published
- 2021-11-01
- Volume
- 7
- Issue
- 11
- Pages
- 1664
- ISSN
- 2374-2437 (ISSN-L)
- PMC
- PMC8446906
- OpenAlex
- W3200810541
- Cited by
- 91
- References
- 23
- Citations by year
- 2026: 14 · 2025: 18 · 2024: 21 · 2023: 23 · 2022: 15
- FWCI
- 5.37
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Locations
- JAMA Oncology (publishedVersion)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- Funders
- National Cancer Institute (R00CA190889, R01CA132829, P50CA102701, R01CA097075, P50CA062924, P30CA006973)
- Topics
- Health Sciences › Medicine › Oncology › Pancreatic and Hepatic Oncology Research
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › BRCA gene mutations in cancer
- Health Sciences › Medicine › Pathology and Forensic Medicine › Genetic factors in colorectal cancer
- Keywords
- ATM gene, germline pathogenic variants, pancreatic cancer risk, lifetime cancer risk, familial pancreatic cancer, cancer susceptibility, segregation analysis, pedigree data, hereditary cancer, genetic testing, relative risk, age at diagnosis
- MeSH terms
- Adult, Aged, Aged, 80 and over, Female, Genetic Testing, Humans, Middle Aged, Pancreatic Neoplasms, Pedigree, Cohort Studies, Germ-Line Mutation, Ataxia Telangiectasia Mutated Proteins
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