Microsatellite instability is an indicator of defects in DNA mismatch repair genes. These genes functions as tumor suppressors, upon inactivation implies defective mismatch repair pathway and dramatically increase replicative error rate. Microsatellite instability has been observed in esophageal cancer. It is more frequent in EAC than ESCC but still less than 10 to 20 percent of the tumors. This could implies it has a minor role in the tumorigensis of esophageal cancer
Genetic alterations associated with esophageal tumorigenesis of esophageal cancers including mutations or loss of p53, disruption of cell cycle control in G1 phase by inactivation of p16, amplification of cyclin D1, activation of oncogens such EGFR and MYC. Most of the genetic alterations are known to mediate in cell cycle.
Like many other cancers, esophageal cancer is also thought to develop in a progressive manner due to series of genetic changes so it is important to characterize these genetic events. EAC these changes occur in the metaplastic epithelium, while for ESCC the changes presumably de nevo in squamous epithelium. However as in EAC, it appears that mutations or loss of p53 and p16 tumor suppressor genes (TSGs) are early in the development of ESCC. For EAC, Several studies revealed the accumulation in the progression of EAC development. The most common early lesions including copy number loss or loss of heterozygosity of CDKN2A(p16) at 9p21, FHIT at 3p14.2, WWOX at 16q23.1 along with point mutations in CDKN2A and tp53(17p13.1) (Li, Galipeau et al. 2008);(Barrett, Sanchez et al. 1996; Li, Galipeau et al. 2008).
The p53 and p16 proteins are encoded by well established tumor suppressor genes that play important role in DNA damage responses, maintenance of genomic stability, cell cycle regulation and apoptosis. Genetic alterations in these genes in Barrett's esophagus also associated with a higher risk of progression from barrett,s esophagus to Esophageal adenocarinoma(Reid, Prevo et al. 2001).
The DNA copy number losses observed at WWOX1 and FHIT loci are both frequent.(Chang, Lee et al. 2005; Miyawaki, Kawachi et al. 2012; Guo, Wang et al. 2013).
The FHIT (fragile histidine triad) locus encodes a diadenosine triphosphate hydrolase that is involved in purine metabolism and WWOX locus encodes a WW domain containing oxidoreductase that may play a role in apoptosis. Both genes are located in the genomic fragile sites FRA3B and FRA16D respectively although both appear to TSGs. Many more genetic aberrations accumulate during the development of esophageal tumorigenesis. Most of these changes are common for both ESCC and EAC, although few are much more frequent in one subtype than the other. KRAS, GATA6, ERBB2 are more frequent in EAC on other hand Sox2, CCND1 more frequent in ESCC and .
And target well known oncogenes and tumor suppressor genes. Interestingly , the genes targeted these genomic events appers to be involved predominantly in transcription regulation, cell cycle progression, growth factor signaling, signal transduction.
Cell cycle regulaions
CDK6, cyclinD1, cyclin E1 genes are frequently amplified in esophageal cancer. Intersetgly all these play important role in regulating the G1 to S Phage transisition in cell cycle (ref). In addition to this, the most common event in both subtypes ESCC and EAC is deletion of cdkn2a (9p21). This encoded protein play a role in cell cycle control in G1 Phage. Cyclin D1 is highly conserved cyclin family proteins interact with cyclin dependent kinases (CDKs) to regulate the cell cycle progression.
The development of tumor and the acquisition of the individual hall marks of cancer requires a reprogramming may normal cellular circuits and functions (Hanahan and Weinberg 2011).
Although, perturbations of single genes such as cell cycle check points and growth factor receptors has potential to affect multiple functions in a single hit.
myc is amplified in both subtypes o esophageal cancer. It is a transcription factor regulate target genes that contol cell growth, cell cycle progression, differentiation, apoptosis. And also dna replication. In addition to amplification myc can be activated in response to various mitogeneic signals such as EGF, WNT.
Although, myc amplified in both EAC and ESCC, three other factors show specificity towards one particular tumor histology. Sox2 gene amplification commonly observed in ESCC (Wilbertz, Wagner et al. 2011)and it is required to maintain embryonic stem cell pluripotency. Furthermore , it has been necessary for normal esophageal squamous epithelium development(Que, Okubo et al. 2007);Wang, Qiao et al. 2014). GATA6 and GATA 4 amplified EAC. These are important for formation of human gastro intestinal mucosaATAa
Amplification Kras and pik3ca is observed frequently in esophageal cancer. It belongs to ras family activates kinases such as MAPK.
PIk3ca activates pi3k/akt/m TOR pathway activates the inhibition of apoptosis, cell cycle progression, cell proliferation and growth.
Like many other cancer, ESCC is also thought to arise from a series of genetic changes so it is important to identify and characterize these genetic events in ESCC. There some common genetic alterations which are known to be involved in ESCC tumorigenesis. P53 is tumor suppressor gene induce the cell cycle arrest and apoptosis due to the stress response (Levine, Finlay et al. 2004). Inactivation of p53 by mutations has been shown to be common events in many human cancers, including in ESCC ((Hollstein et al., 1990). Majority of these mutations occur in the DNA binding domain encoded by exon 5-8 ((Lam 2000). These mutations leads to increase the stability of p53 protein and accumulate in the nuclei and be detected by immunohistochemistry (Wang, Peng et al. 2013).Tobacco and alcohol are the major risk factors for ESCC and correlate strongly with mutational inactivation of p53 gene (Herbster, Ferraro et al. 2012). Loss of heterozgosity in p53 reported in ESCC(An, Fan et al. 2005). P53 polymorphism also could be a possible risk factor in ESCC (Wang, Wang et al. 2010). Elevated expression of EGFR (Nicholson et al., 2001) especially nuclear localization of its phosphorylated form (Hoshino et al., 2007) has been suggested to be a prognostic indicator in ESCC. -catenin nuclear localization is a hallmark of deregulated Wnt signaling which has reported in esophageal cancer (Osterheld, Bian et al. 2002). There are several tumor suppressor genes (FHIT, CDKN2A, CDKN2B, MSH2, Rb) and oncogenes (MYC, Cyclin D, Her2) have been reported to be tumorigenesis of ESCC.
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