Abstract LB-176: Identification of mutations in histone modification genes in Hodgkin lymphoma

Abstract

Abstract Background: Understanding genetic aberrations in cancer has led to discoveries of new targets for cancer therapies. The genomic landscape of Hodgkin lymphoma (HL) has not been fully described. Methods: We performed targeted next generation sequencing (NGS) on 13 archival tumor samples from patients with relapsed/refractory HL treated in the phase I clinical trial with the mTOR inhibitor sirolimus and the HDAC inhibitor vorinostat using the Foundation One NGS panel (Foundation One, Foundation Medicine, MA). Subsequently, we performed whole exome and RNA sequencing on pre- and post-treatment tumor biopsies from 3 patients treated in the same study. Results: In archival samples from 13 HL patients tested using the Foundation One panel, a total of 21 gene aberrations across 13 genes were detected; 12 (92%) tumor samples had mutations in genes involved in immune response, apoptosis, and cell proliferation pathways (SOCS1, PIM1, MCL1, BRCA1, TP53, TNFAIP3, B2M, XPO1, BCL6) and 7 (54%) samples had mutations in DNA repair pathway genes (TP53, BRCA1, ATM, PIM1). In addition, whole exome and RNA sequencing of pre- and post-treatment tumor and germline (peripheral blood mononuclear cells) samples from HL patients treated with sirolimus and vorinostat (complete response, n = 1; stable disease for 3 months, n = 1; progression, n = 1) identified missense point mutations in key histone modification genes not included in the Foundation One panel, including HDAC8 (histone deacetylase 8), JMJD1C (jumonji domain containing 1C), and KDM2A (lysine-specific demethylase 2A) in the patient who progressed on therapy. This same patient additionally had a B2M missense mutation (M1R) affecting the same residue as the B2M event (M1I) identified in the archival cohort. Furthermore, there was a trend towards increased burden of molecular aberrations (median, 67 aberrations) in pre- and post- tumor samples of the patient who progressed compared to the other 2 patients (median, 6 aberrations), who did not progress. Conclusion: While analysis of additional HL specimens is needed, our data suggest that testing for molecular aberrations with NGS is feasible and somatic missense mutations in HDAC8, JMJD1C, and KDM2A may be associated with lack of clinical response to sirolimus and vorinostat. Citation Format: Winnie S. Liang, Bodour Salhia, Adrienne Helland, Shobana Sekar, Ignacio Garrido-Laguna, Michelle Fanale, Yasuhiro Oki, Jason R. Westin, R. Eric Davis, Funda Meric-Bernstam, Filip Janku. Identification of mutations in histone modification genes in Hodgkin lymphoma. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr LB-176. doi:10.1158/1538-7445.AM2015-LB-176