Expressed HNSCC variants by HPV-status in a well-characterized Michigan cohort

While whole-exome DNA sequencing is the most common technology to study genetic variants in known exonic regions, RNA-seq is a cheaper, viable alternative to study expressed mutations in tumors. In this study, we show the utility of RNA-seq-based variant analysis combined with a gene target panel performed on both tumor and matched blood to study expressed variant profiles in the well-characterized University Michigan (UM) head and neck squamous carcinoma (HNSCC) cohort. We found that 441 out of 455 (~97%) identified cancer genes with an expressed mutation in the UM cohort also harbor a somatic mutation in TCGA. Fourteen (39%) patients had a germline mutation in a cancer-related Fanconi Anemia (FA) pathway gene. HPV+ patients had more nonsynonymous rare damaging (NRD) mutations in those genes than HPV- patients. Moreover, the known mutational signatures for DNA mismatch repair and APOBEC activation were attributive to the UM expressed NRD mutations, and the APOBEC signature contribution differed by HPV status. Our results provide additional support to certain TCGA findings and suggest an association of expressed mutations in FA/DNA repair pathways with HPV-associated HNSCC tumorigenesis. These results will benefit future studies on this and other cohorts by providing the mutational status of key cancer-related genes.