Abstract 2119: Gene mapping in high-risk chronic lymphocytic leukemia pedigree identifies risk locus at chromosome 2q22.1
Authors: Feusier Julie Ellen , Madsen Michael J. , Voelkerding Karl , Glenn Martha , Camp Nicola 
Published: September 2020

Abstract
Chronic lymphocytic Leukemia (CLL) is an age-related heterogeneous B-cell leukemia. In familial studies CLL has been consistently shown to be one of the most heritable cancers, indicating that genetics play a factor in the risk of developing CLL. However, only a few genes so far have been found to confer disease-risk of CLL. We used shared genomic segment (SGS) analysis in one exceptionally large high-risk CLL pedigree of European ancestry and identified a genome-wide significant 0.93 Mb region on chromosome 2q22.1. This region was inherited through 26 meiosis to seven cases in the pedigree (p=2.0 × 10−7). This region overlaps a locus identified in a previous CLL linkage study, which adds evidence to this as a candidate region harboring disease risk alleles. There are two genes within our SGS region, CXCR4 and THSD7B. In particular, CXCR4, a B-cell chemokine receptor, is a strong functional candidate as it is overexpressed in many cancers, including CLL, and is current drug target for treatment of CLL. Rare germline mutations in CXCR4 have been previously identified in CLL cases and at least one variant (rs56400844) was found to segregate within a CLL pedigree. Interrogation of the germline coding space of the SGS region in five of the seven sharers did not identify any predicted deleterious shared alleles. Many non-coding alleles were shared, but further investigation will be necessary to prioritize those as potentially regulatory or if a haplotype of multiple alleles modulates the transcriptome. We next explored the germline coding space in the SGS region in two other existing data sources: 48 WGS from early onset, clinical high-risk or familial CLL cases and 161 WES from population-level CLL cases as part of the Oncology Research Information Exchange Network (ORIEN) Avatar Program. We identified a coding missense CXCR4 variant (rs377287446, AF= 0.0000559, CADD=26.2) in one case and an extremely rare 3' UTR variant (*290C&gt;T, AF= 0.000007, singleton in gnomAD v3.0) present in two other cases. In summary, in the single largest high-risk pedigree studied to date, we have identified a genome-wide significant small region (&lt;1 Mb) at 2q22.1 which overlaps a previously suggested susceptibility locus for CLL. Exome sequencing of the region in additional local CLL cohorts and previous studies have identified at least three candidate deleterious mutations in CXCR4, a strong functional candidate gene in the locus. Future work will concentrate on deciphering regulatory variants in the inherited SGS region to establish CXCR4 as a susceptibility risk gene for CLL.
Citation Format: Julie Ellen Feusier, Michael J. Madsen, Karl Voelkerding, Martha Glenn, Nicola Camp. Gene mapping in high-risk chronic lymphocytic leukemia pedigree identifies risk locus at chromosome 2q22.1 [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr 2119.