1Department of Gastroenterological Surgery, Graduate School of Medical Science, Kumamoto University, Kumamoto 860-8556, Japan.
2Department of Gastroenterological Surgery, Cancer Institute Hospital of Japanese Foundation for Cancer Research, Tokyo 135-8550, Japan.
Correspondence Address: Dr. Hideo Baba, Department of Gastroenterological Surgery, Graduate School of Medical Science, Kumamoto University, 1-1-1 Honjo, Kumamoto 860-8556, Japan. Email: firstname.lastname@example.org
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Epigenetic alterations, including DNA methylation, histone modification, loss of genome imprinting, chromatin remodeling and noncoding RNAs, are associated with human carcinogenesis. Among them, DNA methylation is a fundamental epigenetic process to modulate gene expression. In cancer cells, altered DNA methylation includes hypermethylation of site-specific CpG island promoter and global DNA hypomethylation. Detection of aberrant gene promoter methylation has been applied to clinic to stratify risk in cancer development, detect early cancer and predict clinical outcomes. Environmental factors associated with carcinogenesis are also significantly related to aberrant DNA methylation. Importantly, epigenetic changes, including altered DNA methylation, are reversible and thus, used as targets for cancer therapy or chemoprevention. An increasing number of recent studies reported DNA methylation level to be a useful biomarker for diagnosis, risk assessment and prognosis prediction for gastrointestinal cancers. This review summarized the accumulated evidence for clinical application to use aberrant DNA methylation levels in gastrointestinal cancers, including colorectal, gastric and esophageal cancer.
Colorectal cancer, DNA methylation, epigenetic alterations, esophageal cancer, gastric cancer
Epigenetics refers to heriTable changes in gene expression that, unlike mutations, are not attribuTable to alterations in genomic DNA sequences. Epigenetic changes, such as DNA methylation, histone modifications and altered expression of microRNAs, can regulate gene expression through mechanisms other than changes in genomic DNA sequence. Among them, genomic DNA methylation is a major epigenetic mechanism to mediate the X-chromosome inactivation, imprinting and repression of endogenous retroviruses.[1-4] DNA methylation is the covalent post-replicative addition of a methyl group (-CH3) to the 5-carbon of the cytosine ring in CpG dinucleotides. CpG dinucleotides are non-uniformly distributed throughout the human genome.[2-4] Regions of the genome that are rich in sequences of a cytosine preceding a guanine (CpG dinucleotide) are known as CpG islands, which in particular, exist in the promoter regions of approximately half of all coding genes.
Altered DNA methylation in human cancers includes hypermethylation of site-specific CpG island promoter and global DNA hypomethylation.[1-4] DNA methylation in gene promoter CpG islands results in its transcriptional inactivity and silence of protein expression. Thus, hypermethylation of a gene promoter is now recognized as a means of silencing tumor suppressor genes, with effects similar to those of mutation or allelic loss in development of cancer or other diseases. Another DNA methylation alteration in human cancer is genome-wide DNA hypomethylation. Genome-wide DNA hypomethylation appears to play an important role in genomic instability, leading to cancer development.[6-8] Previous experimental studies demonstrated that DNA hypomethylation of repetitive sequences, i.e. short interspersed transposable elements (SINE or Alu elements) or long interspersed transposable elements (LINEs), may predispose cells to chromosomal defects and rearrangements, resulting in genetic instability. As LINE-1 constitutes a substantial portion (approximately 17%) in the human genome, levels of LINE-1 methylation are regarded to be surrogate markers for global DNA methylation. Thus, epigenetic regulation of gene expression has emerged as a fundamental way in pathogenesis of numerous malignancies, including cancers of the digestive system. In fact, many exciting discoveries in epigenetics have emerged from study of gastrointestinal cancers. In this review, we summarized the accumulated evidence supporting the clinical application of DNA methylation level in diagnosis of esophageal, gastric and colorectal cancers.
Esophageal cancer can be classified into two histological types, esophageal squamous cell carcinoma (ESCC) and esophageal adenocarcinoma (EAC). Their incidences vary notably by geographic distribution. ESCC accounts for approximately 90% of esophageal cancers in east Asian countries,[10,11] whereas the highest number of EAC is found in Northern and Western Europe, North America and oceania. These two subtypes also have different epigenetic alterations. Growing evidence suggests that there is a field of epigenetic changes in esophageal cancer[13-15] by particularly emphasized significance of promoter hypermethylation of 14 specific genes (SFRP1, SFRP2, DCC, APC, p16, p14, APBA1, APBA2, APBA3, CACNA1G, PTGS2, DAPK1, MLH1 and MGMT) in noncancerous mucosae from ESCC patients vs. mucosae from healthy volunteers, indicating that aberrant methylation or these 14 gene promoters in esophageal mucosae is associated with ESCC development. An overview of different previous studies of clinical implications of DNA methylation in esophageal cancer is provided in [Table 1]. Aberrant promoter methylation of tumor suppressor genes has also been used to predict clinical outcomes following curative ESCC resections. For example, promoter methylation of APC has been associated with reduced survival of ESCC patients after esophagectomy. Ling et al. showed that MSH2 promoter hypermethylation in circulating tumor DNA was a valuable predictor of disease-free survival of ESCC patients after esophagectomy. Aberrant methylation of FHIT was also reported to associate with exposure to tobacco smoke and individuals with early-stage ESCC whose tumors exhibited FHIT hypermethylation had poor prognoses. CDH1 hypermethylation was detected in 14-61% of ESCC, which was associated with recurrence of early-stage ESCC. Moreover, aberrantly methylated gene promoters were also detected in plasma or sera of ESCC patients. Hibi et al. showed that p16 promoter methylation in ESCC specimens had this same methylation change in their serum DNA in 23% of patients, which implies that detection of serum DNA p16 promoter methylation could serve as a tumor marker. However, few studies have addressed or detected DNA hypomethylation in ESCC. LINE-1 methylation is regarded as a surrogate marker for global DNA methylation. To better understand DNA methylation in ESCC tissues, our group measured their LINE-1 methylation using the pyrosequencing technology. chronic tobacco smoking and heavy alcohol drinking are established as risk factors for ESCC development.[21-25]LINE-1 hypomethylation was significantly associated with tobacco smoking, which supports its plausibility as a surrogate marker for an epigenetic field defect. LINE-1 methylation is highly variable among ESCC specimens (25-92%) and its hypomethylation is strongly associated with poor ESCC prognosis. Moreover, loss of insulin-like growth factor 2 (IGF2) imprinting has been found in ESCC and loss of IGF2 methylation was associated with shorter survival of patients.
Association of gene promoter methylation with clinical outcomes of esophageal cancer patients
|Gene||Histological type||Correlation with clinical outcomes||Reference|
|APC||ESCC||Associated with poor prognosis|||
|CDH1||ESCC||Associated with poor prognosis|||
|p16||ESCC||Associated with poor prognosis, serum promoter methylation||[20,94]|
|Claudin-4||ESCC||Associated with poor prognosis|||
|FHIT||ESCC||Associated with poor prognosis and tobacco/alcohol consumption||[18,96]|
|Integrin α4||ESCC||Associated with poor prognosis|||
|MGMT||ESCC||Association with lymph node metastasis|||
|MSH2||ESCC||Associated with poor prognosis||[17,98]|
|AKAP12||Barrett/BAC||Progression prediction in Barrett’s esophagus|||
|CDH13||Barrett/BAC||Progression prediction in Barrett’s esophagus|||
|p16||Barrett/BAC||Progression prediction in Barrett’s esophagus||[31,99]|
|HPP1||Barrett/BAC||Progression prediction in Barrett’s esophagus||[31,99]|
|NELL1||Barrett/BAC||Progression prediction in Barrett’s esophagus|||
|RUNX3||Barrett/BAC||Progression prediction in Barrett’s esophagus||[31,99]|
|SST||Barrett/BAC||Progression prediction in Barrett’s esophagus|||
|TAC1||Barrett/BAC||Progression prediction in Barrett’s esophagus|||
|IGF2||ESCC||Associated with poor prognosis|||
|LINE-1||ESCC||Associated with poor prognosis and tobacco consumption||[26,27]|
In EAC, methylation patterns of promoter CpG islands in several genes, such as tumor suppressor genes (APC, TIMP3, SFRP1, SFRP2, WIF1, AKAP12, RUNX3, SOCS1 and SOCS3) and DNA repair genes (MGMT), have been reported previously. In Barrett’s esophagus, a pre-malignant condition that can lead to EAC development, aberrant DNA methylation has also been shown to occur in promoters of tumor suppressor genes, adhesion molecules, and DNA repair genes (AKAP12, APC, CDH13, DAPK1, GPX, GST, MGMT, NELL1, REPRIMO/RPRM, p16, SFRP, SOCS, SST, TAC1, TIMP3 and WIF1). Jin et al. reported that promoter hypermethylation of eight genes (p16, RUNX3, HPP1, NELL1, TAC1, SST, AKAP12 and CDH13) could predict neoplastic progression risk in Barrett’s esophagus. However, in study of DNA hypomethylation in Barrett’s esophageal adenocarcinoma (BAC), Alvarez et al. reported a predominance of DNA hypo-methylation rather than DNA hyper-methylation in early-stage BAC carcinogenesis. They also detected DNA hypo-methylation in a series of genes associated with the immune system, such as chemokines (CXCL1 and CXCL3).
Gastric cancer is the fourth most frequently diagnosed cancer and the second leading cause of cancer-related deaths in the world. Gastric adenocarcinoma accounts for 90-95% of gastric cancer and has two histological subtypes (intestinal and diffuse) based on microscopic observation and tumor growth patterns, which differ widely in molecular pathogeneses. Nonetheless, epigenetic alterations play important roles in development of both gastric carcinoma types. Gene promoter methylation has been reported to associate with gastric cancer development, such as CDKN2A, CDK2AP2, CDH1, MGMT, RASSF1, RUNX3, DLC1, ITGA4, ZIC1, PRDM5, PCDH10, TFPI2, RUNX3, SPINT2, BTG4, SFRP2, hMLH1, DKK-3, TCF4, GRIK2, RAR, CHFR, BNIP3, RASSF1A, LRP1B and SFRP5), promoter of which was more frequently methylated in gastric cancer tissues than those of the corresponding normal gastric tissue.[35,36] Furthermore, promoter methylation of many genes with different biological functions has been associated with the clinicopathological characteristics and prognosis of gastric cancer [Table 2]. Of these genes, promoter hypermethylation of CDH1 and MGMT[39,40] was associated with worse outcomes of gastric cancer patients after surgery. However, patients with hypermethylated IGF2 in blood leukocyte DNA reportedly had a significantly better survival rate than those with hypomethylated IGF2. Additionally, DNA methylation of detected in body fluids that can be obtained non-invasively, such as serum and gastric washes, may have a clinical application for gastric cancer; for example, detection of aberrant DNA methylation of CDH1, DAPK, GSTP1, p15, p16, RARβ, RASSF1A, RUNX3 and TFPI2 in serum may be a useful biomarker for gastric cancer.
Association of gene promoter methylation with clinical outcomes of gastric cancer
|Gene||Correlation with clinical outcomes||References|
|BNIP3||Association with poor prognosis||[100,101]|
|CACNA2D3||Correlation with lymph node metastasis|||
|CDH1||Association with poor prognosis, H. pylori infection, and EBV infection||[38,46,49-51]|
|DAPK||Correlation with cell differentiation, lymph node metastasis||[100,103]|
|FLNc||Association with poor prognosis|||
|GPX3||Correlation with lymph node metastasis||[105,106]|
|HAI-2/SPINT2||Correlation with cell differentiation, lymph node metastasis|||
|HoxD10||Association with poor prognosis|||
|LOX||Association with poor prognosis and H. pylori infection|||
|MGMT||Association with poor prognosis||[103,104,109]|
|MLH1||Association with poor prognosis|||
|p15||Association with EBV infection||[49-51]|
|p16||Association with poor prognosis, H. pylori infection and EBV infection||[38,46,49-51,102,104]|
|p73||Association with EBV infection|||
|PAX6||Association with poor prognosis|||
|RASSF1A||Association with poor prognosis||[100,103]|
|RASSF2||Association with poor prognosis|||
|RUNX3||Correlation with TNM stage and H. pylori infection||[110,111]|
|LINE-1||Association with poor prognosis and H. pylori infection||[55,56]|
|SURF||Association with poor prognosis|||
Environmental factors also significantly affect DNA methylation. Etiological studies have closely associated two distinct infectious agents, Helicobacter pylori (H. pylori) and epstein-barr virus (EBV), with gastric carcinogenesis.[43,44] Previous prospective studies showed that H. pylori infection had an essential role in gastric carcinogenesis, and the mechanisms the underlie gastric carcinogenesis due to H. pylori-induced DNA methylation have been indicated. H. pylori infection induced aberrant promoter methylation in tumor-suppressor genes, such as RUNX3, p16, LOX and CDH1.[45,46] Furthermore, IL-1β is thought to be especially significant as a specific single-nucleotide polymorphism of IL-1β in association with increases in both gastric cancer risk and incidence.[47,48] EBV infection occurs at a very early-stage in cancer development and plays an important role in gastric carcinogenesis. Aberrant methylation of tumor suppressor genes, such as CDH1, p15, p16 and p73, are frequently observed in EBV-associated gastric cancer, but are less frequently detected in adjacent non-neoplastic mucosa,[49-52] which suggests that aberrant methylation is a critical mechanism of EBV-related gastric tumorigenesis. Regarding the molecular mechanisms underlying host DNA methylation during early-stage EBV infection in gastric epithelium, LMP2A expression was up regulated through STAT3 phosphorylation, which further induces DNA methyltransferases during EBV infection.
However, few studies addressed or detected DNA hypomethylationin gastric cancer. In gastric cancer, global genomic hypomethylation has been found in premalignant stages of disease. In our previous study that assessed 203 resected gastric cancer specimens, we found gastric cancer tissues had significantly lower LINE-1 methylation levels than that of their matched normal gastric mucosa. LINE-1 hypomethylation in gastric cancer was also associated with shorter survival of patients. Moreover, LINE-1 hypomethylation of noncancerous gastric mucosae in gastric cancer patients significantly correlated with H. pylori infection. Hur et al. reported that gastric cancer tissues had conspicuously higher expression of SULF1 regulated by promoter hypomethylation than that of the normal mucosa. SULF1 is also an independent prognostic factor and LN is a metastasis predictive factor in gastric cancer patients.
Aberrant DNA methylation was reported as an important hallmark of colorectal cancer. Colorectal cancer is a heterogeneous disease and molecularly, it can be classified into three major molecular subtypes, i.e. microsatellite instability (MSI), chromosomal instability, and CpG island methylator phenotype (CIMP). In 1999, Baylin, Issa and others coined the term the “CpG island methylator phenotype,” or CIMP, in which promoter of tumor suppressor genes was methylated to contribute to tumorigenesis-at least in theory-through progressive genetic silence, possibly even in the absence of any genetic mutations. According to epigenetic and clinical profiles, primary colorectal cancer is divided into three distinct subclasses, i.e. CIMP1, CIMP2 and CIMP-negative. CIMP1 tumor often shows mutations of MSI (80%) and BRAF (53%), while CIMP2 tumor often shows K-RAS mutation (92%), but rarely shows microsatellite instability or BRAF or TP53 mutations. Non-CIMP tumor has a high frequency of TP53 mutations (71%). CIMP1 has a favorable prognosis, whereas CIMP2 is associated with poor prognosis. Cancer CIMP status has been assessed as a predictive marker for 5-FU responsiveness.
Colorectal cancer with CIMP is distinct from those with chromosomal instability and there are two forms of nuclear derangement represented alternative pathways for colorectal cancer development,[62,63] which overlap somewhat as hypermethylation can occur in APC and is part of the chromosomal instability pathway, or in the MLH1 gene, triggering MSI.MLH1 accounts for approximately 40% of cases of the hereditary colorectal cancer, Lynch syndrome. Detectionof MLH1 methylation is currently used to discriminate between sporadic colorectal cancer with MSI and familial forms (Lynch syndrome). Methylation of MGMT promoter also occurs during colorectal cancer progression in either pathway and may facilitate the accumulation of point mutations as tumors evolve.
The CpG island methylation affects a number of genes in colon cancer and significance of these epigenetic alterations in colon cancer pathogenesis has been widely reported.[68,69] Hundreds of gene promoters have been found to be aberrantly methylated in the average colorectal cancer genome and their number is ever-growing, including genes of the Wnt signaling pathway such as APC, AXIN2, DKK1, SFRP1, SFRP2 and WNT5A, the DNA repair genes MGMT, hMLH1 and hMLH2, cell cycle-related genes such as p14, p15 and p16, RAS signaling genes RASSF1A and RASSF1B, and many more.[70,71]
Several DNA methylation markers have been proposed as useful early biomarkers for colorectal cancer early detection and prediction of prognosis. For instance, methylation of MLH1 can be detected in colorectal cancer issue samples or blood to help interpret MSI because its presence helps to exclude diagnosis of Lynch syndrome. The presence of aberrantly methylated SEPT9 (which encodes a GTPase that is involved in dysfunctional cytoskeletal organization) in plasma is a valuable and minimally invasive blood-based PCR test with a sensitivity of almost 70% and a specificity of 90% in colorectal cancer detection.[74-78] In fact, an assay that detects hypermethylated SEPT9 is now being commercialized and offered in some parts of Europe to screen colorectal cancer. Moreover, detection of aberrant methylation of vimentin in fecal DNA was reported in colorectal cancer when compared with normal control; the sensitivity and specificity of methylated vimentin for colorectal cancer were 88% and 87%, respectively. Kamimae et al. have recently shown that detection of DNA methylation in mucosal wash fluid from patients undergoing colonoscopy may be a good molecular marker for predicting invasiveness of colorectal tumors.
Promoter hypermethylation of MLH1, MGMT and HIC1 can be detrimental and lead to cancer progression.[82-85] Seven additional genes (TIMP3, CXCL12, ID4, IRF8, CHFR, IGFBP3 and CD109) were frequently methylated in late-stage colorectal cancer and could have a role in colorectal cancer progression and metastasis.[71,86,87] Yi et al. observed that colorectal cancers that have silenced (methylated) genes in the extracellular matrix-remodeling pathway, such as IGFBP3, EVL, CD109 and FLNC, showed worse survival, suggesting that methylation of this pathway-related genes might represent a prognostic signature for colorectal cancer patients. Moreover, hypomethylation of the IGF2 differentially methylated region in colorectal tumors was associated with poor prognosis. However, all of these possible markers need to be further validated before they are used clinically.
Global hypomethylation may influence tumor progression by making chromosomes more susceptible to breakage and causing disruption of normal gene structure and function, leading to reactivating previously silenced retrotransposons.[89-91] Most recent research on LINE-1 methylation levels in gastrointestinal cancers has focused on colorectal cancer; Ogino et al. reported LINE-1 methylation levels widely occurred and approximately normally distributed (range 23.1-90.3%) in a cohort of 869 colorectal cancer patients.LINE-1 hypomethylation was inversely associated to the MSI and CIMP;[92,93] these findings suggest that CIMP/MSI and genomic hypomethylation represent different pathways to colorectal cancer development. A summary of reported gene methylation in stool, blood and tissue samples of patients with colorectal cancer is shown in Table 3 and 4.
Association of gene promoter methylation with diagnosis of colorectal cancer
|Gene||Specimen type||Correlation with clinical outcomes||References|
|AGTR1||Stool||Diagnosis of CRC|||
|ALX4||Blood||Diagnosis of colorectal adenomas and cancers|||
|APC||Blood||Diagnosis of CRC|||
|BMP3||Stool||Diagnosis of colorectal adenomas and cancers|||
|BMP3||Tissue||Diagnosis of colorectal adenomas and cancers|||
|CNIP1||Stool||Diagnosis of CRC|||
|DAPK||Blood||Diagnosis of CRC|||
|FBN1||Stool||Diagnosis of CRC|||
|GATA-5||Stool||Diagnosis of CRC|||
|IGFBP7||Cells||Diagnosis of CRC|||
|INA||Stool||Diagnosis of CRC|||
|MAL||Stool||Diagnosis of CRC|||
|MGMT||Blood||Diagnosis of CRC|||
|MLH1||Blood, cells||Diagnosis of sporadic MSI CRC|||
|NDRG4||Stool||Diagnosis of CRC|||
|NDRG4||Stool||Diagnosis of colorectal adenomas and cancers|||
|NEUROG1||Blood||Diagnosis of CRC|||
|NGFR||Blood||Diagnosis of CRC|||
|p16||Blood||Diagnosis of CRC|||
|RASSF2||Stool||Diagnosis of CRC, distinction from gastric cancer|||
|RASSF2A||Blood||Diagnosis of CRC|||
|RUNX3||Blood||Diagnosis of CRC|||
|SDC2||Blood||Diagnosis of CRC|||
|SEPT9||Blood||Diagnosis of CRC||[74,75]|
|SFRP2||Stool, blood, tissue||Diagnosis of CRC, distinction from gastric cancer|||
|SLIT2||Stool||Diagnosis of CRC|||
|SNCA||Stool||Diagnosis of CRC|||
|SPG20||Stool||Diagnosis of CRC|||
|TFPI2||Stool||Diagnosis of colorectal adenomas and cancers|||
|TMEFF2||Blood||Diagnosis of CRC|||
|Vimentin||Stool, blood||Diagnosis of colorectal adenomas and cancers|||
|WIF1||Blood||Diagnosis of CRC|||
|WNT1||Stool||Diagnosis of CRC|||
Association of gene promoter methylation with prognosis of colorectal cancer
|Gene||Specimen type||Correlation with clinical outcomes||References|
|APC||Tissue||Associated with poor prognosis|||
|CD109||Tissue||Associated with poor prognosis|||
|EVL||Tissue||Associated with poor prognosis|||
|FLNC||Tissue||Associated with poor prognosis|||
|HLTF||Blood||Associated with poor prognosis|||
|HOPX-β||Tissue||Worse prognosis of stage III CRC|||
|HPP1||Blood||Associated with poor prognosis|||
|IGFBP3||Tissue||Associated with poor prognosis|||
|MLH1||Blood||Associated with favorable prognosis|||
|p16||Tissue||Associated with poor prognosis|||
|RASSF2A||Tissue||Associated with poor prognosis|||
|TFPI2||Blood||Associated with poor prognosis|||
|IGF2||Tissue||Associated with prognosis|||
|LINE-1||Tissue||Associated with worse OS|||
In this review, we have summarized the main epigenetic alterations in gastrointestinal cancer-global DNA hypomethylation and site-specific CpG island promoter hypermethylation-with clinical characteristics in patients with gastrointestinal cancers. Epigenetic signatures have a potential usefulness in early diagnosis, screening, monitoring and prediction of prognoses or therapy responses for gastrointestinal cancer patients. Further investigation in this field would increase our knowledge of epigenetic alterations of GI cancer and help to develop novel therapeutic strategies for gastrointestinal cancers.
There are no conﬂicts of interest.
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