Familial adenomatous polyposis is a Mendelian syndrome in which germline loss-of-function mutations of APC are associated with multiple adenomatous polyps of the large bowel, a multiplicity of extracolonic features, and a high lifetime risk of colorectal cancer.
This approach classified CRC into two major groups consistent with previous classification systems: (1) ∼16 % hypermutated cancers with either microsatellite instability (MSI) due to defective mismatch repair (∼13 %) or ultramutated cancers with DNA polymerase epsilon proofreading mutations (∼3 %); and (2) ∼84 % non-hypermutated, microsatellite stable (MSS) cancers with a high frequency of DNA somatic copy number alterations, which showed common mutations in APC, TP53, KRAS, SMAD4, and PIK3CA.
In addition, we have partially transformed the HCEC 1CT line by introducing stable knockdown of wild type APC and TP53, and ectopically introducing a mutant Krasv12 and a mutant version of APC (A1309), all commonly found mutations in colorectal cancer (CRC).
It is also thought that the product of the APC gene can modulate base excision repair (BER) pathway through an interaction with DNA polymerase β (Pol-β) and flap endonuclease 1 (Fen-1) to mediate CRC cell apoptosis.
In colorectal cancer (CRC) miRNAs are deregulated and have critical roles in initiation and progression of CRC by interacting with various oncogenes and tumor suppressor genes including APC, KRAS and p53, or by modulating downstream signal transduction pathways.
In this study, we aimed to determine the relative importance of IL-17A and the master regulator of the Th17 pathway, the transcription factor RORγt, in the sporadic intestinal neoplasia of APC(MIN/+) mice and in human colorectal cancer.
Commonly observed alterations across sporadic CRCs have allowed classification into a (1) hypermutated group that includes defective DNA mismatch repair with microsatellite instability and POLE mutations in ∼15%, containing multiple frameshifted genes and BRAF(V600E); (2) nonhypermutated group with multiple somatic copy number alterations and aneuploidy in ∼85%, containing oncogenic activation of KRAS and PIK3CA and mutation and loss of heterozygosity of tumor suppressor genes, such as APC and TP53; (3) CpG island methylator phenotype CRCs in ∼20% that overlap greatly with microsatellite instability CRCs and some nonhypermutated CRCs; and (4) elevated microsatellite alterations at selected tetranucleotide repeats in ∼60% that associates with metastatic behavior in both hypermutated and nonhypermutated groups.
Here we utilize CRISPR/Cas9 technology for targeted gene modification of four of the most commonly mutated colorectal cancer genes (APC, P53 (also known as TP53), KRAS and SMAD4) in cultured human intestinal stem cells.