Epigenetic loss of heterozygosity of Apc and an inflammation-associated mutational signature detected in Lrig1+/--driven murine colonic adenomas.

ABSTRACT: BACKGROUND:The loss of a single copy of adenomatous polyposis coli (Apc) in leucine-rich repeats and immunoglobulin-like domains 1 (Lrig1)-expressing colonic progenitor cells induces rapid growth of adenomas in mice with high penetrance and multiplicity. The tumors lack functional APC, and a genetic loss of heterozygosity of Apc was previously observed. METHODS:To identify genomic features of early tumorigenesis, and to profile intertumoral genetic heterogeneity, tumor exome DNA (n =?9 tumors) and mRNA (n =?5 tumors) sequences were compared with matched nontumoral colon tissue. Putative somatic mutations were called after stringent variant filtering. Somatic signatures of mutational processes were determined and splicing patterns were observed. RESULTS:The adenomas were found to be genetically heterogeneous and unexpectedly hypermutated, displaying a strong bias toward G:C?>?A:T mutations. A genetic loss of heterozygosity of Apc was not observed, however, an epigenetic loss of heterozygosity was apparent in the tumor transcriptomes. Complex splicing patterns characterized by a loss of intron retention were observed uniformly across tumors. CONCLUSION:This study demonstrates that early tumors originating from intestinal stem cells with reduced Lrig1 and Apc expression are highly mutated and genetically heterogeneous, with an inflammation-associated mutational signature and complex splicing patterns that are uniform across tumors.

SUBMITTER: Preston JL 

PROVIDER: S-EPMC7023705 | biostudies-literature | 2020 Feb

REPOSITORIES: biostudies-literature