Abstract PO-032: Association of a polymorphic variant in JMJD1C with tumor recurrence after adjuvant chemoradiation therapy in head and neck squamous cell carcinoma

Abstract

Abstract Background: Adjuvant chemoradiation therapy (CRT) is the standard treatment for locally advanced head and neck squamous cell carcinomas (HNSCCs). Over 50% of HNSCC cases are diagnosed at the locally advanced stage, with in-field persistence and recurrence major causes of morbidity and poor survival outcome. Apart from human papillomavirus (HPV) status, there are no predictive biomarkers for CRT outcomes. CRT lethality arises from unrepaired double strand breaks (DSBs) in DNA. Recent work has suggested that dynamic changes in lysine modification of chromatin regulate DSB repair. This study investigated the association of germline single nucleotide polymorphisms (SNPs) in lysine-modifying genes with DSB repair and CRT outcomes in HNSCC. Methods: Blood specimens and associated retrospective clinical data from HNSCC patients (n=90; age range=41-89, median age 64; males=69, females=21) were obtained under IRB# 21-9921. The patients had HPV-negative tumors in the larynx or oral cavity, and had received radiation, with some receiving concurrent chemotherapy. Patients receiving concurrent chemotherapy were: 40% in disease-free group, 21% in recurrence disease group, and 38% in never disease-free group. The patients were segregated into 3 groups: disease-free (n=30), recurrent disease (n=28), and never-disease free (n=32). DNA from blood was genotyped for specific germline SNPs in lysine-modifying genes. Isogenic HNSCC lines (Cal-27, SCC9) carrying either the wild type (WT) or homozygous SNP were generated using CRISPR/Cas9 technology, and bulk RNA sequencing and immunofluorescence (IF)-based studies were performed to assess cellular pathways affected. Results: A homozygous variant SNP in the coding region of JMJD1C was significantly enriched in the disease-free group (n=21/30) versus the recurrent disease (n=3/28) and never disease-free (n=2/32) groups (p=0.0003, OR=0, Fisher’s Exact test). Analysis of SNP frequency in large population datasets found that while it was abundant in European Americans (EAs), it is relatively rare in African Americans (AAs) (EA= 0.3139 vs. AA=0.072; gnomAD population). Cal-27 JMJD1C SNP cells were significantly enriched for altered mRNA levels of genes associated with DNA repair, replication, cell cycle, oxidative phosphorylation, and histone kinase activity versus CAL-27 with WT JMJD1C (q-value<0.05). The SCC9 JMJD1C SNP cells were significantly enriched in extracellular matrix organization, cytokine-cytokine receptor interaction, and humoral immune response versus SCC9 with WT JMJD1C (q-value<0.05). On irradiation, the JMJD1C SNP cells had robust activation of the DSB repair pathway (BRCA1- mediated repair foci) versus the WT cell lines. Conclusion and future work: This work provides novel insight into a germline SNP in a lysine-modifying gene effecting DSB repair and associating with CRT outcomes in HNSCC. It may serve as a predictive biomarker for recurrence. Future research will explore racial disparities in tumor recurrence and confirm results in larger HNSCC datasets. Citation Format: Adria Hasan, Elena V. Demidova, Shreya M. Shah, Philip Czyzewicz, Karthik Devarajan, Thomas Galloway, Barbara Burtness, Erica A. Golemis, Joshua E. Meyer, Sanjeevani Arwesd. Association of a polymorphic variant in JMJD1C with tumor recurrence after adjuvant chemoradiation therapy in head and neck squamous cell carcinoma [abstract]. In: Proceedings of the AACR-AHNS Head and Neck Cancer Conference: Innovating through Basic, Clinical, and Translational Research; 2023 Jul 7-8; Montreal, QC, Canada. Philadelphia (PA): AACR; Clin Cancer Res 2023;29(18_Suppl):Abstract nr PO-032.