Genomic, Pathway Network, and Immunologic Features Distinguishing Squamous Carcinomas

Abstract

SUMMARY This integrated, multiplatform PanCancer Atlas study co-mapped and identified distinguishing molecular features of squamous cell carcinomas (SCCs) from five sites associated with smoking and/or human papillomavirus (HPV). SCCs harbor 3q, 5p, and other recurrent chromosomal copy-number alterations (CNAs), DNA mutations, and/or aberrant methylation of genes and microRNAs, which are correlated with the expression of multi-gene programs linked to squamous cell stemness, epithelial-to-mesenchymal differentiation, growth, genomic integrity, oxidative damage, death, and inflammation. Low-CNA SCCs tended to be HPV(+) and display hypermethylation with repression of TET1 demethylase and FANCF, previously linked to predisposition to SCC, or harbor mutations affecting CASP8, RAS-MAPK pathways, chromatin modifiers, and immunoregulatory molecules. We uncovered hypomethylation of the alternative promoter that drives expression of the ΔNp63 oncogene and embedded miR944. Co-expression of immune checkpoint, T-regulatory, and Myeloid suppressor cells signatures may explain reduced efficacy of immune therapy. These findings support possibilities for molecular classification and therapeutic approaches.

HPV‐negative and HPV‐positive HNSCC cell lines show similar numerical but different structural chromosomal aberrations

“…[8][9][10][11][12] However, more recent data demonstrated that both parameters do not or only marginally differ by HPV status. [13][14][15][16][17][18] This was especially apparent in data sets summarized by Hayes et al 17 and Campbell et al 18 including data of The Cancer Genome Atlas (TCGA). 15 These data sets clearly demonstrate that for the vast majority of the genome, the numbers of CNAs of HPV-positive and HPVnegative tumors are highly concordant with both groups showing fairly similar amplifications, especially at 1q, 3q, 5p, and 8q, and deletions at 3p, 5q, and 11q.…”

“…Several studies indicated that HPV‐positive HNSCC might have less copy‐number alterations (CNAs) and amplifications and also less mutations than HPV‐negative HNSCC . However, more recent data demonstrated that both parameters do not or only marginally differ by HPV status . This was especially apparent in data sets summarized by Hayes et al and Campbell et al including data of The Cancer Genome Atlas (TCGA) .…”

Intersection of the p63 and NF‐κB pathways in epithelial homeostasis and disease

“…While shown to be critical in normal epidermal development and homeostasis, p63, particularly overexpression of the ΔNp63α isoform, is associated with squamous cancers including those of the head, neck, lung, and skin . Consistent with this, enriched ΔNp63 messenger RNA was recently identified in a PanCancer Atlas study as a molecular feature distinguishing squamous cell carcinomas across tissue sites including lung, head and neck, esophagus, cervix, and bladder from other cancers . Upon genomic analysis, metastatic cSCCs reportedly share molecular alterations similar to those in HNSCC, including enhanced expression of p63 and activation of NF‐κB signaling pathways .…”

“…It remains to be mechanistically determined whether similar mechanisms occur in other p63‐overexpressing cancers such as HNSCC and cSCC. Of note, the p63 gene is located on the long arm of chromosome 3 at position 28, and 3q28 amplification is a frequent early genomic event in the majority of HNSCCs …”

“…cSCC appears to be immunologically mediated, with an elevated occurrence in immunosuppressed transplant recipients, and cSCC is often, but not always, associated with mutation of the p53 tumor suppressor gene . Another common trait is the overexpression of the p53 homolog, ΔNp63α, which has been linked to squamous cancers spanning a range of tissue types including the skin and head and neck . p63 is a transcription factor that exists as multiple isoforms, with both p53‐like and opposing functions.…”