Updates On The Molecular Genetics Of Colorectal Cancer-Books Pdf

Updates on the Molecular Genetics of Colorectal Cancer
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Colorectal Cancer Open Access,Vol 3 No 1 2,ISSN 2471 9943. Table 1 List of genetic changes in CRC patients,Study Author Month. Gene Function Regulation role in Colon Cancer Type of Study. year of publication, Encodes DNA helicase plays Homozygous c 672 673delGGinsC mutation in. Genome mapping study in two, an essential role in homologous MCM9 chr6 119243200 caused a frame shift. Goldberg 12 2015 1 MCM9 consanguineous Ashkenazi, recombination mediated double strand leading to premature truncation associated with.
break repair polyposis and early onset CRC, POT1 Telomere length maintenance Disruptive mutation Whole exome sequencing was. Subunit of polymerase epsilon enzyme Mutation causes polymerase proofreading performed on 1 006 patients. Chubb 6 2016 2 complex associated polyposis with early onset familial CRC. Double strand break repair nuclease 55 years who also had a first. MRE11 Inactivated in mismatch repair deficient cancer degree relative with CRC. involved in homologous recombination,Investigated effects of ATF3. Member of ATF CREB family of basic, ATF3 was overexpressed in human colorectal on apoptosis cell cycle. Jiang 2 2016 3 AFT3 region leucine zipper bZip proteins. cancer cells cell migration and epithelial,regulates transcription by binding DNA. mesenchymal transition EMT, TET consists of a family of Analyzed both the mRNA and.
Nuclear expression of TET2 is absent in a, enzymes that catalyze the oxidation protein level of the TET family. Huang 1 2016 4 TET2 significant portion of CRC tissues in association. of 5 methylcytosine 5mC to members in our colorectal cancer. w metastasis,5 hydroxymethylcytosine 5hmC specimens. CpG island methylator phenotype,CIMP is due to hypermethylation of. multiple CpG islands that encompass the,CIMP CpG promoter regions of multiple genes This. Poorer prognosis for pts w CIMP CIMP H CRC, Jia 3 2016 5 island methylator may prevent the binding of transcription Systematic review of 36 studies.
than with CIMP CIMP L CRC,phenotype factors to tumor suppressor genes. Consequently the suppressor genes are,silenced which lead to the progression. Association of processed meat w CRC was,strongest among individuals with the rapid. Bioactivate heterocyclic aromatic amines NAT2 phenotype intermediate among those w Meta analysis Studied in. Wang 12 2015 6 N acetyltransferase, formed in cooked meat intermediate NAT2 phenotype and null among Japanese and African Americans. those w slow phenotype Similar interaction was,found for NAT2 and total red meat.
Gene located in intestinal epithelial Down regulation is associated with MMR. Caudal related Evaluation of 191 tumor biopsies, cells that that plays an important deficiency right sided tumors and poor. homeobox from colon cancer patients to, Olsen 2 2016 7 role in intestinal development and differentiation at both the mRNA and protein. transcription factor 2 investigate CDX2 expression in. differentiation by encoding intestine level,CDX2 colon cancer. specific transcription factors,Thoc1 is involved in the development and. Gene that encodes nuclear matrix, THO complex 1 progression of CRC and elevated expression of Evaluation of 185 CRC samples.
Liu 12 2015 8 protein playing vital roles in transcription. Thoc1 Thoc1 is associated with aggressive phenotype for Thoc1 activity. elongation and mRNA export,and poor prognosis in CRC. Enzyme that catalyzes the degradation Both CD147 and MMP 11 were over expressed. MMP 11 of 1 antitrypsin and insulin like growth on both the mRNA and protein level in CRC. factor binding protein 1 IGF BP 1 tissue samples They also found a direct. correlation between CD147 and MMP 11 Evaluated the expression of. Tian 10 2015 9 protein expression in CRC tissues CD147 and CD147 and MMP 11 in 56 tissue. Stimulates the secretion of MMPs from MMP 11 expression also influenced lymph biopsies with known CRC. CD147 tumor cells as well as regulates their node metastasis distant metastasis and TNM. expression and activity stage Increased expression of both genes also. correlated with a shorter survival time,miR 320b expression was down regulated in. MicroRNAs miRNAs are small,both CRC tissues and cells Overexpression. noncoding RNAs that potentially,of miR 320b in CRC cells was statistically. play a critical role in tumorigenesis, correlated with a decrease of cell growth in vitro Evaluated miR 320b activity in.
Wang 10 2015 10 miR 320b Mounting evidence indicates that one. and in vivo while c MYC was identified as a CRC tissues of 48 patients. specific miRNA miR 320b is down,target gene of miR 320b in CRC Furthermore. regulated in numerous human cancers,it was found that up regulation of c Myc can. including colorectal cancer CRC,attenuate the effects induced by miR 320b. miRNA 206 levels are significantly lower in CRC, microRNAs miRNAs are small non tissue compared to control tissue. coding RNAs that play important role in patients with low miR 206 expression had Evaluated miR 206 activity in. a variety of biological processes and significantly poorer overall survival CRC tissues and compared it to. Sun 2015 11 miR 206, aberrant expression of miRNA is always over expression of miR 206 can inhibit CRC cell adjacent healthy tissues in 80.
associated with tumor progression and migration and invasion miR 206 functions as a patient. invasion tumor suppressor by inhibiting CRC migration. and invasion, 2 This article is available in http colorectal cancer imedpub com archive php. Colorectal Cancer Open Access,Vol 3 No 1 2,ISSN 2471 9943. Whole genome expression,profiling to evaluate the role. of epigenetic processes on, MAL PRIMA1 DNA hypermethylation and decreased mRNA the progression of CRC They. Kalmar 10 2015 12, PTGDR SFRP1 expression in colorectal adenoma and cancer evaluated 49 colorectal adenoma.
and 49 CRC samples and,compared their gene expression. to 49 healthy samples,Examined MUC5AC activity in,218 serrated colorectal polyps. MUC5AC hypomethylation occurs early in,including 42 goblet cell rich. the serrated pathway and it is specific for,hyperplastic polyps GCHP. Gastric mucin gene linked to the serrated polyps with MSI CIMP H or the BRAF. Renaud 3 2016 13 MUC5AC 68 microvesicular hyperplastic. serrated pathway in CRC formation mutation These findings indicate that MUC5AC. polyps MVHP 100 sessile,hypomethylation may be a marker specific for.
serrated adenomas SSA,malignant precursors of the serrated pathway. and eight traditional serrated,adenomas TSA,TCF21 was down regulated via promoter. Plays an important role in organ Compared the expression. hypermethylation in CRC tissues There was, Dai 1 2016 14 TCF21 development by promoting the transition of TCF21 in 151 CRC tissue. also a direct correlation between TCF21, of mesenchymal to epithelial cells MET samples to 30 normal samples. methylation and lymph node invasion,Transient Receptor.
Family of ion channels that consist of Significant decrease in the expression of. Potential TRP Investigated the expression of, multiple subsets of genes including TRPV3 TRPV4 TRPV5 TRPM4 and TRPC6. Sozucan 9 2015 15 gene family TRPV3 TRPM TRPV and TRPC in CRC. TRPM melastatin TRPV vanilloid genes in CRC tissues compared to healthy. TRPV4 TRPV5 tissue samples in 93 patients,and TPRC canonical tissue. TRPM4 and TRPC6,Secretory glycoprotein that plays, Increased activity of ANGPTL4 in CRC tissue Examined the molecular. many essential roles in tumorigenesis, Li 11 2015 16 ANGPTL4 compared to normal tissue and an even higher mechanism of ANGPTL4 in 54. including migration invasion and, level correlated with liver metastasis colon cancer tissue samples.
Genome wide analysis of 3494,Multiple SNPs at 6p12 1 nearest the ELOVL5. Phipps 1 2016 SNPs at 6p12 1 patients with metastatic CRC. gene which correlated with a poorer prognosis,across six prospective cohorts. rR evaluation of a genome wide, Locus 14q23 1 SNP SNP at 14q23 1 rs17094983 correlated with an. Lemire 11 2015 17 association study GWAS of, rs17094983 Single nucleotide polymorphisms SNPs increased risk of CRC. 16 517 patients,are the most common type of genetic.
variation and they play an important role CASC8 gene SNP of rs7837328 and rs6983267. in the development and progression of are risk factors for CRC among both Caucasian. SNPs single Meta analysis of 34 articles which, many diseases including cancer and Asian whereas rs7014346 and rs10505477. nucleotide included 90 studies to evaluate,are risk factors only in Caucasian. Yao 11 2015 18 polymorphisms for the correlation between SNPs of. SMAD7 gene rs4939827 and rs4464148 are,CASC8 gene and the CASC8 and SMAD7 genes. risk factors for CRC among Caucasian whereas,SMAD7 gene and CRC. rs12953717 is a risk factor in both Caucasians,and Asians.
CRC 55 years who also had a first degree relative with CRC ATF3 may also play a role in metastasis as increased expression. 15 16 of these patients were noted to have rare germline in colorectal cancer cells is linked with invasion Over expression. mutations in known CRC genes compared to healthy controls of ATF3 increases the expression cluster of differentiation 44. However POT1 POLE2 and MRE11 were newly identified in this CD44 and also decreases retinoblastoma Rb expression both. study POT1 works in maintaining telomere length and three of which are CRC stem cell markers 18 ATF3 also decreased the. disruptive mutations were noted in the CRC group 15 POLE2 expression of epithelial mesenchymal transition EMT inducing. is a component of the polymerase epsilon enzyme complex A transcription factors which are essential for cancer metastasis. 18 These findings suggest multiple roles for ATF3 in the CRC. mutation in POLE2 leads to polymerase proofreading associated. progression likely through regulating apoptosis and invasion. polyposis 15 MRE11 is a nuclease involved in double strand. break repair and it is active in mismatch repair deficient cancer TET2 mutation. 15 The findings in this study support DNA replication and repair. defects as a basis for inherited CRC Ten eleven translocation TET consists of a family of enzymes. that catalyze the oxidation of 5 methylcytosine 5mC to. ATF3 mutation 5 hydroxymethylcytosine 5hmC 19 TET1 suppresses tumor. progression by inhibiting the WNT pathway 20 In CRC a. Activating transcription factor 3 AFT3 a member of ATF CREB decrease in TET1 messenger RNA mRNA has previously been. family of basic region leucine zipper bZip proteins regulates observed leading to decreased or absent levels of 5hmC 19. transcription by binding DNA 16 This gene is up regulated in However a recent study by Huang et al also revealed a loss of. response to cellular stress such as hypoxia anoxia carcinogens nuclear expression of TET2 in CRC cells 19 In fact loss of TET2. and DNA damage 17 A study by Jiang et al revealed that ATF3 is was linked to a more aggressive phenotype with metastasis 19. overexpressed in human colorectal cancer cells 18 In CRC cells The role of TET2 in CRC is unclear but it has been proposed as. ATF3 down regulates the expression of the B cell lymphoma 2 a tumor suppressor through post translational modification. Bcl 2 a gene that inhibits apoptosis 18 On the other hand 19 TET2 regulates gene expression by binding with DNA in the. ATF3 up regulates the activity of Bak a protein of the BCL 2 nucleus 20 Thus TET1 and TET2 suppress the progression of. family that induces apoptosis 18 CRC through separate mechanisms. 3 This article is available in http colorectal cancer imedpub com archive php. Colorectal Cancer Open Access,Vol 3 No 1 2,ISSN 2471 9943. CpG island methylator phenotype CIMP with a more aggressive phenotype thus leading to decreased. survival Their results suggest that Thoc1 may be used as a. CpG island methylator phenotype CIMP is due to prognostic marker for CRC. hypermethylation of multiple CpG islands that encompass the. promoter regions of multiple genes 21 This may prevent CD147 and MMP 11. binding of transcription factors to tumor suppressor genes 22. Matrix metalloproteinases MMPs are group of enzymes that. Consequently the suppressor genes are silenced which lead to. play an essential role in tumor invasion and metastasis via. the progression of CRC 23 A systematic review of thirty six. degradation of the extracellular matrix ECM during tissue. studies by Jia et al revealed a poorer prognosis in CRC patients. growth and turnover MMP expression is usually down regulated. with high CIMP H or positive CIMP than those with low CIMP L. in healthy tissue but levels are increased in pathological states. or negative CIMP 24,including inflammation and tumorigenesis 36. N acetyltransferase 2 NAT2 genotype Unlike other MMPs MMP 11 also called stromelysin 3 does not. Prior studies have established a correlation between red and play a direct role in ECM remodeling It catalyzes the degradation. processed meat consumption and CRC possibly due to exposure of 1 antitrypsin and insulin like growth factor binding protein 1. to heterocyclic amines HAAs 25 27 HAAs are chemicals that IGF BP 1 37 38 CD147 plays a role in tissue remodeling via. are produced when meats are cooked at high temperatures 27 stimulation of extracellular matrix metalloproteinase inducer. N acetyltransferase2 NAT2 is a gene that activates HAAs via EMMPRIN It stimulates the secretion of MMPs from tumor. O acetylation which forms a reactive N acetoxy species that binds cells as well as regulates their expression and activity Increased. DNA 28 There are multiple genetic polymorphisms of NAT2 CD147 activity is linked to tumor growth and metastasis CD147. that affect its ability to catalyze HAAs Populations with a higher has been linked to MMP 9 and MMP 2 but its correlation with. frequency of the rapid NAT2 phenotype Native Alaskans and MMP 11 has been unclear 39. Japanese Americans have been noted to have a higher incidence. A study by Tian et al evaluated the expression of CD147 and. of CRC Contrastingly populations with a lower frequency of this. MMP 11 in 56 tissue biopsies with known CRC 40 Compared. phenotype North Africans have a lower incidence of CRC 29. with normal mucosa they found that both CD147 and MMP 11. A meta analysis by Wang et al examined the correlation between were over expressed on both the mRNA and protein level in CRC. CRC and frequency of rapid NAT2 phenotype in Japanese and tissue samples 40 They also found a direct correlation between. African Americans 29 The Japanese American population had CD147 and MMP 11 protein expression in CRC tissues CD147. a high frequency of rapid NAT2 phenotype whereas the African and MMP 11 expression also influenced lymph node metastasis. American population had an intermediate frequency In both distant metastasis and TNM stage Increased expression of both. populations there was a direct correlation between NAT2 activity genes also correlated with a shorter survival time therefore. and processed and red meat intake There was also a stronger they independently have prognostic value in CRC. correlation between the rapid NAT2 phenotype and CRC than the. intermediate phenotype The slow phenotype had no correlation miR 320b and miR 206. with CRC 29 MicroRNAs miRNAs are a class of small noncoding RNAs that. CDX2 gene are essential in post transcriptional regulation They degrade. mRNA and inhibit translation which leads to decreased gene. Caudal related homeobox transcription factor 2 CDX2 is a gene expression 41 43 MiRNA deregulation plays an important role. located in intestinal epithelial cells that that plays an important in tumor formation and metastasis 44. role in intestinal development and differentiation by regulating. intestine specific transcription factors 30 31 A study by Olsen A study by Wang et al 19 evaluated the role of miR 320b in. et al evaluated 191 tumor biopsies from colon cancer patients CRC tissues of 48 patients They found that miR 320b activity was. to investigate CDX2 expression in colon cancer 31 They decreased in the CRC tissues and cells Contrastingly they also. discovered that CDX2 mRNA was downregulated in tumors with found a direct correlation with up regulation of miR 320b and a. mismatch repair MMR deficiency right sided tumors and decrease in CRC cell growth They also found that up regulation. poorly differentiated tumors 31 of miR 320b down regulated the expression of c MYC thus. identifying it as a target gene Moreover c Myc overexpression. Thoc1 gene diminished the effects of miR 320b 45, The THO complex 1 Thoc1 is a gene that encodes a nuclear Sun et al examined the activity of miR 206 in CRC tissues and. matrix protein which binds the retinoblastoma protein and compared it to adjacent healthy tissues in 80 patients 43 They. facilitates transcription elongation and mRNA export 32 34 A found that miRNA 206 activity was significantly down regulated. study by Liu et al evaluated Thoc1 activity in 185 CRC samples in the CRC samples Furthermore there was also a correlation. 35 They discovered that Thoc1 mRNA and protein expression with low miR 206 expression and poorer survival MiR 206. was significantly higher in CRC tissue than adjacent samples of may function as a tumor suppressor as up regulation inhibits. normal colonic tissue 35 A higher level of Thoc1 was associated migration and invasion of CRC cells 43. Under License of Creative Commons Attribution 3 0 License 4. Colorectal Cancer Open Access,Vol 3 No 1 2,ISSN 2471 9943. MAL PRIMA1 PTGDR and SFRP1 in CRC tissues There was also a direct correlation between. TCF21 methylation and lymph node invasion Furthermore. DNA hypermethylation is an epigenetic event that occurs at TCF21 activity was restored with demethylation of CRC cell lines. gene regulatory sites often in tumor suppressor genes It inhibiting cell growth and invasion and promoting apoptosis. causes decreased or absent gene expression leading to the These results indicate that the TCF21 gene may serve as a tumor. development of CRC 46 48 MiRNAs as previously described in suppressor 53. the Wang et al 19 and Sun et al 43 studies are epigenetic. regulators through the posttranscriptional and translation Transient Receptor Potential TRP gene family. processes of mRNAs Altered expression of certain miRNAs leads. Transient Receptor Potential TRP is a family of ion channels that. to CRC progression 49, consist of multiple subsets of genes including TRPM melastatin.
Kalmar et al performed whole genome expression profiling to TRPV vanilloid and TPRC canonical 54 Up regulation of. evaluate the role of epigenetic processes on the progression certain TRP s have previously been described in cancer cells and. of CRC They evaluated 49 colorectal adenoma and 49 CRC it has been suggested that they are involved in multiple processes. samples and compared their gene expression to 49 healthy including cell proliferation tumor invasion cell differentiation. samples 50 They identified 18 genes including MAL SFRP1 angiogenesis and apoptosis 54 55 Sozucan et al investigated. SULT1A1 PRIMA1 and PTGDR which were down regulated in the expression of TRPM TRPV and TRPC in CRC tissue samples. both the adenoma and carcinoma samples compared to healthy in 93 patients 56 They discovered that there was a significant. tissues Three of these genes COL1A2 SFRP2 SOCS3 exhibited decrease in the expression of TRPV3 TRPV4 TRPV5 TRPM4 and. hypermethylation and THBS2 showed hypomethylation BCL2 TRPC6 genes in CRC tissues compared to healthy tissue possibly. PRIMA1 and PTGDR were also hypermethylated but only in the due to epigenetic factors. CRC samples In adenoma samples miR 21 was overexpressed. 50 Epigenetic alterations of the identified genes and miRNAs ANGPLT4. may play an important role in CRC formation Angiopoietin like protein 4 ANGPTL4 is a secreted protein that. plays many essential roles in tumorigenesis including migration. MUC5AC invasion and apoptosis 57 58 ANGPTL4 is up regulated in. MUC2 and MUC5AC are intestinal and gastric mucin genes CRC tissues and a study by Li et al examined the molecular. respectively that have been linked to the serrated pathway in mechanism of this gene in 54 colon cancer tissue samples 57. CRC formation 12 They determined that there was increased activity of ANGPTL4 in. CRC tissue compared to normal tissue and an even higher level. Renaud et al examined MUC2 and MUC5AC activity in 218. correlated with liver metastasis Molecular analysis revealed that. serrated colorectal polyps including 42 goblet cell rich. over expression of ANGPTL4 up regulated bone morphogenetic. hyperplastic polyps GCHP 68 microvesicular hyperplastic. protein 7 BMP7 Furthermore silencing of BMP7 expression. polyps MVHP 100 sessile serrated adenomas SSA and eight. reversed ANGPTL4 activity in HCT116 cells They concluded that. traditional serrated adenomas TSA They demonstrated that. ANGPTL4 may be a promoter of CRC metastasis via up regulation. MUC5AC hypomethylation occurs early in the serrated pathway. of BMP7 57, and it is specific for serrated polyps with MSI CIMP H or the BRAF. mutation These findings indicate that MUC5AC hypomethylation Single nucleotide polymorphisms. may be a marker specific for malignant precursors of the serrated. pathway 51 Single Nucleotide Polymorphisms SNPs Single nucleotide. polymorphisms SNPs are the most common type of genetic. They also demonstrated that MUC5AC hypomethylation was variation 59 and they play an important role in the development. found only in MVHPs and SSAs but not GCHPs Therefore and progression of many diseases including cancer. it may also be used as a marker to distinguish GCHPs from. MVHPs and SSAs There was also a gradual increase in MUC5AC A genome wide analysis of 3494 patients with metastatic CRC. hypomethylation frequency from MVHP to SSA indicating that across six prospective cohorts was done by Phipps et al 60 They. MVHP may give rise to SSA and sessile serrated adenomas with discovered multiple SNPs at 6p12 1 nearest the ELOVL5 gene. dysplasia SSA D 51 which correlated with a poorer prognosis These SNPs have been. associated with a two fold shorter survival and include the minor. 13 TCF21 alleles at rs17544464 rs209489 and rs1442089 60 The ELOVL5. Transcription factor 21 TCF21 plays an important role in organ gene encodes a fatty acid elongase and knockout of this gene in. development by promoting the transition of mesenchymal to mouse models has been associated with hepatic steatosis 61. epithelial cells MET Down regulation of TCF21 via promoter which is an independent risk factor for distant metastatic CRC. hypermethylation has been associated with multiple cancers 62. including lung kidney and heart 52, Lemire et al 63 performed a re evaluation of a genome wide. A study by Dai et al compared the expression of TCF21 in 151 association study GWAS of 16 517 patients It revealed that an. CRC tissue samples to 30 normal samples They demonstrated SNP at 14q23 1 rs17094983 correlated with an increased risk. that TCF21 was down regulated via promoter hypermethylation of CRC This locus is associated with the Reticulon 1 RTN1 gene. 5 This article is available in http colorectal cancer imedpub com archive php. Colorectal Cancer Open Access,Vol 3 No 1 2,ISSN 2471 9943. which regulates cancer cell proliferation and survival This gene patients SNPs of rs7014346 and rs10505477 also correlated with. is up regulated in healthy colon tissue but down regulated in an increased risk of CRC but only in Caucasians 3. cancer cells 63, A rs12953717 SNP of the SMAD7 gene correlated with an. CASC8 and SMAD7 gene polymorphisms Cancer susceptibility increased risk of CRC in both Caucasians and Asians On the. candidate 8 CASC8 gene is a noncoding RNA lncRNA located other hand rs4939827 and rs4464148 SNPs correlated with an. on 8q24 21 which regulates gene expression 64 65 SMAD7 increased risk of CRC only in Caucasians 3. is a gene located on 18q21 It is a member of the transforming. growth factor TGF family in the anti inflammatory signaling Future Directions. pathway which also plays a role in the metastasis of solid tumors The identification of new genes and SNPs associated with CRC. 66 68 SMAD7 inhibits TAK1 by binding TAB2 and TAB3 which in the aforementioned studies provide new insights into the. potentiates the effects of TGF 66 67 pathophysiology and progression for CRC These genes may. Yao et al conducted a meta analysis of 34 articles which serve as CRC prognostic markers as well as molecular targets. included 90 studies to evaluate the correlation between SNPs for novel CRC therapies Additional studies focusing on potential. of the CASC8 and SMAD7 genes and CRC 3 They discovered interactions between these genes and known CRC molecular. that the rs7837328 and rs6983267 SNPs of the CASC8 gene were pathways such as APC Wnt signaling will further enhance our. linked with an increased risk of CRC in both Caucasian and Asian understanding of molecular genetics of CRC. 6 This article is available in http colorectal cancer imedpub com archive php. Colorectal Cancer Open Access,Vol 3 No 1 2,ISSN 2471 9943.
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