摘要：The tumor suppressor gene adenomatous polyposis coli (
APC) is the initiating mutation in approximately 80% of all colorectal cancers (CRC), underscoring the importance of aberrant regulation of intracellular WNT signaling in CRC development. Recent studies have found that early-onset CRC exhibits an increased proportion of tumors lacking an
APC mutation. We set out to identify mechanisms underlying
APC mutation-negative (
APC
mut–
) CRCs. We analyzed data from The Cancer Genome Atlas to compare clinical phenotypes, somatic mutations, copy number variations, gene fusions, RNA expression, and DNA methylation profiles between
APC
mut–
and
APC mutation-positive (
APC
mut+
) microsatellite stable CRCs. Transcriptionally,
APC
mut–
CRCs clustered into two approximately equal groups. Cluster One was associated with enhanced mitochondrial activation. Cluster Two was strikingly associated with genetic inactivation or decreased RNA expression of the WNT antagonist
RNF43, increased expression of the WNT agonist
RSPO3, activating mutation of
BRAF, or increased methylation and decreased expression of
AXIN2.
APC
mut–
CRCs exhibited evidence of increased immune cell infiltration, with significant correlation between M2 macrophages and
RSPO3.
APC
mut–
CRCs comprise two groups of tumors characterized by enhanced mitochondrial activation or increased sensitivity to extracellular WNT, suggesting that they could be respectively susceptible to inhibition of these pathways.
