The investigators found that rare germline ataxia telangiectasia–mutated (ATM) variants, when considered in aggregate, are more common in patients with chronic lymphocytic leukaemia (CLL) compared with other lymphoid and myeloid disorders. These ATM variants have prognostic and functional significance. Patients with germline ATM variants are diagnosed at a younger age and are twice as likely to have CLL with 11q deletion, an adverse marker associated with more rapid disease progression. In particular, the variant ATM p.L2307F is enriched in patients with CLL and is also significantly associated with the development of 11q-deleted disease. Lymphocytes with an endogenous ATML2307F mutation have an impaired DNA damage response compared with lymphocytes with wild-type ATM.
The results, published by Dr. Jennifer R. Brown of the Dana-Farber Cancer Institute in Boston, MA, US and colleagues on 31 October 2022 in the Journal of Clinical Oncology, require validation in prospective data sets to determine the true clinical significance of these variants and to provide additional rationale for routine next-generation sequencing (NGS) testing in patients with newly diagnosed CLL.
The authors wrote in the background that although some pathogenic germline variants contribute to oncogenesis, the majority of germline variants are missense mutations with an unclear impact on gene function and are therefore termed variants of uncertain significance (VUS). With the increasing use of NGS in the clinic, the incidental identification of germline VUS has become frequent.
CLL is a B-cell malignancy that has a strong hereditary component. Genome-wide association studies have identified more than 40 loci potentially linked to CLL development, but all have low penetrance and many are not assessed by routine clinical testing, making it difficult to apply to individual patients.
Targeted association analyses of polymorphisms in genes important in B-cell biology have repeatedly identified missense variants in the gene ATM as potential risk loci, and a recent whole-exome sequencing study identified ATM as the cancer-related gene with one of the highest number of rare germline variants in a cohort of patients with B-cell malignancies. In addition, a retrospective unbiased exome-wide comparison of rare germline variants identified rare ATM variants as enriched in CLL cases compared with controls.
Although the repeated identification of ATM VUS is suggestive, these studies have been limited by low numbers of patients with variants, heterogeneity of sequencing methods, and heterogeneity of control populations.
ATM encodes a protein kinase and tumour suppressor that facilitates the repair of DNA double-strand breaks. Pathogenic, inactivating somatic mutations in ATM are seen in 4-15% of CLL cases, and deletion of the long arm of chromosome 11 that contains ATM occurs in 11-17% of patients with untreated CLL. Somatic inactivation of ATM predicts shorter time to first treatment, shorter progression-free survival after chemoimmunotherapy, and shorter overall survival in patients with CLL. ATM loss is particularly important in CLL disease biology, and germline ATM variants could potentially influence clinical outcomes. Some missense variants, typically classified in clinical reports as VUS, may actually be significant.
ATM p.F858L and p.P1054R were enriched in patients with CLL in a study of single nucleotide polymorphisms in DNA-damage response genes. The whole-exome sequencing analysis in 516 patients with CLL and ethnically matched normal controls identified ATM p.L2307F as one of the most enriched variants in patients with CLL.
Based on these findings, the study team systematically studied the prevalence of all ATM variants, as uniformly assessed by clinical-grade NGS, in a large consecutive population of patients with haematologic malignancies, including CLL. They then examined whether rare germline ATM variants affect either the phenotype of CLL that develops or the in vitro behaviour of lymphocytes bearing a uniquely enriched rare variant, p.L2307F.
The authors identified 3,128 patients, including 825 patients with CLL, who had received clinical-grade sequencing of the entire coding region of ATM. They ascertained the comparative frequencies of germline ATM variants in categories of haematologic neoplasms, and, in patients with CLL, they determined whether these variants affected CLL-associated characteristics such as somatic 11q deletion.
The study team found that rare germline ATM variants are present in 24% of patients with CLL, significantly greater than that in patients with other lymphoid malignancies (16% prevalence), myeloid disease (15%), or no haematologic neoplasm (14%). Patients with CLL with germline ATM variants are younger at diagnosis and twice as likely to have 11q deletion. The ATM variant p.L2307F is present in 3% of patients with CLL, is associated with a 3-fold increase in rates of somatic 11q deletion, and is a hypomorph in cell-based assays.
The authors concluded that a high frequency of germline ATM variants is uniquely present in patients with CLL. 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 treatment or account for some of the inherited risk of CLL.
This investigators' research was supported in part by the US NCI at the NIH grants, the team 3G of the Pan-Mass Challenge, the Okonow Lipton Family Lymphoma Research Fund, the Tree of Life team of the Jimmy Fund Walk, and the Multiple Myeloma Research Foundation.
The study was presented in part at the 61st American Society of Hematology Annual Meeting from 7 to 10 December 2019 in Orlando, FL, US and at the 27th Congress of the European Hematology Association virtual meeting from 9 to 12 June 2022 (Vienna, Austria).
Lampson BL, Gupta A, Tyekucheva S, et al. Rare Germline ATM Variants Influence the Development of Chronic Lymphocytic Leukemia. JCO; Published online 31 October 2022. DOI: 10.1200/JCO.22.00269