Individuals With Pathogenic ATM Variant Have an Increased Lifetime Risk of Developing Pancreatic Cancer

Individuals with a germline pathogenic ATM variant appear to have an increased lifetime risk of developing pancreatic cancer compared with those without the variant, according to findings from a multicohort study of pancreatic cancer family registries published in JAMA Oncology.

Pancreatic cancer cumulative risk for individuals with the germline pathogenic ATM variant was estimated by age increased from 0.08% (95% CI, 0.07%-0.09%) at 30 years to 0.30% (95% CI, 0.25%-0.36%) at 40 years, 1.08% (95% CI, 0.83%-1.33%) at 50 years, 3.03% (95% CI, 2.12%-3.94%) at 60 years, 6.28% (95% CI, 3.90%-8.66%) at 70 years, and 9.53% (95% CI, 5.04%-14.02%) at 80 years.

“These findings underscore the need to develop appropriate surveillance and intervention strategies for these individuals at high-risk of developing pancreatic cancer,” the investigators wrote.

The study enrolled kindreds who were included in family registries participating in the Pancreatic Cancer Genetic Epidemiology Consortium, which included the National Familial Pancreas Tumor Registry from Johns Hopkins University, the Biospecimen Resource for Pancreas Research from the Mayo Clinic, GI Cancer Genetics from Dana-Farber Cancer Institute, and the Ontario Pancreas Cancer Study from Mount Sinai Hospital, University of Toronto.

In order to be eligible, families were required to have at least 1 member who had been diagnosed pancreatic cancer and 1 family member with a germline ATM pathogenic variant.

Study population included 2227 individuals from 130 families. Notably, 95% of families were white and 49% of patients were women. The patient population had a mean age of 58 years. Of this population, 155 individuals returned a positive test result for an ATM pathogenic variant.

Although an increased prevalence of pancreatic cancer was seen among individuals not carrying the variant compared with untyped individuals, this was due to “preferential genetic testing of patients with cancer over cancer-free individuals.” Although other pedigree members had a missing pancreatic cancer status and/or age, they were included in order to complete the family structure; this was believed to have had a limited influence on estimated risk.

Within the families included in the study, 217 individuals had pancreatic cancer. Moreover, 78 families had 1 member with the disease, 34 families had 2 members, and 18 families had 3 or more members. Patients were an average of 64 years of age (range, 31-98) upon being diagnosed.

To determine whether there were findings to support penetrance differences between men and women, sex specific penetrance was examined. However, the study model did not appear to be significant (β = 0.12; SE, 0.11; P = .29). Compared with individuals without the ATM variant, the relative risk estimate of pancreatic cancer was 6.5 (95% CI, 4.5-9.5) for individuals with the ATM variant.

“Compared with studies that have estimated a 2.2- to 6.6-fold increased risk of pancreatic cancer in BRCA2 variant carriers, the risk estimates of the present study strongly support inclusion of ATM variant carriers in screening trials,” the investigators wrote.

The main limitation of the research centered around the European ancestry, which encompassed the majority of families included in the study population. The investigators suggest that future studies focus on non-European populations to better understand the risk of germline ATM variants.

Reference

Hsu FC, Roberts NJ, Childs E, et al. Risk of pancreatic cancer among individuals with pathogenic variants in the ATM Gene. JAMA Oncol. Published online September 16, 2021. doi:10.1001/jamaoncol.2021.3701