Jennifer R. Brown, MD, PhD

Inherited germline variation can predispose individuals to cancer and affect the biology of the disease as it grows. The rare germline ataxia telangiectasia-mutated (ATM) variants found in chronic lymphocyte leukemia (CLL), such as ATM p.L2307F, have functional implications and should not be overlooked, as these variants can affect the phenotype of CLL, according to Jennifer R. Brown, MD, PhD. A tumor suppressor, the ATM gene on chromosome 11 contains more than 1,000 germline missense variants. With the expansion of next-generation sequencing, Dr. Brown explains, germline missense variants of unknown significance in cancer-related genes are increasingly being identified.

“We previously published a study in which we found that rare variants in the ATM gene were inherited more often in patients with CLL compared with people without cancer,” Dr. Brown says. “In fact, we found that rare inherited variants in ATM are enriched in patients with CLL compared with patients with other hematologic malignancies.”

Furthermore, she adds, the type of CLL that develops in patients with rare germline ATM variants is more likely to have 11q deletion and somatic ATM mutations, consistent with tumor suppressor activity.

Rare Germline ATM Variants Observed in 24% of Patients With CLL

For a study published in the Journal of Clinical Oncology, Dr. Brown and colleagues sought to determine if rare germline ATM variants occur more often in CLL compared with other hematologic malignancies and if they affect the clinical characteristics of CLL. A total of 3,128 patients (N=825 with CLL) from a hematologic malignancy clinic who had received clinical-grade sequencing of the entire ATM coding region were identified. To assess whether these variants affected CLL-linked characteristics such as somatic 11q deletion, the study team established the comparative occurrence of germline ATM variants in categories of patients with CLL and of hematologic neoplasms in general.

In 24% of patients with CLL, the researchers observed rare germline ATM variants at considerably greater rates than that seen in patients with myeloid disease (15%), other lymphoid malignancies (16%), or no hematologic neoplasm (14%). Additionally, patients with CLL with germline ATM variants are twice as likely to have 11q deletion and be younger at diagnosis. The ATM variant p.L2307F found in 3% of patients with CLL, a hypomorph in cell-based assay, is linked with a three-fold increase in rates of somatic 11q deletion.

“The inherited variant in ATM has clinical significance and affects the function of the ATM gene,” Dr. Brown says. “For the most common variant, we demonstrated in assays in vitro that the variant was hypofunctional compared with the normal ATM. The study has potential implications for reclassification of variants previously thought to be of unknown significance into variants that do confer disease risk.”

The study team concurs that further studies are needed to determine whether these variants account for some of the inherited risk for CLL or affect the response to therapy.