Developing an Evidence Basis for Precision Risk Assessment in Pancreatic Cancer Families with ATM Variants of Uncertain Significance
Abstract
Background and Aims: Understanding the genetic basis of inherited pancreatic cancer risk is essential to improving patient care and outcomes. Clinical care guidelines now recommend genetic testing for patients with pancreatic cancer and their first-degree relatives. Inherited, disease-causing variants in ATM, a critical component of DNA double strand break repair and a high-risk pancreatic cancer susceptibility gene, are identified in 2%-3% of all patients with pancreatic cancer. However, over 10% of patients are found to have a variant of unknown significance (VUS) that cannot currently be classified as disease-causing or benign. This is the cause of significant uncertainty as individuals with an ATM VUS without a strong family history of pancreatic cancer are not eligible for screening to detect pancreatic cancer early under current guidelines. In Aim 1, we will determine the functional consequence of 200 ATM VUS identified in patients with pancreatic cancer using a cell-based assay. We will determine which VUS damages ATM function and can be reclassified as disease-causing based on clinically used variant interpretation guidelines. In Aim 2, we will estimate risk of pancreatic cancer by age in individuals with a VUS classified as damaging to ATM function. FY21 PCARP Focus Areas: (1) Early detection research for pancreatic cancer, including studies of individuals with pre-diabetes and diabetes and/or those in underserved ethnic and minority communities. (2) Understanding precursors, origins and early progression of pancreatic cancer. Innovation: To elucidate the contribution of ATM VUS to inherited risk of pancreatic cancer, we will use a novel, validated, cell-based assay to assess the functional consequence of over 200 ATM variants. Our assay will introduce variants into the ATM gene so that expression of the variant is under control of ATM promoters and enhancers. We will determine variant functional consequence using sequencing and a custom analysis pipeline. Our large-scale classification of ATM variants will provide a novel understanding of the ATM gene, including insight on the importance of specific genetic sequences and on how specific changes impact function. We will determine the prevalence of a VUS that damages ATM function and can be reclassified as disease-causing. We will also establish, for the first-time, the risk of pancreatic cancer in individuals with a VUS that damages ATM function and determine how risk changes with age. We will identify pancreatic cancer families with a VUS that damages ATM function and will contribute to future research of cancer genetics and biology, disease epidemiology, early detection, and intervention. Impact: The proposed research has immediate impact on the lives of patients and their relatives. We will functionally characterize and reclassify 200 ATM VUS identified in patients with pancreatic cancer. Reclassification of ATM VUS as either disease-causing or benign will bring certainty to these patients, their relatives, and their health care providers. Specifically, patients with disease-causing ATM variants, including reclassified VUS, may have tumors that are more responsive to radiation therapy. Relatives with ATM VUS reclassified as disease-causing will now be eligible for screening initiatives to detect pancreatic cancer early when patient outcomes are improved. Our risk estimates for pancreatic cancer in individuals with a VUS that damages ATM function will be important to inform these early detection initiatives, for example, by guiding when to initiate screening and the type of screening test used. This research will also provide data to support development of a clinical assay to functionally characterize ATM VUS identified in patients with pancreatic cancer in future.
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- Dec 28, 2022
- Source ID
- W81XWH2210325
Entities
People
- Nicholas J Roberts
Organizations
- Johns Hopkins University
- United States Army