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Genetic and Epigenetic Landscapes of Laterally Spreading Tumors of the Colorectum

ABSTRACT: Laterally spreading tumors (LSTs) are colorectal adenomas that develop into extremely large lesions but rarely become malignant. Elucidating their molecular profiles, and how these contrast with colorectal cancer (CRC), offers the opportunity to understand their biology and how they are able to grow to such large lesions without progressing to cancer. Profiling of 11 LSTs with multiple genome-wide approaches showed mutation rates comparable with microsatellite stable CRCs at 2.4 versus 2.6 mutations per megabase respectively, however copy number alterations are infrequent (averaging 1.5 per LST). Only 28.5% of genes with promoter CpG island hypermethylation showed >2-fold downregulation of expression in LST tissue relative to paired normal mucosa. Integration of genetic and epigenetic data identified driver genes not previously implicated in colorectal neoplasia (ANO5, MED12L, EPB41L4A, RGMB, SLITRK1, NRXN1, ANK2), including genes targeted by both genetic and epigenetic alterations. Alterations to pathways commonly mutated in CRCs, namely the p53, PI3K and TGFb pathways, are rare. Instead LST-altered genes converge on axonal guidance, Wnt and actin cytoskeleton signalling. Non-granular morphology, which is associated with an elevated risk of cancer, correlates with low frequencies of epigenetic inactivation and KRAS mutations and the hyperactivation of CXCR4 signalling. These data show that mutation load is a poor predictor of invasive potential and that genomic structural aberrations or alterations in key pathways is important in progression to cancer. By integrating genetic, epigenetic and transcriptional data this study identifies novel genes important in early colorectal neoplasia.

ORGANISM(S): Homo sapiens

PROVIDER: GSE77635 | GEO | 2016/11/12

SECONDARY ACCESSION(S): PRJNA311063

REPOSITORIES: GEO

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