Characteristics of Familial CLL Evaluated in the CLL Research Consortium Cohort
Authors: Brown Jennifer R , Rassenti Laura , Neuberg Donna , Greaves Andrew , Byrd John C. , Grever Michael R , Gribben John G. , Kay Neil E. , Keating Michael , Rai Kanti R. , Wierda William G. , Kipps Thomas J 
Published: April 2020

Abstract
Approximately 10–15% of patients with CLL report a family history (FH) of CLL or a related lymphoproliferative disorder. Whether the biologic features of CLL that occurs within families differ from those that occur sporadically is unknown. A recent study addressing this question has reported that mutated IgVH is significantly more common among familial than sporadic CLL, 68% vs 47%, although the distribution of VH genes used was similar (Blood111:5691, 2008). Therefore we compared IgVH mutational status and gene usage, as well as other biologic features, between familial and sporadic CLL derived from patients enrolled on the CLL Research Consortium (CRC) Tissue Core. Of 4533 patients enrolled in the CRC database and tissue bank, 3328 had adequate family history information, and these were subdivided into 4 groups: FH of CLL (n=468), FH of other heme cancer but not CLL (n=421), FH of non-heme cancer (n=1444), and sporadic cases (no FH of any cancer) (n=995). Of those patients reporting a FH of CLL, 63% had at least one affected 1st degree relative, 20% at least one affected 2nd or greater degree relative, and 17% unknown. 68% of those reporting a FH of CLL also had other cancers in their family. Patients reporting a FH of CLL or non-CLL heme cancers were more frequently white (91%), compared to 87% of those with FH non-heme cancer and 84% of sporadic CLL patients (p=0.005). The proportion of CLL cases that were female was similar among groups, at 37.6% of patients with FH CLL, as compared to 32.5% of sporadic patients (p=0.12). The age at diagnosis of CLL also did not differ among the four groups, although a trend toward a difference was observed between the FH CLL patients, whose mean age at diagnosis was 54.9 (range 30, 93), and the sporadic patients, whose mean age at diagnosis was 56.1 (range 30, 84) (p=0.08). No significant difference was observed among groups in the frequency of IgVH mutation (defined as &lt;98% homology to the most similar germline VH gene), which was present in 50.3% (95% CI 44.5–56.2) of patients with FH CLL, 56.3% (95% CI 49.7–62.7) of patients with FH other heme cancer, 51.9% (95% CI 48.5–55.3) of patients with FH non-heme cancer, and 51.3% (95% CI 47.0–55.5) of sporadic patients (p=0.53). The pattern of IgVH family gene usage also did not differ among the groups; the VH3 subgroup was most commonly used, at 45%, 52%, 46% and 47% of patients with FH CLL, FH other heme cancer, FH non-heme cancer and sporadic, respectively. The VH1 subgroup was next most common in all 4 groups, at 28%, 24%, 26% and 25%, respectively, followed by the VH4 subgroup, at 19%, 17%, 21% and 21%. In addition, no significant difference was observed in the distribution of ZAP-70 expression amongst the four family history subgroups (mean %ZAP-70 expression, 22.8% for FH CLL patients and 24.4% for sporadic patients, p=0.31), or in the fraction considered ZAP-70 positive (&gt;20% expression), which was 40% for FH CLL patients and 45% for sporadic patients (p=0.16). The relative expression of CD23 and CD38 did not differ among groups, nor did levels of beta-2-microglobulin or IgG determined at time of CRC enrollment. Time from diagnosis to initial treatment for each of the subgroups is currently being analyzed. These data on patterns of biologic risk factors in this large group of familial CLLs compared to sporadic CLLs suggest that familial and sporadic CLL are biologically similar and therefore likely to have similar pathogenetic mechanisms, including perhaps an underlying genetic susceptibility.