Colorectal Cancer Immunohistochemistry Markers
Colorectal carcinoma (CRC) affects 4% of the population, and up to 30% of patients have a family history of the disease. Identified hereditary syndromes such as Lynch syndrome (Hereditary
nonpolyposis colorectal cancer or HNPCC) and Familial adenomatous polyposis (FAP), however, only account for 10% of patients (Liccardo, 2017) and risk factors such as age, diet and smoking,
or diseases such as diabetes and chronic inflammatory bowel diseases have also been implicated as increasing risk for the development of CRC (Siegel, 2017).
Early detection and screening methods such as sigmoidoscopy, colonoscopy or stool-based tests for the detection of fecal blood (guaiac) or mutations (FIT-DNA) can reduce CRC deaths by detecting
cancers and removing polyps at early stages, but once the cancer develops, treatment is often surgical with chemotherapy. Newer drugs for targeted therapy include
to slow the growth of the cancer, or
to prevent the formation of blood vessels necessary for tumor growth.
IHC is used to identify CRC in tumors of unknown primary. CRCs express nuclear transcription factor CDX2
which is highly specific for intestinal epithelial cells, and Villin
, which is specific to adenocarcinomas of the GI tract.
codes for a membranous protein that is expressed in a majority of colorectal tumors,
and it is an effective marker particularly for...
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CDX2 codes for a homeobox protein involved in intestinal cell differentiation and tumor suppression in the colon (Platet, 2017), and loss of expression of this protein is correlated with colorectal tumorigenesis and poor survival (Platet, 2017; Dalerba, 2016). Platet et al found that higher levels of expression in the colon are correlated with a lack of cellular deformability and an increase in anti-metastatic structural properties (Platet, 2017). Furthermore, loss of expression of this protein may lead to tumor cells attaining stem cell attributes, as described by Lundberg IV et al in their findings that CDX2 downregulation is linked with upregulation of Yamanaka factor SOX2, involved in embryonic development and implicated in the induction of pluripotency (Lundberg, 2016; Takahashi, 2006). They found this to be a frequent phenomenon in MSI-positive (microsatellite unstable) and CIMP (CpG Island Methylator Phenotype) tumors. Jiang et al also found a link between methylation silencing of CDX2 (hypermethylation is a driving factor of CIMP) and colorectal cancer (Jiang, 2016). Downregulation of CDX2 may also be caused by FBXW7, a tumor suppressor with frequent mutations in cancer that manages the degradation of a large number of proteins including the Yamanaka factor Myc (Kumar, 2016; Takeishi, 2014). FBXW7 has been found to negatively regulate CDX2 expression by promoting its degradation together with the serine-threonine kinase GSK3B (Kumar, 2016).
Staining is expected to be nuclear.
BRAF, a MAPK/ERK signaling pathway kinase, is one of the most frequently somatically mutated genes in some cancers, particularly melanoma, thyroid carcinomas, and colorectal cancer (Chang, 2016; Zhang, 2014; Cantwell-Dorris, 2011). BRAF mutation occurs in roughly 10% of colorectal cancers, where detection of the V600E (rs113488022) mutation is useful for subtyping CIMP (CpG Island Methylator Phenotype), particularly when it accompanies the disappearance of the repair protein MLH1 (Cantwell-Dorris, 2011). These microsatellite-unstable (MSI) tumors typically propagate along the sessile serrated adenoma development pathway (Rhee, 2016; Cantwell-Dorris, 2011) and experience epigenetic silencing and loss of function frameshift in a large number of tumor suppressor and cell cycle regulation genes including TGFBR2, BAX, RNF43, CASP5 and KMT2C (MLL3) (Cortes-Ciriano, 2017). This is caused by the hypermethylation-induced silencing of mismatch repair protein MLH1, which occurs subsequent to and may even be caused by BRAF mutation (Fang M, 2014; Cantwell-Dorris, 2011). BRAF V600E is a pro-proliferative mutation, and while the adoption of V600E-mutant BRAF protein alone is not a pathogenic event (this mutation is the source of overproliferation in many benign nevi) (Wu, 2007), when combined with mutations in tumor suppressor genes it leads to carcinogenesis.
Staining may be nuclear, cytoplasmic or membranous.
RECQL4 is a RECQ-like helicase involved in aging and DNA repair that forms a complex with TP53 (Qiao, 2016; Croteau, 2012). This protein has mutations, amplified copy numbers and upregulation in a number of cancers including colorectal, breast and gastric cancer (Qiao, 2016; Cancer Genome Atlas Network, 2012; Mo, 2016; Arora, 2016; Lao, 2013; Buffart, 2005; Giannakis, 2016). Amplification of this protein in metastatic colorectal cancer seems to be correlated with other oncogenes on chromosome 8, including Yamanaka factor MYC, SLA, PTK2, PTP4A3, TPD52, MOS (Buffart, 2005), as well as PLEC, EPPK1, RAD21, and PDS5B (Cancer Genome Atlas Network, 2012; Buffart, 2005; Giannakis, 2016). In gastric cancer cells, high levels of expression of RECQL4 have been linked to drug resistance and activation of the multi-drug resistant protein 1 (MDR1 / P-glycoprotein 1 / ABCB1 / CD243) (Mo, 2016). IHC (immunohistochemistry) staining of RECQL4 in colorectal cancer showed this protein localizing to the nucleus (Lao, 2013).
Staining is expected to be predominantly nuclear.
Lynch and FAP Related Markers