Detection of Rare Germline Variants in the Genomes of Patients with B-Cell Neoplasms

SIMPLE SUMMARY: The global importance of rare variants in tumorigenesis has been addressed by some pan-cancer analysis, revealing significant enrichments in protein-truncating variants affecting genes such as ATM, BRCA1/2, BRIP1, and MSH6. Germline variants can influence treatment response and contribute to the development of treatment-related second neoplasms, especially in childhood leukemia. We aimed to analyze the genomes of patients with B-cell lymphoproliferative disorders for the discovery of genes enriched in rare pathogenic variants. We discovered a significant enrichment for two genes in germline rare and dysfunctional variants. Additionally, we detected rare and likely pathogenic variants associated with disease prognosis and potential druggability, indicating a relevant role of these events in the variability of cancer phenotypes. ABSTRACT: There is growing evidence indicating the implication of germline variation in cancer predisposition and prognostication. Here, we describe an analysis of likely disruptive rare variants across the genomes of 726 patients with B-cell lymphoid neoplasms. We discovered a significant enrichment for two genes in rare dysfunctional variants, both of which participate in the regulation of oxidative stress pathways (CHMP6 and GSTA4). Additionally, we detected 1675 likely disrupting variants in genes associated with cancer, of which 44.75% were novel events and 7.88% were protein-truncating variants. Among these, the most frequently affected genes were ATM, BIRC6, CLTCL1A, and TSC2. Homozygous or germline double-hit variants were detected in 28 cases, and coexisting somatic events were observed in 17 patients, some of which affected key lymphoma drivers such as ATM, KMT2D, and MYC. Finally, we observed that variants in six different genes were independently associated with shorter survival in CLL. Our study results support an important role for rare germline variation in the pathogenesis and prognosis of B-cell lymphoid neoplasms.