In a single-institution analysis reported in the Journal of Clinical Oncology, Benjamin L. Lampson, MD, and colleagues found a higher prevalence of rare germline ATM variants in chronic lymphocytic leukemia (CLL) vs other lymphoid and myeloid disorders. They also determined that patients with CLL with vs without these variants were diagnosed younger and were more likely to have a somatic 11q deletion.
Benjamin L. Lampson, MD
Study Details
The study included 3,128 patients seen by 21 clinicians in the hematologic malignancies division of Dana-Farber Cancer Institute between August 2014 and August 2019 who had next-generation sequencing performed on peripheral blood or bone marrow. Among these patients: 825 (26%) had CLL, monoclonal B lymphocytosis, or B-cell prolymphocytic leukemia; 1,101 (35%) had other lymphoid disorders; 1,059 (34%) had myeloid disorders; and 143 (5%) had no neoplastic process. A total of 158 rare germline variants, defined as those present at total population allelic frequency of ≤ 1%, were identified and included in the analysis.
Key Findings
Rare germline ATM variants were found in 24% of patients with CLL, a prevalence significantly higher vs patients with non-CLL lymphoid malignancies (16%, P < 1 × 10-5), myeloid disease (15%, P < 1 × 10-5), or no hematologic neoplasms (14%, P < .05).
Patients with CLL with vs without germline ATM variants were younger at diagnosis (median age = 58 vs 61 years, P = .012) and more likely to have 11q deletion (24.5% vs 13.3%, P < .0005). The frequency of ATM-aberrant disease, defined as 11q deletion or somatic ATM mutation, was higher in those with germline variants (29.8% vs 15.0%, P < 1 × 10-5).
The ATM variant p.L2307F was the most common rare variant in patients with CLL (3%). Patients with p.L2307F were more likely to have somatic 11q deletion vs patients with no germline variants (35% vs 13.3%, P = .009). In cell-based assays, the variant was found to be a hypomorph, exhibiting partial loss of gene function.
The investigators concluded, “Germline ATM variants cluster within CLL and affect the phenotype of CLL that develops, implying that some of these variants (such as ATM p.L2307F) have functional significance and should not be ignored. Further studies are needed to determine whether these variants affect the response to therapy or account for some of the inherited risk of CLL.”
Jennifer R. Brown, MD, PhD, of Dana-Farber Cancer Institute, is the corresponding author for the Journal of Clinical Oncology article.
Disclosure: The study was supported by the National Cancer Institute, Team 3G of the Pan-Mass Challenge, Multiple Myeloma Research Foundation, and others. For full disclosures of the study authors, visit ascopubs.org.
