The role of epigenetic alterations in colon cancer

William M. Grady 한국당과학회 2011 한국당과학회 학술대회 Vol.2011 No.1

Colorectal cancer arises as the consequence of the accumulation of genetic alterations (e.g. gene mutations, gene amplification, etc.) and epigenetic alterations (e.g. aberrant DNA methylation, chromatin modifications, etc.) that transform colonic epithelial cells into colon adenocarcinoma cells. The loss of genomic and epigenomic stability and resulting gene alterations appears to be a key molecular and pathogenic step that occurs early in the tumorigenesis process and permits the acquisition of a sufficient number of alterations in tumor suppressor genes and oncogenes in a clone of cells to result in their ultimate transformation into cancer. It has also become clear that epigenetic alterations are common in many cancers and affect the formation and behavior of the tumors. With regards to DNA methylation, it is present normally throughout the majority of the genome and is maintained in relatively stable patterns that are established during development1. In humans, approximately 70% of CpG dinucleotides carry this epigenetic modification. However, there are regions that are enriched for CpG dinucleotides, called CpG islands, that are present in the 5’ region of approximately 50-60% of genes and are normally maintained in an unmethylated state. In cancers, many of these CpG islands become aberrantly methylated, and this aberrant methylation can be accompanied by transcriptional repression2,3. The significance of these epigenetic alterations in the pathogenesis of cancer has been a point of significant controversy4,5. Nonetheless, there is sufficient data to demonstrate that the aberrant methylation of at least some of these genes, such as MLH1, can be pathogenetic in cancer6-8. The aberrant methylation of MLH1 occurs in approximately 80% of sporadic MSI colorectal cancers, and the restoration of MLH1 expression and function by demethylating the MLH1 promoter in MSI colorectal cancer cell lines, strongly supports the idea that such aberrant methylation is a cause rather than a consequence of colorectal carcinogenesis6,7,9. Furthermore, the epigenetic inactivation of MLH1 appears to proceed the onset of mutations in genes with coding region microsatellite repeats, such as TGFBR2, suggesting epigenetic events can predispose tumor cells to mutations that drive the tumorigenesis process. Indeed, aberrantly methylated genes HLTF SLC5A8, MGMT, MINT1, and MINT31 can be found in aberrant crypt foci, demonstrating that aberrant promoter methylation occurs early in the adenoma sequence, although it does not confirm that the aberrant methylation is a primary rather than a secondary event in the tumorigenesis process10-12. The aberrant methylation of genes affects genes that are commonly targets of mutational inactivation in colon cancers and contributes to the deregulation of signaling pathways that are known to be important in these tumors13,14. Finally, a subset of colorectal cancers that hypermethylate genes belong to a distinct subclass of colorectal cancers, termed the CpG island methylator phenotype (CIMP) has been identified and appear to have a worse prognosis15-19. These aberrantly methylated genes have been shown to be early detection markers and prognostic markers for a variety of cancers14,20, and some methylated genes are already being used in clinically available assays in the United States21,22. The potential for methylated genes to be used as risk stratification markers, early detection markers, and predictive markers is high, and it is anticipated that they will move into common clinical use in the future. Finally, therapies directed at these genetic and epigenetic alterations are under active development and hold the promise to improve the treatment of colorectal cancer.

TGF-β inactivation and TGF-α overexpression cooperate in an in vivo mouse model to induce hepatocellular carcinoma that recapitulates molecular features of human liver cancer

Baek, Ji Yeon,Morris, Shelli M.,Campbell, Jean,Fausto, Nelson,Yeh, Matthew M.,Grady, William M. Wiley Subscription Services, Inc., A Wiley Company 2010 International journal of cancer: Journal internati Vol.127 No.5

<P>Hepatocellular carcinoma (HCC) results from the cumulative effects of deregulated tumor suppressor genes and oncogenes. The tumor suppressor and oncogenes commonly affected include growth factors, receptors and their downstream signaling pathway components. The overexpression of transforming growth factor alpha (TGF-α) and the inhibition of TGF-β signaling are especially common in human liver cancer. Thus, we assessed whether TGF-α overexpression and TGF-β signaling inactivation cooperate in hepatocarcinogenesis using an in vivo mouse model, MT1/TGFa;AlbCre/Tgfbr2<SUP>flx/flx</SUP> mice (“TGFa;Tgfbr2<SUP>hepko</SUP>”), which overexpresses TGF-α and lacks a TGF-β receptor in the liver. TGF-β signaling inactivation did not alter the frequency or number of cancers in mice with overexpression of TGF-α. However, the tumors in the TGFa;Tgfbr2<SUP>hepko</SUP> mice displayed increased proliferation and increased cdk2, cyclin E and cyclin A expression as well as decreased Cdkn1a/p21 expression compared to normal liver and compared to the cancers arising in the TGF-α overexpressing mice with intact TGF-β receptors. Increased phosphorylated ERK1/2 expression was also present in the tumors from the TGFa;Tgfbr2<SUP>hepko</SUP> mice and correlated with downregulated Raf kinase inhibitor protein expression, which is a common molecular event in human HCC. Thus, TGF-β signaling inactivation appears to cooperate with TGF-α in vivo to promote the formation of liver cancer that recapitulates molecular features of human HCC.</P>

Predicting Barrett's Esophagus in Families: An Esophagus Translational Research Network (BETRNet) Model Fitting Clinical Data to a Familial Paradigm

Sun, Xiangqing,Elston, Robert C.,Barnholtz-Sloan, Jill S.,Falk, Gary W.,Grady, William M.,Faulx, Ashley,Mittal, Sumeet K.,Canto, Marcia,Shaheen, Nicholas J.,Wang, Jean S.,Iyer, Prasad G.,Abrams, Julia American Association for Cancer Research 2016 Cancer Epidemiology, Biomarkers & Prevention Vol.25 No.5

<P><B>Background:</B> Barrett's esophagus is often asymptomatic and only a small portion of Barrett's esophagus patients are currently diagnosed and under surveillance. Therefore, it is important to develop risk prediction models to identify high-risk individuals with Barrett's esophagus. Familial aggregation of Barrett's esophagus and esophageal adenocarcinoma, and the increased risk of esophageal adenocarcinoma for individuals with a family history, raise the necessity of including genetic factors in the prediction model. Methods to determine risk prediction models using both risk covariates and ascertained family data are not well developed.</P><P><B>Methods:</B> We developed a Barrett's Esophagus Translational Research Network (BETRNet) risk prediction model from 787 singly ascertained Barrett's esophagus pedigrees and 92 multiplex Barrett's esophagus pedigrees, fitting a multivariate logistic model that incorporates family history and clinical risk factors. The eight risk factors, age, sex, education level, parental status, smoking, heartburn frequency, regurgitation frequency, and use of acid suppressant, were included in the model. The prediction accuracy was evaluated on the training dataset and an independent validation dataset of 643 multiplex Barrett's esophagus pedigrees.</P><P><B>Results:</B> Our results indicate family information helps to predict Barrett's esophagus risk, and predicting in families improves both prediction calibration and discrimination accuracy.</P><P><B>Conclusions:</B> Our model can predict Barrett's esophagus risk for anyone with family members known to have, or not have, had Barrett's esophagus. It can predict risk for unrelated individuals without knowing any relatives' information.</P><P><B>Impact:</B> Our prediction model will shed light on effectively identifying high-risk individuals for Barrett's esophagus screening and surveillance, consequently allowing intervention at an early stage, and reducing mortality from esophageal adenocarcinoma. <I>Cancer Epidemiol Biomarkers Prev; 25(5); 727–35. ©2016 AACR</I>.</P>

상부위장관 : 위암과 대장암에서 Ena/VASP-like Protein (EVL) 유전자 촉진자 과메틸화의 빈도와 의의

민병훈,김재준,권영주,김영호,이준행,장동경,손희정,이풍렬,이종철,( William M. Grady ) 대한소화기학회 2007 대한소화기학회 추계학술대회 Vol.2007 No.-