Prognostic Gene Signature for Squamous Cell Carcinoma with a Higher Risk for Treatment Failure and Accelerated MEK-ERK Pathway Activity

SIMPLE SUMMARY: Squamous cell carcinoma (SCC) is the most prevalent type of human cancer worldwide and represents the majority of head and neck tumors. As SCC from aerodigestive or genitourinary tracts share not only common etiology and histological features but also molecular patterns, the major objectives of this study were the establishment of a pan-SCC-related prognostic gene signature by an integrative analysis of multi-omics data and the elucidation of underlying oncogenic pathway activities as potential vulnerabilities for a more efficient and less toxic therapy. Our approach delivers a reliable molecular classifier to identify HNSCC and other SCC patients at higher risk for treatment failure with tumors characterized by a more prominent MAPK activity, who might benefit from a targeted treatment with MEK inhibitors. ABSTRACT: Squamous cell carcinoma (SCC) is the most prevalent histological type of human cancer, including head and neck squamous cell carcinoma (HNSCC). However, reliable prognostic gene signatures for SCC and underlying genetic and/or epigenetic principles are still unclear. We identified 37 prognostic candidate genes by best cutoff computation based on survival in a pan-SCC cohort (n = 1334) of The Cancer Genome Atlas (TCGA), whose expression stratified not only the pan-SCC cohort but also independent HNSCC validation cohorts into three distinct prognostic subgroups. The most relevant prognostic genes were prioritized by a Least Absolute Shrinkage and Selection Operator Cox regression model and were used to identify subgroups with high or low risks for unfavorable survival. An integrative analysis of multi-omics data identified FN1, SEMA3A, CDH2, FBN1, COL5A1, and ADAM12 as key nodes in a regulatory network related to the prognostic phenotype. An in-silico drug screen predicted two MEK inhibitors (Trametinib and Selumetinib) as effective compounds for high-risk SCC based on the Cancer Cell Line Encyclopedia, which is supported by a higher p-MEK1/2 immunohistochemical staining of high-risk HNSCC. In conclusion, our data identified a molecular classifier for high-risk HNSCC as well as other SCC patients, who might benefit from treatment with MEK inhibitors.