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Alterations in signaling pathways that accompany spontaneous transition to malignancy in a mouse model of BRAF mutant microsatellite stable colorectal cancer.

07:00 EST 11th January 2020 | BioPortfolio

Summary of "Alterations in signaling pathways that accompany spontaneous transition to malignancy in a mouse model of BRAF mutant microsatellite stable colorectal cancer."

The serrated neoplasia pathway gives rise to a distinct subgroup of colorectal cancers distinguished by the presence of mutant BRAF and the CpG Island Methylator Phenotype (CIMP). BRAF mutant CRC are commonly associated with microsatellite instability, which have an excellent clinical outcome. However, a proportion of BRAF mutant CRC retain microsatellite stability and have a dismal prognosis. The molecular drivers responsible for the development of this cancer subgroup are unknown. To address this, we established a murine model of BRAF mutant microsatellite stable CRC and comprehensively investigated the exome and transcriptome to identify molecular alterations in signaling pathways that drive malignancy. Exome sequencing of murine serrated lesions (mSL) and carcinomas identified frequent hot spot mutations within the gene encoding β-catenin (Ctnnb1). Immunohistochemical staining of β-catenin indicated that these mutations led to an increase in the presence of aberrant nuclear β-catenin that resulted in gene expression changes in targets of β-catenin transcription. Gene expression profiling identified a significant enrichment for transforming growth factor-β (TGF-β) signaling that was present in mSL and carcinomas. Early activation of TGF-β suggests that this pathway may be an early cue directing mSL to microsatellite stable carcinoma. These findings in the mouse model support the importance of alterations in WNT and TGF-β signaling during the transition of human sessile serrated lesions to malignancy.

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This article was published in the following journal.

Name: Neoplasia (New York, N.Y.)
ISSN: 1476-5586
Pages: 120-128

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