Integrated Genetic, Epigenetic, and Transcriptional Profiling Identifies Molecular Pathways in the Development of Laterally Spreading Tumors

Laterally spreading tumors (LST) are colorectal adenomas that develop into extremely large lesions with predominantly slow progression to cancer, depending on lesion subtype. Comparing and contrasting the molecular profiles of LSTs and colorectal cancers offers an opportunity to delineate key molecular alterations that drive malignant transformation in the colorectum. In a discovery cohort of 11 LSTs and paired normal mucosa, we performed a comprehensive and unbiased screen of the genome, epigenome, and transcriptome followed by bioinformatics integration of these data and validation in an additional 84 large, benign colorectal lesions. Mutation rates in LSTs were comparable with microsatellite-stable colorectal cancers (2.4 vs. 2.6 mutations per megabase); however, copy number alterations were infrequent (averaging only 1.5 per LST). Frequent genetic, epigenetic, and transcriptional alterations were identified in genes not previously implicated in colorectal neoplasia (ANO5, MED12L, EPB41L4A, RGMB, SLITRK1, SLITRK5, NRXN1, ANK2). Alterations to pathways commonly mutated in colorectal cancers, namely, the p53, PI3K, and TGFβ pathways, were rare. Instead, LST-altered genes converged on axonal guidance, Wnt, and actin cytoskeleton signaling. These integrated omics data identify molecular features associated with noncancerous LSTs and highlight that mutation load, which is relatively high in LSTs, is a poor predictor of invasive potential. Implications: The novel genetic, e...
Source: Molecular Cancer Research - Category: Cancer & Oncology Authors: Tags: Genomics Source Type: research