Genomic Aberrations of Antisense Gene Transcripts in Head and Neck Cancer

Highlights: What are the main findings? Only 2.3% (52 total) of all human antisense genes have been examined in head and neck cancer (HNC) thus far. HOXA10-AS, LEF1-AS1, MSC-AS1, and ZEB2-AS1 have clinical promise for future biomarker development. What are the implications of the main findings? Robust cross-validations on antisense gene aberrations will promote biomarker development and implementation in the HNC field, as genetic biomarkers are lacking. Antisense gene aberrations and treatment responses are underexplored and warrant future studies. Antisense genes (usually suffixed by -AS) represent a class of long non-coding RNAs (lncRNAs) transcribed from the opposite strand of annotated human genes or exon(s). A total of ~2236 human antisense genes exist in the human genome. Their genomic locations with respect to the corresponding sense genes, their dysregulated expression patterns in cancer specimens, and clinical associations with patient outcomes reveal their potential importance in clinical settings. As of today, there lacks a comprehensive review of HNC-associated antisense genes/transcripts to help move forward the antisense field for genetic biomarker development or future drug research. In total, 2.3% (52/2236 antisense genes) of all known human antisense genes have been investigated in head and neck cancer (HNC). Thus, we perform a comprehensive review of the genomic aberrations (mutations, copy number changes, RNA-expression dysregulation, and single nucleotide polymorphisms) associated with HNC patient prognosis, disease progression, cancer cell signaling, drug sensitivity, and radio-resistance. Four antisense genes, namely HOXA10-AS, LEF1-AS1, MSC-AS1, and ZEB2-AS1, have been clinically cross-validated and have consistently demonstrated to be associated with patient outcomes in multiple independent cohorts by different research teams, with clear evidence for the prioritization of clinical biomarker development in HNC. Single nucleotide polymorphisms (SNPs) of antisense genes with evidence for HNC risk or outcomes should be further validated in different ethnic groups, for potential global HNC applications.