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.

LRIG1, a regulator of stem cell quiescence and a pleiotropic feedback tumor suppressor

“…Interestingly, loss of the second Apc allele in Lrig1 + cells resulted in dysplastic adenomas in the jejunum and distal colon [ 29 , 62 ]. Genomic profiling of the adenomas resulting from inducible loss of a single Apc allele in Lrig1 +/− colonic stem cells revealed increased mutation and reduced DNA repair as well as increased inflammation [ 63 ]. Intra-tumoral genomic heterogeneity was observed in these hypermutated tumors although transcriptomes and splicing patterns (including loss of intron retention) were relatively uniform [ 63 ].…”