1040 - Exploring the impact of germline ATM mutations in cancer susceptibility and inheritance in chronic lymphocytic leukemia

Background: Chronic lymphocytic leukemia (CLL) patients have an increased, but still poorly defined, risk of secondary neoplasms (Tsimberidou,2009). Also, CLL has a strong inherited susceptibility, much of which has not been explained by common variants identified by GWAS (Goldin,2009). Germline Ataxia-telangiectasia mutated (ATM) mutations are among the most common hereditary cancer risk mutations in CLL and other cancers (Hall, 2021). Rare germline ATM variants are present in 24% of CLL patients, greater than other hematologic neoplasms (Lampson,2022) or the general population (Tiao,Improgo,2017). In CLL cases, loss of ATM heterozygosity through 11q23 deletion is associated with adverse prognosis and short progression-free survival following chemotherapy (Choi,2016). Whether these ATM variants predispose to other malignancies among CLL patients is unknown and could have implications for cancer screening in patients and their families.
To evaluate this potential risk, we undertook a single-center retrospective study to analyze the impact of germline ATM in the predisposition to secondary neoplasm or other ATM-related syndromes in CLL patients and their relatives.

Methods: Five hundred and eighty-five patients seen at Dana-Farber Cancer Institute and who had NGS performed to evaluate germline ATM status, either through direct germline sequencing of saliva or by inference according to the hierarchical algorithm we recently published (Lampson, 2022), were mailed a questionnaire between April 2022 and May 2023. Of these, 320 patients (55%) replied. The questionnaire investigated: demographics; personal and family history of any cancer; non-medical radiation and Agent Orange exposure; ataxia-telangiectasia syndrome. European descendance was categorized based on the United Nations geoscheme (UNSD,2019), one of the systems used to classify countries into subregional groups. Information collected from our Database included FISH and IGHV status.
Patients were stratified into four groups, based on ATM mutational status and del(11q), to analyze clinical and demographic characteristics: Group-1, ATM germline mutation alone (N=61) Group-2, ATM germline with somatic ATM mutation and/or del(11q)(N=23) Group-3, ATM somatic aberration alone (including del(11q)) (N=43) and Group-4, no ATM aberration (N=195)(Figure 1). The patients were stratified into two groups based on the presence or absence of ATM germline mutation to analyze the cancer incidence (groups 1-2 vs 3-4). All patients had provided written informed consent prior to sample and data collection.

Results: Out of the 320 patients in our cohort, demographic and clinical characteristics among the 4 groups were balanced at baseline, except for unmutated IGHV status. Eighteen (86%) and 37 (86%) patients of groups 2 and 3 had this feature compared to 21 (34%) and 72 (37%) of groups 1 and 4, respectively (p < 0.01) (Table 1). A total of 211 cancers were reported in the 159 patients (50%) who had a history of another malignant neoplasm before or after CLL diagnosis. This incidence was reduced to 30% (97 patients) excluding patients with only non-melanoma skin cancers. When comparing the patients with germline ATM mutation present (82 patients) with germline ATM absent (238 patients), the incidence of colon cancer was slightly higher in patients with germline aberrations (3 patients, 4% versus 1, 0.4%, p=0.05).
Two hundred and seventy-three patients (85%) reported at least one relative, including first, second and third-degree, with a cancer history, with a median of 2 relatives affected (1-16). The incidence of familial CLL was significantly higher (p=0.04) in patients with germline ATM present (N=20, 24%) compared to germline ATM absent (N=35, 15%). No difference in the incidence of other hematologic and solid malignancies was found between the relatives in the two groups. No group had an increased number of first-degree relatives with cancer, compared to the other. No patient reported familial or personal history of Ataxia Telangiectasia syndrome.

Conclusions: Germline ATM variants in CLL lead to an earlier diagnosis and an increased likelihood of del11q or somatic ATM mutation, leading to more rapid disease progression. These mutations have been previously associated with increased risk of developing other cancers, such as breast and gastrointestinal (Pearlman, 2017); however, a certain role in the development of colon cancer is still unclear. Our results suggest a higher incidence of CLL inheritance, and a slightly increased incidence of colon cancer, in CLL patients who carry germline ATM mutation. Our study is limited by the relatively small sample size which we hope to further expand to explore this question more fully.