Investigating the influence of germline ATM variants in chronic lymphocytic leukemia on cancer vulnerability

Abstract

Chronic lymphocytic leukemia (CLL) patients have an increased risk of secondary cancers, along with predisposition to CLL in 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.

Figure 1.

Classification of patients according to germline and somatic AT M status. CLL: chronic lymphocytic leukemia.

Figure 2.

Characterization of AT M variants identified in our cohort. (A) Pie chart demonstrating the prevalence of AT M variants in the whole cohort along with the frequencies of germline AT M variants and somatic AT M mutation. The germline AT M variants group includes 6% of patients who also harbor somatic AT M mutation. No germline AT M variant is included in the somatic AT M mutation group. (B) Bar chart with the predicted pathogenicity of each variant according to American College of Medical Genetics and Genomics (ACMG) classification rules, broken down by germline or somatic status. VUS: variant of uncertain significance.

Figure 3.

Comparison of prevalence of malignancies in relatives of patients with chronic lymphocytic leukemia. (A) Prevalence of familial B-cell lymphoproliferative disorders in patients with and without germline ATM variant. (B) Prevalence of familial chronic lymphocytic leukemia (CLL) in patients with and without germline ATM variant. (C) Prevalence of familial CLL in patients with and without Ashkenazi Jewish origin. *P<0.05; **P<0.01.

Figure 4.

Comparison of secondary malignancies between patients with and without germline AT M variants. (A) Bar chart showing the frequency of secondary tumor divided in different subtypes. For prostate cancer, the prevalence was evaluated among male patients; for breast cancer, the prevalence was evaluated among female patients (one male patient with breast cancer was excluded from the analysis). (B) Age at secondary tumor diagnosis in patients with and without germline AT M variants. CLL: chronic lymphocytic leukemia; NMSC: non-melanoma skin cancer.

Figure 5.

Patients treated for chronic lymphocytic leukemia. (A) Percentage of patients who were treated in each group, according to International Workshop on Chronic Lymphocytic Leukemia (iwCLL) criteria. The pairwise comparison using the Dwass-Steel-Critchlow-Fligner test showed a difference between Group 2 and Group 4 (P=0.018) and between Group 3 and Group 4 (P=0.009). Between Group 1 versus Group 2 and Group 3, statistical significance was almost achieved (P=0.067 and P=0.068, respectively). No differences were observed in the pairwise comparison between Group 1 and Group 4 (P=0.969) and Group 2 and Group 3 (P=0.938). (B) Time to first treatment for each group. Group 1: Germline AT M variants without 11q deletion and/or somatic variants; Group 2: Germline AT M variants with 11q deletion and/ or somatic variants; Group 3: Somatic AT M variants and/or 11q deletion; Group 4: No AT M mutations and/or 11q deletion. TTFT: time to first treatment; HR: Hazard Ratio. *P<0.05; **P<0.01.