Chronic Lymphocytic Leukemia - Investigating the influence of germline ATM variants in chronic lymphocytic leukemia on cancer vulnerability

Sep 21, 2026

Chronic lymphocytic leukemia (CLL) patients carry an elevated risk of secondary cancers and often show familial predisposition. Germline ATM variants were previously linked to CLL risk, and this study evaluates whether those variants also shape susceptibility to secondary neoplasms in CLL patients and their relatives. Among 333 respondents, family cancer history was more frequent with germline ATM variants. Secondary cancer prevalence did not differ overall. Time to first CLL treatment was not altered for germline ATM carriers, while TTFT differences were observed for somatic ATM events. Overall, germline ATM variants correlate with increased B-cell lymphoproliferative disorders, including familial CLL.

LanguageEnglish

CategoryResearch & Report

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Pages10

Reading Time25 min

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Abstract

Introduction

ATM gene and germline variant rationale

ARTICLE-Chronic Lymphocytic Leukemia Investigating the influence of germline ATM variants in chronic lymphocytic leukemia on cancer vulnerability Roberta S. Azevedo,1,2* Francesca Morelli,1,3* Kiyomi Mashima1, Rayan Fardoun1, Svitlana Tyekucheva,4,5 Stacey Fernandes1, Samantha Shupe1, Marissa Terra1, Anisha Patel1, Matthew S. Davids,1,6 Joseph Yu1 and Jennifer R. Brown1,6 1 Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA, USA; 2 Hospital Nove de Julho, São Paulo, Brazil; 3 Department of Hematology, University of Florence, Florence, Italy; 4 Department of Data Science, Dana-Farber Cancer Institute, Boston, MA, USA; 5 Department of Biostatistics, Harvard T. H. Chan School of Public Health, Boston, MA, USA and 6 Department of Medicine, Harvard Medical School, Boston, MA, USA *RSA and FM contributed equally as first authors. Abstract Correspondence: J. R. Brown [jennifer_brown@dfci.harvard.edu](jennifer_brown@dfci.harvard.edu) [Received:](Received: June 13)[ June 13](Received: June 13), 2024. Accepted: November 14, 2024. Early view: November 21, 2024. [https://doi.org/10.3324/haematol.2024.286031](https://doi.org/10.3324/haematol.2024.286031) ©2025 Ferrata Storti Foundation Published under a CC BY-NC license Chronic lymphocytic leukemia (CLL) patients have an increased risk of secondary cancers, along with predisposition to CLLin their relatives. We have previously identified germline ATM variants as associated with CLL risk. Here, we present their impact on predisposition to secondary neoplasms in CLL patients and their relatives. Patients enrolled in our tissue bank who had germline ATM status available were mailed a questionnaire between April 2022 and May 2023. Of the 333 patients who replied to the questionnaire, 283 patients (85%) reported at least one relative with a cancer history. The prevalence of family history of B-cell lymphoproliferative disorders was significantly higher (P=0.02) in patients with germline ATM variants (32%) compared to those without germline ATM variants (21%) including familial CLL (25% vs. 18%) (P=0.04) . No significant difference in the prevalence of secondary cancers was found between patients with and without germline ATM variants (P=0.73), although the role for individual ATM variants in other malignancies could not be excluded given the small sample size. Time to first CLL treatment (TTFT) was shorter in patients harboring somatic ATM events while no difference was observed in patients with germline ATM variants. In conclusion, we demonstrate a higher prevalence of B-cell lymphoproliferative disorders, including familial CLL, in relatives of CLL patients carrying germline ATM variants. The presence of these germline variants did not impact TTFT compared to patients harboring somatic ATM mutations. Introduction Patients with chronic lymphocytic leukemia (CLL) exhibit approximately twice the incidence of secondary malignancies compared to the general population, including common cancer types such as melanoma, breast, and prostate cancer 1-5 Several mechanisms have been proposed to explain this association, including immunosuppression secondary to CLL, environmental exposure, and damage related to chemoimmunotherapy. Additionally, considering the role of genetic factors in the development of CLL and other cancers, shared genetic predisposition should be considered.6-8 Chronic lymphocytic leukemia has a strong inherited genetic component, with first-degree relatives of CLL patients having an 8.5-fold relative risk for developing CLL and other lymphoproliferative disorders.9,10 This familial risk increaseseven further, up to 27.13, for relatives of CLL cases with two or more first-degree relatives with CLL 11 However, the impact of specific ethnicity on the development of familial CLL is unknown. While genome-wide association studies (GWAS) have identified variants explaining approximately 17% of the genetic heritability of incident C

FAQs

What was the study’s primary goal regarding germline ATM variants?

To determine whether germline ATM variants in CLL patients influence predisposition to secondary neoplasms in both patients and their relatives.

Did germline ATM variants change the prevalence of secondary cancers overall?

No significant difference in secondary cancer prevalence was found between patients with and without germline ATM variants.

How did germline ATM variants relate to time to first CLL treatment (TTFT)?

Germline ATM variants did not impact TTFT compared with patients harboring somatic ATM mutations.

Sep 21, 2026

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