JENNIFER BROWN (BOSTON)
GENETIC PREDISPOSITION
Chronic lymphocytic leukemia (CLL) is one of the most prevalent leukemias of adults
and has a strong hereditary component. Relatives of CLL patients have an increased risk for
CLL (RR = 5.6 - 8.5) and about 13% of CLL patients have a first degree relative with a
lymphoproliferative disorder. Families with near Mendelian type inheritance have been
described and generally found to have private mutations in genes otherwise involved in CLL
biology. However, most families do not have a clear-cut pattern of inheritance. Investigation
of common variants by GWAS has identified ~40 common variants with strong statistical
association with disease risk, accounting for an estimated 34% of CLL heritability. A recent
study described a combined polygenic risk score based on 41 GWAS risk alleles, with an odds
ratio for CLL of 2.491. Hence much of the heritability of CLL is still unexplained.
We hypothesized that some of this missing heritability in CLL may lie in rare germline variants
with larger effect sizes identifiable by exome sequencing. We performed an exomewide
association analysis comparing rare germline variants among 646 CLL patients and 8920
ancestry-matched controls and demonstrated that rare missense germline variants in ATM
are significantly associated with CLL risk2. Furthermore, CLL patients with a rare missense
germline variant in ATM had increased risk of somatic loss of the other allele through 11q
deletion or somatic ATM mutation, consistent with tumor suppressor behavior2. W e
therefore sought to validate these findings in our clinical CLL population as compared to
patients with other hematologic malignancies. Using the Brigham and Women’s Hospital
Rapid Heme Panel (RHP), a NGS assay that interrogates 95 cancer-related genes in a CLIA
approved laboratory, we evaluated rare ATM variants with a total population allelic frequency
(PAF) <1%, comparing 384 pts with CLL, 615 pts with other lymphomas and 876 patients with
myeloid disorders. 25.3% of CLL patients carried a rare germline ATM variant, compared to
14.8% of other lymphoma patients and 16.3% of patients with myeloid diseases (p<0.001)3.
Furthermore, extremely rare ATM variants, with PAF < 0.001%, were seen in 18.6% of CLL
patients vs 10.5% of NHL patients and 3.8% of myeloid disease patients. One of the most
common rare variants, ATM L2307F, is present in 2-3% of CLL patients and associated with an
odds ratio of 10.1 for CLL2. Carrying any rare germline ATM variant in this clinical cohort was
again statistically significantly associated with somatic 11q deletion (p=3x10-6) and associated
with a lower rate of somatic TP53 aberrancy (p=0.04). Functional validation of these variants
is in progress.
References
1. Kleinstern G, Camp NJ, Goldin LR, et al: Association of polygenic risk score with the risk of
chronic lymphocytic leukemia and monoclonal B-cell lymphocytosis. Blood 131:2541-2551, 2018
2. Tiao G, Improgo MR, Kasar S, et al: Rare germline variants in ATM are associated with
chronic lymphocytic leukemia. Leukemia 31:2244-2247, 2017
3. Lampson B, Tyekucheva S, Shaughnessy C, et al: Incidence of Germline ATM Variants in a
Consecutive Clinical Cohort of CLL Patients. Blood 134 (Supplement_1):1731, 2019