Inactivation Of Tumor Suppressor Genes Research Articles

Genetic Alterations in Gastric Cancer Associated with Helicobacter pylori Infection.

Gastric cancer is a world health problem and depicts the fourth leading mortality cause from malignancy in Mexico. Causation of gastric cancer is not only due to the combined effects of environmental factors and genetic variants. Recent molecular studies have transgressed a number of genes involved in gastric carcinogenesis. The aim of this review is to understand the recent basics of gene expression in the development of the process of gastric carcinogenesis. Genetic variants, polymorphisms, desoxyribonucleic acid methylation, and genes involved in mediating inflammation have been associated with the development of gastric carcinogenesis. Recently, these genes (interleukin 10, Il-17, mucin 1, β-catenin, CDX1, SMAD4, SERPINE1, hypoxia-inducible factor 1 subunit alpha, GSK3β, CDH17, matrix metalloproteinase 7, RUNX3, RASSF1A, TFF1, HAI-2, and COX-2) have been studied in association with oncogenic activation or inactivation of tumor suppressor genes. All these mechanisms have been investigated to elucidate the process of gastric carcinogenesis, as well as their potential use as biomarkers and/or molecular targets to treatment of disease.

Promotion of Wilms' tumor cells migration and invasion by mono-2-ethyhexyl phthalate (MEHP) via activation of NF-κB signals

Wilms tumor is a pediatric kidney cancer associated with inactivation of the WT1 tumor-suppressor gene in 5–10% of cases. There is an urgent need to illustrate risk factors which can trigger the motility of Wilms tumor cells. Our present study revealed that mono-(2-ethylhexyl) phthalate (MEHP) exposure can significantly increase the in vitro migration and invasion of G401 and WiT49 cells. Real time PCR and western blot analysis revealed that MEHP treatment can increase the expression of metalloproteinase-2 (MMP-2) and MMP-9, while had no effect on the expression of MMP-1, MMP-3, or MMP-12. The si-MMP-2 and si-MMP-9 can reverse MEHP induced migration and invasion of G401 cells. MEHP can activate both ERK1/2 and p65 in WT cells, while had no obvious effect on Akt or PKA. However, only BAY 11-7082, the inhibitor of NF-κB, while not ERK1/2 (PD 98059), can reverse MEHP induced migration and invasion of WT cells. BAY 11-7082 also can attenuate MEHP induced up regulation of MMP-2 and MMP-9. The inhibitor of estrogen receptor reversed MEHP induced activation of NF-κB and up regulation of MMP-2/-9. In addition, MEHP also increased the mRNA and protein expression, nuclear translocation, and transcriptional activities of NF-κB in WT cells. Collectively, our study found that MEHP stimulated the Wilms' tumor progression via NF-κB signals.

Effects of long-term ethanol consumption and Aldh1b1 depletion on intestinal tumourigenesis in mice.

Ethanol and its metabolite acetaldehyde have been classified as carcinogens for the upper aerodigestive tract, liver, breast, and colorectum. Whereas mechanisms related to oxidative stress and Cyp2e1 induction seem to prevail in the liver, and acetaldehyde has been proposed to play a crucial role in the upper aerodigestive tract, pathological mechanisms in the colorectum have not yet been clarified. Moreover, all evidence for a pro-carcinogenic role of ethanol in colorectal cancer is derived from correlations observed in epidemiological studies or from rodent studies with additional carcinogen application or tumour suppressor gene inactivation. In the current study, wild-type mice and mice with depletion of aldehyde dehydrogenase 1b1 (Aldh1b1), an enzyme which has been proposed to play an important role in acetaldehyde detoxification in the intestines, received ethanol in drinking water for 1 year. Long-term ethanol consumption led to intestinal tumour development in wild-type and Aldh1b1-depleted mice, but no intestinal tumours were observed in water-treated controls. Moreover, a significant increase in DNA damage was detected in the large intestinal epithelium of ethanol-treated mice of both genotypes compared with the respective water-treated groups, along with increased proliferation of the small and large intestinal epithelium. Aldh1b1 depletion led to increased plasma acetaldehyde levels in ethanol-treated mice, to a significant aggravation of ethanol-induced intestinal hyperproliferation, and to more advanced features of intestinal tumours, but it did not affect intestinal tumour incidence. These data indicate that ethanol consumption can initiate intestinal tumourigenesis without any additional carcinogen treatment or tumour suppressor gene inactivation, and we provide evidence for a role of Aldh1b1 in protection of the intestines from ethanol-induced damage, as well as for both carcinogenic and tumour-promoting functions of acetaldehyde, including increased progression of ethanol-induced tumours. Copyright © 2016 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd.

Inactivation of tumor suppressor genes and cancer therapy: An evolutionary game theory approach

Inactivation of alleles in tumor suppressor genes (TSG) is one of the important issues resulting in evolution of cancerous cells. In this paper, the evolution of healthy, one and two missed allele cells is modeled using the concept of evolutionary game theory and replicator dynamics. The proposed model also takes into account the interaction rates of the cells as designing parameters of the system. Different combinations of the equilibrium points of the parameterized nonlinear system is studied and categorized into some cases. In each case, the interaction rates’ values are suggested in a way that the equilibrium points of the replicator dynamics are located on an appropriate region of the state space. Based on the suggested interaction rates, it is proved that the system doesn't have any undesirable interior equilibrium point as well. Therefore, the system will converge to the desirable region, where there is a scanty level of cancerous cells. In addition, the proposed conditions for interaction rates guarantee that, when a trajectory of the system reaches the boundaries, then it will stay there forever which is a desirable property since the equilibrium points have been already located on the boundaries, appropriately. The simulation results show the effectiveness of the suggestions in the elimination of the cancerous cells in different scenarios.

Inhibition of DNA and Histone Methylation by 5-Aza-2'-Deoxycytidine (Decitabine) and 3-Deazaneplanocin-A on Antineoplastic Action and Gene Expression in Myeloid Leukemic Cells.

Epigenetic alterations play an important role in the development of acute myeloid leukemia (AML) by silencing of genes that suppress leukemogenesis and differentiation. One of the key epigenetic changes in AML is gene silencing by DNA methylation. The importance of this alteration is illustrated by the induction of remissions in AML by 5-aza-2′-deoxycytidine (5-AZA-CdR, decitabine), a potent inhibitor of DNA methylation. However, most patients induced into remission by 5-AZA-CdR will relapse, suggesting that a second agent should be sought to increase the efficacy of this epigenetic therapy. An interesting candidate for this purpose is 3-deazaneplanocin A (DZNep). This analog inhibits EZH2, a histone methyltransferase that trimethylates lysine 27 histone H3 (H3K27me3), a marker for gene silencing. This second epigenetic silencing mechanism also plays an important role in leukemogenesis as shown in preclinical studies where DZNep exhibits potent inhibition of colony formation by AML cells. We reported previously that 5-AZA-CdR in combination with DZNep exhibits a synergistic antineoplastic action against human HL-60 AML cells and the synergistic activation of several tumor suppressor genes. In this report, we showed that this combination also induced a synergistic activation of apoptosis in HL-60 cells. The synergistic antineoplastic action of 5-AZA-CdR plus DZNep was also observed on a second human myeloid leukemia cell line, AML-3. In addition, 5-AZA-CdR in combination with the specific inhibitors of EZH2, GSK-126, or GSK-343, also exhibited a synergistic antineoplastic action on both HL-60 and AML-3. The combined action of 5-AZA-CdR and DZNep on global gene expression in HL-60 cells was investigated in greater depth using RNA sequencing analysis. We observed that this combination of epigenetic agents exhibited a synergistic activation of hundreds of genes. The synergistic activation of so many genes that suppress malignancy by 5-AZA-CdR plus DZNep suggests that epigenetic gene silencing by DNA and histone methylation plays a major role in leukemogenesis. Targeting DNA and histone methylation is a promising approach that merits clinical investigation for the treatment of AML.

Epigenetic silencing of protocadherin 10 in colorectal cancer.

Colorectal cancer (CRC) is one of the most common types of malignant tumor in the world and occurs through a multi-step process resulting from the accumulation of genetic and epigenetic alterations of the genome. Although the molecular mechanisms of the pathogenesis of CRC remain unclear, the inactivation of tumor suppressor genes (TSGs) through promoter methylation serves an important role. Aberrant methylation is a well-defined marker of CRC. At present, the epigenetic silencing of protocadherin 10 (PCDH10) has been identified as an important TSG with key roles in colorectal carcinogenesis, invasion and metastasis as a frequent and early event. Advances in gene methylation detection in tumor tissues and body fluids have led to the development of non-invasive screening methods for CRC. The present study aimed to review the epigenetic alteration of PCDH10 in CRC development, and the potential of PCDH10 to be a non-invasive biomarker for CRC.

Reversal of hypermethylation and reactivation of glutathione S-transferase pi 1 gene by curcumin in breast cancer cell line.

One of the mechanisms for epigenetic silencing of tumor suppressor genes is hypermethylation of cytosine residue at CpG islands at their promoter region that contributes to malignant progression of tumor. Therefore, activation of tumor suppressor genes that have been silenced by promoter methylation is considered to be very attractive molecular target for cancer therapy. Epigenetic silencing of glutathione S-transferase pi 1, a tumor suppressor gene, is involved in various types of cancers including breast cancer. Epigenetic silencing of tumor suppressor genes can be reversed by several molecules including natural compounds such as polyphenols that can act as a hypomethylating agent. Curcumin has been found to specifically target various tumor suppressor genes and alter their expression. To check the effect of curcumin on the methylation pattern of glutathione S-transferase pi 1 gene in MCF-7 breast cancer cell line in dose-dependent manner. To check the reversal of methylation pattern of hypermethylated glutathione S-transferase pi 1, MCF-7 breast cancer cell line was treated with different concentrations of curcumin for different time periods. DNA and proteins of treated and untreated cell lines were isolated, and methylation status of the promoter region of glutathione S-transferase pi 1 was analyzed using methylation-specific polymerase chain reaction assay, and expression of this gene was analyzed by immunoblotting using specific antibodies against glutathione S-transferase pi 1. A very low and a nontoxic concentration (10 µM) of curcumin treatment was able to reverse the hypermethylation and led to reactivation of glutathione S-transferase pi 1 protein expression in MCF-7 cells after 72 h of treatment, although the IC50 value of curcumin was found to be at 20 µM. However, curcumin less than 3 µM of curcumin could not alter the promoter methylation pattern of glutathione S-transferase pi 1. Treatment of breast cancer MCF-7 cells with curcumin causes complete reversal of glutathione S-transferase pi 1 promoter hypermethylation and leads to re-expression of glutathione S-transferase pi 1, suggesting it to be an excellent nontoxic hypomethylating agent.

Molecular Mechanisms Underlying the Inhibitory Effects of Qingzaojiufei Decoction on Tumor Growth in Lewis Lung Carcinoma.

Objective: Qingzaojiufei decoction (QD) is an empirical herbal formula from traditional Chinese medicine that is used for the treatment of lung-related diseases. However, the effect of QD on the growth of lung tumor cells has not been investigated. The aim of this study was to examine the antitumor activity of QD in Lewis lung carcinomas (LLC) in vivo and in vitro, and to elucidate the underlying mechanisms. Methods: The LLC cells were used to assess the antitumor activity of QD by Cell Counting Kit-8 assay in vitro. In vivo, mice were randomly assigned to 5 groups (n = 10/group): the model control (MC) group was intragastrically administered physiological saline (0.9% NaCl) twice daily from day 2 after tumor implantation for 2 weeks. The QD groups were intragastrically administered QD twice daily from 2 weeks before to 2 weeks after tumor implantation for 4 weeks. The mRNA levels were detected by quantitative polymerase chain reaction, the proteins expression was determined by immunohistochemistry or western blotting. Results: Compared with the model group, QD showed inhibition of proliferation of LLC cells and reductions in tumor weight and proliferating cell nuclear antigen protein expression. Furthermore, QD up-regulated p53 mRNA expression, and downregulated c-myc and Bcl-2 mRNA expression, while MMP-9, VEGF, and VEGFR protein expression was suppressed. Phosphorylated ERK1/2 levels were also reduced by QD in a dose-dependent manner. Conclusion: Our findings suggest that QD inhibited lung tumor growth and proliferation, by activation of tumor suppressor genes, inactivation of oncogenes, suppressing the potential for invasion and metastasis, and attenuating angiogenesis. The ERK/VEGF/MMPs signaling pathways may play an important role in QD-induced inhibition of malignant tumor cell proliferation.

Bi-allelic inactivation is more prevalent at relapse in multiple myeloma, identifying RB1 as an independent prognostic marker

The purpose of this study is to identify prognostic markers and treatment targets using a clinically certified sequencing panel in multiple myeloma. We performed targeted sequencing of 578 individuals with plasma cell neoplasms using the FoundationOne Heme panel and identified clinically relevant abnormalities and novel prognostic markers. Mutational burden was associated with maf and proliferation gene expression groups, and a high-mutational burden was associated with a poor prognosis. We identified homozygous deletions that were present in multiple myeloma within key genes, including CDKN2C, RB1, TRAF3, BIRC3 and TP53, and that bi-allelic inactivation was significantly enriched at relapse. Alterations in CDKN2C, TP53, RB1 and the t(4;14) were associated with poor prognosis. Alterations in RB1 were predominantly homozygous deletions and were associated with relapse and a poor prognosis which was independent of other genetic markers, including t(4;14), after multivariate analysis. Bi-allelic inactivation of key tumor suppressor genes in myeloma was enriched at relapse, especially in RB1, CDKN2C and TP53 where they have prognostic significance.

Promoter Hypermethylation and Its Impact on Expression of MGMT Gene in the GIT Malignant Patients of Kashmiri Origin

ABSTRACTEpigenetic alterations, in addition to multiple gene abnormalities, are involved in the genesis and progression of human cancers. Gastrointestinal tract (GIT) cancer is a major medical and economic burden worldwide. Aberrant methylation of CpG islands within promoter regions is associated with transcriptional inactivation of various tumor suppressor genes. Although a number of cancer-associated genes have been found to be hypermethylated in GIT cancer, valuable methylation markers for early diagnosis and prognostic evaluation of this cancer remain largely unknown. O6-methyguanine DNA methyltransferase (MGMT) is a DNA-repair gene that removes mutagenic and cytotoxic adducts from the O6 position of guanine induced by alkylating agents. MGMT promoter hypermethylation and reduced expression have been found in some primary human carcinomas. We studied DNA methylation of CpG islands of the MGMT gene and its relation with MGMT protein expression in human GIT carcinomas. A total of 210 GIT tumor samples and 90 adjacent normal tissues were analyzed for MGMT promoter methylation by methylation-specific polymerase chain reaction after bisulfite modification of DNA and same samples were analyzed for MGMT protein expression by Western blotting. The methylation frequencies of MGMT gene promoter were 41.4%, 34.2%, and 44.2% in stomach, esophageal, and colorectal cancer cases while as 16.6, 13.3, and 13.3 in respective controls. MGMT protein was found downregulated in controls of all GIT. The results suggest that methylation at CpG islands of MGMT may be responsible for the downregulation of MGMT protein expression in GIT cancers.

P63 in Squamous Cell Carcinoma of the Skin: More Than a Stem Cell/Progenitor Marker

The p63 gene is often overexpressed in squamous cell carcinomas; however, how its overexpression contributes to tumor formation and expansion is still incompletely understood. Devos etal. report the development of a versatile mouse model demonstrating that p63 facilitates squamous cell carcinoma formation in skin and providing an excellent tool to dissect the relevance of its downstream signaling pathways in tumorigenesis.

Inactivation of the PBRM1 tumor suppressor gene amplifies the HIF-response in VHL−/− clear cell renal carcinoma

Most clear cell renal carcinomas (ccRCCs) are initiated by somatic inactivation of the VHL tumor suppressor gene. The VHL gene product, pVHL, is the substrate recognition unit of an ubiquitin ligase that targets the HIF transcription factor for proteasomal degradation; inappropriate expression of HIF target genes drives renal carcinogenesis. Loss of pVHL is not sufficient, however, to cause ccRCC. Additional cooperating genetic events, including intragenic mutations and copy number alterations, are required. Common examples of the former are loss-of-function mutations of the PBRM1 and BAP1 tumor suppressor genes, which occur in a mutually exclusive manner in ccRCC and define biologically distinct subsets of ccRCC. PBRM1 encodes the Polybromo- and BRG1-associated factors-containing complex (PBAF) chromatin remodeling complex component BRG1-associated factor 180 (BAF180). Here we identified ccRCC lines whose ability to proliferate in vitro and in vivo is sensitive to wild-type BAF180, but not a tumor-associated BAF180 mutant. Biochemical and functional studies linked growth suppression by BAF180 to its ability to form a canonical PBAF complex containing BRG1 that dampens the HIF transcriptional signature.

Expression of Mammaglobin and Carcinoembryonic Antigen in Peripheral Blood of Patients with Breast Cancer Using Real Time Polymerase Chain Reaction

Background and Objectives: Breast cancer is among the most common causes of cancer related mortality in women worldwide. Early detection and prompt diagnosis of tumor is the first step to prevent cancer-related morbidity and mortality, and a comprehensive understanding of the involved molecular mechanisms can greatly help in this respect. Breast cancer, like many other types of cancer, is caused by a combination of genetic and epigenetic changes such as inactivation of tumor suppressor genes. Materials and Methods: This study was performed on 40 breast cancer patients and 40 healthy controls. Quantitative real time reverse transcription polymerase chain reaction (real time qRT-PCR) was used to assess the expression of carcinoembryonic antigen (CEA) and mammaglobin mRNA in the peripheral blood of patients and healthy controls. The two groups were compared using t-test. Results: The two groups were not significantly different in terms of the mean age. Twenty-nine out of 40 cancer patients were positive for CEA mRNA and its sensitivity was calculated to be 72.5%. Twelve out of 40 healthy controls were positive for CEA mRNA. Twenty-six out of 40 patients were positive for mammaglobin mRNA indicative of 65% sensitivity while only five out of 40 healthy controls were positive for mammaglobin mRNA. Conclusion: Both CEA and mammaglobin mRNA had high sensitivity in cancer patients; thus, they can be used for screening and early detection of breast cancer patients. Further studies with larger sample sizes are required to confirm the current findings.

Promoter Hypermethylation of the ATM Gene as a Novel Biomarker for Breast Cancer

Background:Breast cancer may be induced by activation of protooncogenes to oncogenes and in many cases inactivation of tumor suppressor genes. Ataxia telangiectasia mutated (ATM) is an important tumor suppressor gene which plays central roles in the maintenance of genomic integrity by activating cell cycle checkpoints and promoting repair of double-strand breaks of DNA. In breast cancer, decrease ATM expression correlates with a poor outcome; however, the molecular mechanisms underlying downregulation are still unclear. Promoter hypermethylation may contribute in downregulation. Hence the present investigation was designed to evaluate promoter methylation and expression of the ATM gene in breast cancer cases, and to determine links with clinical and demographic manifestations, in a South Indian population.Methods:Tumor biopsy samples were collected from 50 pathologically confirmed sporadic breast cancer cases. DNA was isolated from tumor and adjacent non-tumorous regions, and sodium bisulfite conversion and methylation-specific PCR were performed using MS-PCR primers for the ATM promoter region. In addition, ATM mRNA expression was also analyzed for all samples using real-time PCR.Results:Fifty eight percent (58%) of cancer tissue samples showed promoter hypermethylation for the ATM gene, in contrast to only 4.44% of normal tissues (p= 0.0001). Furthermore, ATM promoter methylation was positively associated with age (p = 0.01), tumor size (p=0.045) and advanced stage of disease i.e. stages III and IV (p =0.019). An association between promoter hypermethylation and lower expression of ATM mRNA was also found (p=0.035).Conclusion:We report for the first time that promoter hypermethylation of ATM gene may be useful as a potential new biomarker for breast cancer, especially in the relatively young patients.

MTE12.01 Clinically Relevant Signal Transduction Pathways

MTE12.01 Clinically Relevant Signal Transduction Pathways

Tumor suppressor genes in familial adenomatous polyposis.

Colorectal cancer (CRC) is mostly due to a series of genetic alterations that are being greatly under the influence of the environmental factors. These changes, mutational or epigenetic modifications at transcriptional forefront and/or post-transcriptional effects via miRNAs, include inactivation and the conversion of proto-oncogene to oncogenes, and/or inactivation of tumor suppressor genes (TSG). Here, a thorough review was carried out on the role of TSGs with the focus on the APC as the master regulator, mutated genes and mal-/dysfunctional pathways that lead to one type of hereditary form of the CRC; namely familial adenomatous polyposis (FAP). This review provides a venue towards defining candidate genes that can be used as new PCR-based markers for early diagnosis of FAP. In addition to diagnosis, defining the modes of genetic alterations will open door towards genome editing to either suppress the disease or reduce its progression during the course of action.

Runx3 in Immunity, Inflammation and Cancer.

In this chapter we summarize the pros and cons of the notion that Runx3 is a major tumor suppressor gene (TSG). Inactivation of TSGs in normal cells provides a viability/growth advantage that contributes cell-autonomously to cancer. More than a decade ago it was suggested that RUNX3 is involved in gastric cancer development, a postulate extended later to other epithelial cancers portraying RUNX3 as a major TSG. However, evidence that Runx3 is not expressed in normal gastric and other epithelia has challenged the RUNX3-TSG paradigm. In contrast, RUNX3 is overexpressed in a significant fraction of tumor cells in various human epithelial cancers and its overexpression in pancreatic cancer cells promotes their migration, anchorage-independent growth and metastatic potential. Moreover, recent high-throughput quantitative genome-wide studies on thousands of human samples of various tumors and new investigations of the role of Runx3 in mouse cancer models have unequivocally demonstrated that RUNX3 is not a bona fide cell-autonomous TSG. Importantly, accumulating data demonstrated that RUNX3 functions in control of immunity and inflammation, thereby indirectly influencing epithelial tumor development.

Screening of Tumor Suppressor Genes in Metastatic Colorectal Cancer.

Most tumor suppressor genes are commonly inactivated in the development of colorectal cancer (CRC). The activation of tumor suppressor genes may be beneficial to suppress the development and metastasis of CRC. This study analyzed genes expression and methylation levels in different stages of CRC. Genes with downregulated mRNA expression and upregulated methylation level in advanced CRC were screened as the potential tumor suppressor genes. After comparing the methylation level of screened genes, we found that MBD1 gene had downregulated mRNA expression and upregulated methylation levels in advanced CRC and continuously upregulated methylation level in the progression of CRC. Enrichment analysis revealed that genes expression in accordance with the elevated expression of MBD1 mainly located on chromosomes 17p13 and 17p12 and 8 tumor suppressor genes located on chromosome 17p13. Further enrichment analysis of transcription factor binding site identified that SP1 binding site had higher enrichment and could bind with MBD1. In conclusion, MBD1 may be a tumor suppressor gene in advanced CRC and affect the development and metastasis of CRC by regulating 8 tumor suppressor genes through binding with SP1.

DNA Double-Strand Breaks Caused by Different Microorganisms: A Special Focus on Helicobacter pylori.

The association between inflammation and cancer has long been recognized. Several studies have found that different types of tumors develop at sites of chronic inflammation. It is stated that over 15%-20% of malignancies worldwide can be related to infections caused by viruses, bacteria, and schistosomes. Inflammatory conditions are characterized by overexpression of inducible nitric oxide synthase (iNOS) and overproduction of nitric oxide/reactive nitrogen species (ROSs/RNSs) in epithelial cells. Reactive oxygen species (ROSs) may also lead to cellular alterations and eventually to inflammation. A variety of chronic infectious diseases can generate steady-state levels of ROSs/RNSs within infected cells and possibly lead to different types of DNA lesions. Accumulation of DNA lesions may finally lead to mutations that may activate oncogenes or inactivate tumor suppressor genes. Helicobacter pylori has been shown to generate ROSs/RNSs, induce DNA damage, and lead to chronic inflammation in gastric epithelial cells. A limited number of studies have addressed the effects of Helicobacter pylori on DNA damage, particularly its impact on single-strand and double-strand DNA breaks. This bacterium is classified as a Group I carcinogen by the International Agency for Research on Cancer on the basis of numerous animal and epidemiological studies. Chronic Helicobacter pylori infection can lead to increased risk of gastric cancer and mucosa-associated lymphoid tissue (MALT) lymphoma. This review addresses the DNA-damaging and double-strand break-inducing effects of different microorganisms and their toxins, specifically focusing on Helicobacter pylori.

Factores genéticos y epigenéticos del cáncer gástrico

Gastric cancer (GC) is the leading cause of cancer death in Colombia, gastric tumorigenesis is a gradual and long evolution process involving genetic and epigenetic changes that activate protooncogenes and inactivate Tumor suppressor genes (GST). The genetic changes include loss of heterozygosity (LOH), microsatellite instability (MSI), translocations, aneuploidy, and mutations in GST; and mutations in protooncogenes or amplifications. Meanwhile, methylation of promoters is the commonest epigenetic alteration. Actually, CG is a public health problem in the country for three factors: high rates of incidence/mortality, overruns treatments for advanced disease stages and lack of public access to services health. This review the genetic and epigenetic alterations that are found more often in CG, and its association with different types of CG.