Molecular and immune landscape of FH-mutated kidney cancer.

Abstract

382 Background: Hereditary leiomyomatosis and renal cell cancer (HLRCC) syndrome is caused by inactivating germline mutations in fumarate hydratase ( FH), predisposing individuals to development of certain cancers. Sporadic FH mutations have been described in different types of cancers, including kidney cancers, but the implications of somatic mutations are not well described. Here, we characterize the molecular landscape of kidney tumors with FH mutations. Methods: Tumors were analyzed using next generation sequencing of DNA (NextSeq, 592 genes and NovaSeq, WES) and RNA (NovaSeq). Immune cell fraction was estimated by immune deconvolution (Quantiseq). Significance was determined by chi-square and Wilcoxon rank sum test and adjusted for multiple comparisons (q-value <0.05). Results: Of 1956 kidney tumors, 31 had somatic pathogenic or likely pathogenic (P+LP; 1.58%) and 21 had variant of unknown significance (VUS; 1.07%) mutations in FH. Among the most commonly co-mutated genes, VHL (29.03% vs 38.1% vs 55.2%) and PBRM1 (9.68% vs 20% vs 29.8%) were less frequently mutated in P+LP compared to VUS and WT tumors; while NF2 (22.6% vs 5% vs 5.65%) was more frequently mutated in P+LP tumors compared to the others. In P+LP tumors, the HIPPO pathway (22.6% vs 4.76% vs 5.62%) was more frequently altered while the chromatin remodeling pathway (25.8% vs 28.6% vs 51.1%) was less frequently altered compared to VUS or WT tumors. P+LP tumors showed decreased NK cell infiltration (q=0.01) compared to VUS and WT tumors. Additionally, there was a trend towards increased CD8+ T cells and CTLA4 and PDCD1 expression in P+LP tumors compared to VUS but not WT tumors. Of the 1,956 kidney tumors, 315 were of clear cell renal cell carcinoma (ccRCC) histology. P+LP (n=4) ccRCC tumors showed a trend towards higher expression of immune checkpoint genes CTLA4 and IDO1 compared to VUS tumors (n=5). VHL expression was higher in P+LP ccRCC compared to VUS ccRCC tumors. P+LP ccRCC tumors showed a trend toward increased CD4+ (2.59% vs 0%) and CD8+ (2.14% vs 0%) T cells as well as T cell inflammation (25% vs 0%) and median Interferon score compared to VUS ccRCC tumors. Conclusions: P+LP FH mutated kidney tumors may have a different mutational and immune landscape than VUS FH mutated and WT tumors. Despite the small sample size, our study highlights potential therapeutic implications that will require further study.[Table: see text]