Abstract

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 (APCmut–) 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 APCmut– and APC mutation-positive (APCmut+) microsatellite stable CRCs. Transcriptionally, APCmut– 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. APCmut– CRCs exhibited evidence of increased immune cell infiltration, with significant correlation between M2 macrophages and RSPO3. APCmut– 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.

Highlights

  • Colorectal cancer (CRC) is the second deadliest cancer in the United States, with an estimated 147,950 individuals diagnosed and 53,200 deaths in ­20201

  • After disregarding overlapping genomic alterations, BRAF mutations were the most abundant (10%), followed by mutations in ADGRL1 (6%), ERBB3 (5%), and ZAP70 (5%). Supporting these findings, we found that BRAF mutations in the GSE35896 dataset and mutations in RNF43, ERBB3, and ZAP70 in the CPTAC-2 dataset were more frequent in APCmut– colorectal cancers (CRC) than in APCmut+ CRCs (Supplementary Fig. 1). (No additional mutation information was provided with the GSE35896 dataset.)

  • AXIN2 and RNF43 are negative regulators of WNT signaling that are transcriptionally activated by nuclear β-catenin, consistent with the notion that epigenetic silencing of negative regulators plays a critical role in tumor formation in ligand-dependent, APCmut– CRCs

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Summary

Introduction

Colorectal cancer (CRC) is the second deadliest cancer in the United States, with an estimated 147,950 individuals diagnosed and 53,200 deaths in ­20201. Molecular analysis has shown that < 20% of earlyonset CRC cases are explained by genetically determined hereditary ­syndromes[4] and a variety of environmental factors have been postulated to underlie its i­ncrease[5], suggesting that a unitary cause of early-onset CRC will be elusive. Somatic mutation of the adenomatous polyposis coli (APC) gene is the initiating event in approximately 80% of all CRCs, but APC mutations are significantly less frequent in early-onset ­CRCs6–8. Failure to regulate β-catenin by degradation due to mutational inactivation of APC throws colorectal epithelial cells into a continuous “WNT-activated” state; they no longer require activation by WNTs to maintain the stem cell c­ ompartment[10]. The fact that early-onset CRCs more frequently lack an APC mutation suggests that many of these tumors depend on alternative molecular mechanisms. Stable (MSS) CRCs that lack APC mutations? Here, we comprehensively compare molecular profiles of MSS APC mutation-positive CRCs (APCmut+) and MSS APC mutation-negative (APCmut–) CRCs to identify novel APCindependent mechanisms driving CRC subtypes

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