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

Abstract

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 PARTICIPANTSThis 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 MEASURESObservational age-specific risk of pancreatic cancer. Penetrance was estimated using modified segregation analysis. RESULTSThe 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 RELEVANCEThis 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.

A Genome-First Approach to Estimate Prevalence of Germline Pathogenic Variants and Risk of Pancreatic Cancer in Select Cancer Susceptibility Genes

“…Low risk was seen for CHEK2 (both cohorts). The high risk of PDAC in ATM heterozygotes has been described before in a multicenter cohort [28]. Interestingly, this finding contrasts with the more moderate risk that has been estimated for breast cancer in this gene [29].…”

Whole genome sequencing identifies rare genetic variants in familial pancreatic cancer patients

“…Variants in BRCA and ATM genes occur in both hereditary and sporadic PDAC causing deficiency in DNA repair pathways and provoke genomic instability (Perkhofer et al., 2021). In a recent study of 130 families with 2,227 family members with FPC predisposition, it was shown that individuals with an ATM variant had a cumulative risk for pancreatic cancer of 6.3% by age 70 and 9.5% by age 80 (Hsu et al., 2021). Both ATM and BRCA2 variants have previously been identified as inherited germline variants related to pancreatic cancer (Hu et al., 2018; Huang et al., 2018; Zhen et al., 2015).…”

Current Screening Strategies for Pancreatic Cancer

“…Ataxia telangiectasia is a complex autosomal recessive syndrome caused by germline mutations in the ATM gene, which increase sensitivity of cells to potentially mutagenic environmental factors (e.g., sunlight) and susceptibility to malignant transformation. The disease is known for neurological manifestations and vascular anomalies, but the ATM variant carriers also have a 6.5-fold risk of PDAC [ 42 ].…”