Abstract 4172: Identification of familial Hodgkin lymphoma predisposing genes by whole genome sequencing

Hodgkin lymphoma (HL) originates from germinal center B-cells and accounts for about 10% of newly diagnosed lymphomas and 1% of all de-novo neoplasms worldwide. Though familial risk for HL is among the highest of all cancers, not many genetic risk factors have been identified besides associations with the human leukocyte antigen (HLA) complex and few germline variants in familial classical Hodgkin lymphoma and nodular lymphocyte predominant Hodgkin lymphoma. With the aim of identifying novel predisposing germline variants in familial Hodgkin lymphoma, we performed whole genome sequencing (WGS) on seven affected and nine unaffected family members from three HL-prone families (families I, II and III). WGS identified a total of 98564, 170551 and 113654 variants in families I, II and III, respectively at ≤0.1% minor allele frequency. Variants were prioritized using the Familial Cancer Variant Prioritization Pipeline version 2 (FCVPPv2) developed by us. Pedigree-based filtering reduced the number of variants to 18158, 496 and 26851. Non-synonymous SNVs were the most represented exonic variants. Application of FCVPPv2 criteria resulted in prioritization of 19, 6 and 13 potentially causative exonic variants in families I, II and III, respectively. Variants affecting promoters, enhancers, super-enhancers, transcription factor binding sites and microRNA seed sequences were identified using FANTOM5 (Functional Annotation of the Mammalian Genome 5), SEA (Super-Enhancer Archive), SNPnexus and TargetScan tools. Pathway analysis of the involved genes using Ingenuity Pathway Analysis showed enrichment of B-cell receptor signaling, PI3K signaling in B lymphocytes and protein kinase A signaling pathways. Implementation of FCVPPv2 on data from family I resulted in confirmation and functional validation of a novel heterozygous missense variant (c.T5133G: p.I1711M) in the tumor suppressor gene DICER1 as potential HL predisposition factor. In order to identify the causal variants in families II and III, the variants short listed based on our pipeline are being investigated for segregation, frequency in large cohorts and functional consequences. In conclusion, WGS data analysis of three HL-prone families allowed us to prioritize coding and non-coding variants and identify enrichment of B-cell activating pathways. We aim to select and validate novel cancer predisposing variants that can facilitate genetic counseling and personalized therapy in these families as well as screening of other individuals at risk of developing Hodgkin lymphoma. Citation Format: Sara Giangiobbe, Aayushi Srivastava, Abhishek Kumar, Nagarajan Paramasivam, Dagmara Dymerska, Wolfgang Benisch, Mathias Witzens-Harig, Mathias Schlessner, Jan Lubinski, Kari Hemminki, Asta Forsti, Obul R. Bandapalli. Identification of familial Hodgkin lymphoma predisposing genes by whole genome sequencing [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 4172.