An expanded universe of cancer targets.

The characterization of cancer genomes has provided insight into somatically altered genes across tumors, transformed our understanding of cancer biology, and enabled tailoring of therapeutic strategies. However, the function of most cancer alleles remains mysterious, and many cancer features transcend their genomes. Consequently, tumor genomic characterization does not influence therapy for most patients. Approaches to understand the function and circuitry of cancer genes provide complementary approaches to elucidate both oncogene and non-oncogene dependencies. Emerging work indicates that the diversity of therapeutic targets engendered by non-oncogene dependencies is much larger than the list of recurrently mutated genes. Here we describe a framework for this expanded list of cancer targets, providing novel opportunities for clinical translation.

Acquired Uniparental Disomy Regions Are Associated with Disease Outcome in Patients with Oral Cavity and Oropharynx But Not Larynx Cancers.

Acquired uniparental disomy (aUPD) regions pinpoint homozygousity and monoallelic expressed genes. We analyzed The Cancer Genome Atlas single-nucleotide polymorphism arrays and expression data from oral cavity, oropharynx, and larynx cancers to identify frequency of aUPD in each tumor type and association of aUPD regions and differentially expressed genes in the regions with survival. Cox proportional hazard models were used for survival function; and Student's t test, for differentially expressed genes between groups. The frequency of aUPD was highest in larynx cancers (88.35%) followed by oral cavity (81.11%) and oropharynx cancers (73.85%). In univariate analysis, 11 regions at chromosome 9p were associated with overall survival (OS) in oral cavity cancers. Two regions at chromosome 17p were associated with OS in oropharyngeal cancers, but no aUPD region was associated with survival in patients with larynx cancers. Overexpression of SIGMAR1, C9orf23, and HINT2 was associated with reduced OS in patients with oral cavity cancers, and upregulation of MED27 and YWHAE was associated with shorter OS in patients with oropharynx cancers. In multivariate analysis, four aUPD regions at chromosome 9p and overexpression of HINT2 were associated with shorter OS in oral cavity cancers, and overexpression of MED27 was associated with worse OS in patients with oropharynx cancers. aUPD regions and differentially expressed genes in those regions influence the outcome and may play a role in aggressiveness in oral cavity and oropharynx cancers but not in patients with larynx cancers.