Clinical Sequencing Defines the Genomic Landscape of Metastatic Colorectal Cancer

Abstract

Metastatic colorectal cancers (mCRCs) are clinically heterogeneous, but the genomic basis of this variability remains poorly understood. We performed prospective targeted sequencing of 1,134 CRCs. We identified splice alterations in intronic regions of APC and large in-frame deletions in CTNNB1, increasing oncogenic WNT pathway alterations to 96% of CRCs. Right-sided primary site in microsatellite stable mCRC was associated with shorter survival, older age at diagnosis, increased mutations, and enrichment of oncogenic alterations in KRAS, BRAF, PIK3CA, AKT1, RNF43, and SMAD4 compared with left-sided primaries. Left-sided tumors frequently had no identifiable genetic alteration in mitogenic signaling, but exhibited higher mitogenic ligand expression. Our results suggest different pathways to tumorigenesis in right- and left-sided microsatellite stable CRC that may underlie clinical differences.

Clinical relevance of circulating tumor DNA assessed through deep sequencing in patients with metastatic colorectal cancer

“…The use of a blood samples collected at different time points also precluded appropriate comparison of RAS mutational status between tissue and plasma, and single‐point blood sampling makes it impossible to analyze time‐course change in ctDNA during chemotherapies, which could be more useful information to assess the chemotherapeutic response. Moreover, the frequencies of mutated genes in plasma ctDNA of patients with CRC in our study were inconsistent with those in tissue DNA which had been reported in mutation database including The Cancer Genome Atlas . Although the mutation frequency of APC gene in CRC tissue has been reported to be ~80%, it revealed only 23.7% in our data (plasma), which was significantly lower frequency than that in tissue.…”

“…Moreover, the frequencies of mutated genes in plasma ctDNA of patients with CRC in our study were inconsistent with those in tissue DNA which had been reported in mutation database including The Cancer Genome Atlas. 53,54 Although the mutation frequency of APC gene in CRC tissue has been reported to be ~80%, 53,55 it revealed only 23.7% in our data (plasma), which was significantly lower frequency than that in tissue. The difference of the above frequencies could be partially explained by insufficient coverage of mutation detection in APC gene of the panel used in our ctDNA study.…”

Synbindin deficiency inhibits colon carcinogenesis by attenuating Wnt cascade and balancing gut microbiome

“…APC inactivating mutations lead to aberrant activation of Wnt signaling via β‐catenin stabilization and KRAS mutations result in uncontrolled ERK signaling . It was reported that around 80%–96% of human CRCs involve APC mutation and half of CRCs contain activating mutations in KRAS , highlighting the dominating roles of Wnt and ERK signaling in the development of CRC . In addition to APC , several mutations in β‐catenin, Axin, and GSK3 genes in Wnt pathway also cause significantly deregulated nuclear β‐catenin accumulation, aberrant cell proliferation, and malignant transformation in the colon epithelium …”

Epithelial‐mesenchymal transition is activated in CD44‐positive malignant ascites tumor cells of gastrointestinal cancer

“…Generally, somatic mutations of TGF‐beta signaling‐related genes are reported to contribute to unresponsiveness to TGF‐beta‐induced EMT . In particular, SMAD4 mutation occurs in 32% of pancreatic cancer, 16% of non‐hyper‐mutated colorectal cancer and 8% of non‐hyper‐mutated gastric cancer patients . Dominant negative mutation of SMAD2 , SMAD3 and SMAD4 resulted in unresponsiveness to TGF‐beta‐induced EMT through disruption of canonical SMAD‐mediated TGF‐beta signaling, although EMT can be induced in control cells by TGF‐beta stimulation .…”