P037: High breadth whole exome sequencing of circulating tumor DNA identifies novel recurrent genetic alterations in Hodgkin lymphoma

Hodgkin lymphoma (HL) is a B-cell lymphoma with a generally favorable prognosis. However, side effects of aggressive front-line treatment and difficult-to-treat relapsed/refractory disease are still a clinical challenge. A better understanding of the biological diversity of HL at baseline might help to further individualize the treatment of patients and thus ultimately improve outcome. A broad characterization of the genetic drivers of HL is highly important to improve our understanding of the biological diversity of HL. Here, we present the results of our study using whole-exome sequencing of circulating tumor (ct)DNA to broadly characterize the HL oncogenome in 165 patients. After extraction of germline and cell-free DNA, WES was performed, targeting 37 Mb of the human genome. An in-house customized bioinformatic pipeline including twofold error reduction using unique molecular identifiers (UMIs) and digital error suppression was used as previously described by us (Sobesky et. al., Med, 2021). The median ctDNA concentration per patient was 2.26 log haploid genome equivalents per milliliter (log hGE/ml) (range: 1.41–4.18 log hGE/ml) without significant correlation with clinical parameters such as sex, international prognostic score (IPS) or clinical stage. In addition to the detection of several genetic aberrations involved in the pathogenesis of HL (such as B2M, CSF2RB, GNA13, SOCS1), we were able to detect several novel, recurrently mutated potential oncogenes and tumor suppressor genes. Among the most frequently mutated genes not previously described in HL were olfactory receptor family 10 subfamily G member 7 (OR10G7) (11.5%), Apolipoprotein B (APOB) (10.3%) and Filaggrin 2 (FLG2) (9.7%). Furthermore, several previously undescribed copy number variations (CNV) were detected (losses: 13q13.1, 1p36.13a, 6p21.33; gains: 19q13.42, 9p24, 12q12). To decipher the detected genes’ and CNVs’ contribution to the biological diversity of HL, we performed non-negative matrix factorization. Furthermore, neoantigen load was assessed through human-leukocyte antigen (HLA) sequencing. Detailed results will be presented at the meeting. In conclusion, our ctDNA based WES approach provides sufficient sensitivity to both perform genotyping in HL and detecting novel genomic aberrations potentially involved in the pathogenesis of HL.