Tumor mutation burden and PD-L1 expression in SDH/FH mutated solid tumors

1524 Background: Succinate Dehydrogenases and Fumarate Hydratase (SDH/FH) deficient tumors are characterized by succinate/fumarate accumulation and resultant pesudohypoxia that drives malignant transformation. This state of pseudohypoxia leads to dysregulation of PD-1 receptor-ligand signaling. In this study, we explored tumor mutation burden (TMB), gene expression of PD-L1, and expression of other immune checkpoint- associated genes in a diverse cohort of human tumors harboring SDH A, B, C, D and FH mutations. Methods: Retrospective analysis was performed on whole exome sequencing (WES; ~150x coverage) and whole transcriptomic RNAseq (~200x106 reads per tumor) data from NantHealth to identify tumors harboring SDHx and/or FH mutations. WES was performed on tumor tissue and matched normal for each patient to assess TMB. TMB was measured by counting all somatic-specific non-synonymous exonic mutations, with > 200 mutations qualified as TMB-high. Immune checkpoint therapy-related gene expression was evaluated for PDL1, CTLA4 , IDO, LAG3, FOXP3, PDL2, TIGIT, TIM3 and OX40 . Results: Among tumor samples from 3377 patients analyzed, 42 patients were found to harbor potentially-pathogenic & pathogenic mutations in the SDHA, B, C, D and FH genes. The most common tumor types with SDH/FH mutations were lung (n = 7), breast (n = 6), and colon cancer (n = 6). Our analysis revealed that TMB was positively correlated with the presence of SDH/FH mutations (p < 0.001). High PD-L1 expression was also significantly correlated with the presence of SDH/FH mutation (p < 0.05), while CTLA4, IDO, LAG3, FOXP3, and OX40 expression was significantly higher in SDH/FH mutated samples (p < 0.05). Conclusions: We report for the first time an association between increased TMB and increased PD-L1 expression in a variety of SDH/FH mutated tumors. These key parameters, imply that a higher TMB may drive the evolutionary pressure to select clones with a PDL1 high phenotype. This observation supports a potential therapeutic role for inhibition of PD-1/PD-L1 pathway in these tumors.