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

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.

LINC00173 blocks GATA6‐mediated transcription of COL5A1 to affect malignant development of oral squamous cell carcinoma

“…18 In HNSC, COL5A1 has been identified as one of the key nodes in a regulatory work correlating with prognostic phenotype. 19 Moreover, it has been defined as a hub gene linking to perineural invasion, a key pathological characteristic of HNSC predicting poor survival. 20 Likewise, the upregulation and the potential involvement of COL5A1 in tumorigenesis was found in OSCC.…”

“…Upregulation of COL5A1 has been found in multiple human solid tumors and affected spanning cellular behaviors, such as proliferation and motility and linked to immunosuppression 18 . In HNSC, COL5A1 has been identified as one of the key nodes in a regulatory work correlating with prognostic phenotype 19 . Moreover, it has been defined as a hub gene linking to perineural invasion, a key pathological characteristic of HNSC predicting poor survival 20 .…”

The extracellular matrix glycoprotein fibrillin-1 in health and disease

“…It is highly expressed in papillary thyroid carcinoma, and silencing of FBN1 inhibits cell viability and colony formation in vitro and inhibits tumor growth in vivo ( Ma et al, 2016 ). In addition, FBN1 is also a key gene associated with the prognosis of squamous cell carcinoma through a comprehensive analysis of multi-omics data ( Feng et al, 2021 ). In renal clear cell carcinoma, microarray analysis reveals that FBN1 induction is accompanied by a higher malignancy grade and progression.…”

Activation of the EGFR/PI3K/AKT pathway limits the efficacy of trametinib treatment in head and neck cancer

“…Trametinib has been approved for the treatment of melanoma, non‐small cell lung cancer, and thyroid cancer patients harboring the BRAF V600E mutation [14–16]. In line with the prediction that it would be effective in the treatment of high‐risk HNSCC [17], trametinib was tested in a phase II neoadjuvant window‐of‐opportunity clinical trial—with promising results [18]. However, a follow‐up study showed that tumors developed resistance to trametinib monotherapy via upregulation of yes‐associated protein 1 (YAP1) [19].…”