Germline missense variants of unknown significance in cancer-related genes are increasingly being identified with the expanding use of next-generation sequencing. The ataxia telangiectasia–mutated (ATM) gene on chromosome 11 has more than 1,000 germline missense variants of unknown significance and is a tumor suppressor. We aimed to determine if rare germline ATM variants are more frequent in chronic lymphocytic leukemia (CLL) compared with other hematologic malignancies and if they influence the clinical characteristics of CLL.

We identified 3,128 patients (including 825 patients with CLL) in our hematologic malignancy clinic who had received clinical-grade sequencing of the entire coding region of ATM. We ascertained the comparative frequencies of germline ATM variants in categories of hematologic neoplasms, and, in patients with CLL, we determined whether these variants affected CLL-associated characteristics such as somatic 11q deletion.

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 hematologic 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 three-fold increase in rates of somatic 11q deletion, and is a hypomorph in cell-based assays.

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.

CONTEXT

Key Objective

Inherited germline variation can predispose to cancer and affect the biology of the disease that develops. This study examined, in a consecutive clinical cohort of more than 3,000 patients with hematologic neoplasia, whether rare germline variants in ATM are associated with and influence the biology of the hematologic malignancies that develop.

Knowledge Generated

Patients with chronic lymphocytic leukemia (CLL) have a uniquely high rate of rare germline variants in ATM compared with patients with other hematologic malignancies. Furthermore, the 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 behavior. Certain ATM variants such as p.L2307F are hypofunctional and may explain these observations.

Relevance (J.W. Friedberg)

The observed high frequency of germline ATM variants has implications on both etiology and outcome of CLL. These results 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 testing of patients with newly diagnosed CLL.*

*Relevance section written by JCO Editor-in-Chief Jonathan W. Friedberg, MD.

Presented in part at the 61st American Society of Hematology Annual Meeting, Orlando, FL, December 7-10, 2019, and the 27th Congress of the European Hematology Association virtual meeting, Vienna, Austria, June 9-12, 2022.

The investigators' research was supported in part by the NCI at the NIH (grants R01CA258924 and R01CA213442 to J.R.B.), by Team 3G of the Pan-Mass Challenge (to J.R.B.), by the Okonow Lipton Family Lymphoma Research Fund (to J.R.B.), by the Tree of Life team of the Jimmy Fund Walk (to J.R.B.), and by the Multiple Myeloma Research Foundation (to A.S.K.).

Conception and design: Benjamin L. Lampson, Annette S. Kim, Jennifer R. Brown

Financial support: Jennifer R. Brown

Administrative support: Annette S. Kim, Jennifer R. Brown

Provision of study materials or patients: Annette S. Kim, Jennifer R. Brown

Collection and assembly of data: Benjamin L. Lampson, Aditi Gupta, Kiyomi Mashima, Natalia Wojciechowska, Conner J. Shaughnessy, Peter O. Baker, Stacey M. Fernandes, Samantha Shupe, John-Hanson Machado, Rayan Fardoun, Jennifer R. Brown

Data analysis and interpretation: Benjamin L. Lampson, Aditi Gupta, Svitlana Tyekucheva, Kiyomi Mashima, Zixu Wang, Conner J. Shaughnessy, Rayan Fardoun, Jennifer R. Brown

Manuscript writing: All authors

Final approval of manuscript: All authors

Accountable for all aspects of the work: All authors

AUTHORS' DISCLOSURES OF POTENTIAL CONFLICTS OF INTEREST

Rare Germline ATM Variants Influence the Development of Chronic Lymphocytic Leukemia

The following represents disclosure information provided by authors of this manuscript. All relationships are considered compensated unless otherwise noted. Relationships are self-held unless noted. I = Immediate Family Member, Inst = My Institution. Relationships may not relate to the subject matter of this manuscript. For more information about ASCO's conflict of interest policy, please refer to www.asco.org/rwc or ascopubs.org/jco/authors/author-center.

Open Payments is a public database containing information reported by companies about payments made to US-licensed physicians (Open Payments).

Aditi Gupta

Employment: Strand Life Sciences

Conner J. Shaughnessy

Employment: Loxo Oncology

Stock and Other Ownership Interests: Eli Lilly

Annette S. Kim

Honoraria: Cleveland Clinic, University of Massachusetts

Consulting or Advisory Role: Aushon Biosciences/Quanterix, Inc, PapGene, Inc, LabCorp

Research Funding: Multiple Myeloma Research Foundation

Uncompensated Relationships: College of American Pathologists, American Society of Hemotology, Association for Molecular Pathology, Society of Hematopathology, American Society of Clinical Pathologists, Association of Community Cancer Centers (ACCC), American Association of Cancer Research

Jennifer R. Brown

Consulting or Advisory Role: AbbVie, Acerta/AstraZeneca, BeiGene, Bristol Myers Squibb/Celgene/Juno, Catapult Therapeutics, Lilly, Genentech/Roche, HUTCHMED, iOnctura, Janssen, MEI Pharma, MorphoSys, Novartis, Pharmacyclics

Research Funding: BeiGene (Inst), Gilead Sciences (Inst), Loxo/Lilly (Inst), MEI Pharma (Inst), Secura Bio (Inst), Sun Pharma (Inst), TG Therapeutics (Inst)

No other potential conflicts of interest were reported.