The serrated neoplasia pathway gives rise to a distinct subgroup of colorectal cancers distinguished by the presence of mutant BRAFV600E 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 BRAFV600E 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.

中文翻译：

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在BRAF突变型微卫星稳定结直肠癌的小鼠模型中，信号途径的变化伴随自发转移至恶性肿瘤。

锯齿状的瘤形成途径引起了大肠癌的一个独特的亚组，其特征在于存在突变型BRAFV600E和CpG岛甲基化表型（CIMP）。BRAF突变型CRC通常与微卫星不稳定性相关，具有极好的临床效果。然而，一定比例的BRAF突变CRC保留了微卫星稳定性，预后不良。尚不清楚导致该癌症亚组发生的分子驱动因素。为了解决这个问题，我们建立了BRAFV600E突变型微卫星稳定CRC的小鼠模型，并全面研究了外显子组和转录组，以鉴定驱动恶性肿瘤的信号通路中的分子变化。鼠类锯齿状病变（mSL）和癌的外显子组测序确定了编码β-catenin（Ctnnb1）的基因内频繁出现热点突变。β-catenin的免疫组织化学染色表明，这些突变导致异常核β-catenin的存在增加，导致β-catenin转录靶基因表达改变。基因表达谱鉴定出了显着富集的转化生长因子-β（TGF-β）信号，存在于mSL和癌症中。TGF-β的早期活化表明该途径可能是将mSL导向微卫星稳定癌的早期提示。小鼠模型中的这些发现支持了在人类无柄锯齿状病变向恶性转变过程中WNT和TGF-β信号改变的重要性。β-catenin的免疫组织化学染色表明，这些突变导致异常核β-catenin的存在增加，导致β-catenin转录靶基因表达改变。基因表达谱鉴定出了显着富集的转化生长因子-β（TGF-β）信号，存在于mSL和癌症中。TGF-β的早期活化表明该途径可能是将mSL导向微卫星稳定癌的早期提示。小鼠模型中的这些发现支持了在人类无柄锯齿状病变向恶性转变过程中WNT和TGF-β信号改变的重要性。β-catenin的免疫组织化学染色表明，这些突变导致异常核β-catenin的存在增加，导致β-catenin转录靶基因表达改变。基因表达谱鉴定出了显着富集的转化生长因子-β（TGF-β）信号，存在于mSL和癌症中。TGF-β的早期活化表明该途径可能是将mSL导向微卫星稳定癌的早期提示。小鼠模型中的这些发现支持了在人类无柄锯齿状病变向恶性转变过程中WNT和TGF-β信号改变的重要性。基因表达谱鉴定出了显着富集的转化生长因子-β（TGF-β）信号，存在于mSL和癌症中。TGF-β的早期活化表明该途径可能是将mSL导向微卫星稳定癌的早期提示。小鼠模型中的这些发现支持了在人类无柄锯齿状病变向恶性转变过程中WNT和TGF-β信号改变的重要性。基因表达谱鉴定出了显着富集的转化生长因子-β（TGF-β）信号，存在于mSL和癌症中。TGF-β的早期活化表明该途径可能是将mSL导向微卫星稳定癌的早期提示。小鼠模型中的这些发现支持了在人类无柄锯齿状病变向恶性转变过程中WNT和TGF-β信号改变的重要性。