Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0596263 (carcinogenesis)
 64,820 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Gastric cancer is one of the most common malignancies. DNA methylation is implicated in DNA mismatch repair genes deficiency. In the present study, we evaluated the methylation status of MLH1, MSH2, MSH6 and PMS2 in 20 diffuse- and 26 intestinal-type gastric cancer samples and 20 normal gastric mucosal of gastric cancer patients from Northern Brazil. We found that none of the nonneoplastic samples showed methylation of any gene promoter and 50% of gastric cancer samples showed at least one methylated gene promoter. Methylation frequencies of MLH1, MSH2, MSH6 and PMS2 promoter were 21.74%, 17.39%, 0% and 28.26% respectively in gastric cancer samples. MLH1 and PMS2 methylation were associated with neoplastic samples compared to nonneoplastic ones. PMS2 methylation was associated with diffuse- and intestinal-type cancer compared with normal controls. Intestinal-type cancer showed significant association with MLH1 methylation. Diffuse-type cancer was significantly associated with MSH2 methylation. Our findings show differential gene methylation in tumoral tissue, which allows us to conclude that methylation is associated with gastric carcinogenesis. Methylation of mismatch repair genes was associated with gastric carcinogenesis and may be a helpful tool for diagnosis, prognosis and therapies. However, MSH6 does not seem to be regulated by methylation in our samples.
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PMID:DNA mismatch repair gene methylation in gastric cancer in individuals from northern Brazil. 1918 Nov 86

The prevalence and development of microsatellite instability (MSI) and underlying mismatch repair (MMR) deficiency in the carcinogenesis of adenocarcinomas of the papilla of Vater and their precursor lesions are not well established. We analyzed 120 ampullary adenomas (31 pure adenomas and 89 carcinoma-associated adenomas) and 170 pure adenocarcinomas for MSI, immunohistochemical expression of MMR proteins and specific histopathologic features. The most common histologic subtype was intestinal (46.5%), followed by pancreatobiliary (23.5%), poorly differentiated adenocarcinomas (12.9%), intestinal-mucinous (8.2%), and invasive papillary carcinomas (5.3%). Eight of 89 adenomas (9%) and 15/144 carcinomas (10%) showed high microsatellite instability (MSI-H), 10/89 adenomas (11%) and 5/144 carcinomas (4%) showed low microsatellite instability (MSI-L), and 71/89 adenomas (80%) and 124/144 carcinomas (86%) were microsatellite stable (MSS). MSI analysis from carcinomas contiguous with an adenomatous component (n=54) exhibited concordant results in 6/8 (75%) MSI-H and 42/46 (91.3%) MSS tumors. Of 14 carcinomas with MSI-H, 7 showed loss of MLH1 and 5/6 (83%) MLH1 promoter methylation, and 2 carcinomas showed simultaneous loss of MSH2 and MSH6. Two carcinomas and 3 adenomas with MSI-H revealed exclusive loss of MSH6. MSI-H cancers were significantly associated with intestinal mucinous subtype (P<0.001), high tumor grade (P=0.003), expansive growth pattern (P=0.044), and marked lymphoid host response (P=0.004). Patients with MSI-H carcinoma had a significantly longer overall survival (P=0.0082) than those with MSI-L or MSS tumors. Our findings indicate that the MSI-phenotype is an early event, which develops at the stage of adenoma and is reliably detectable in the precursor lesion. The MMR deficient molecular pathway of carcinogenesis is associated with a histopathologic phenotype in ampullary cancer, similar to the one that has been well described in colon cancer.
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PMID:Histopathologic features and microsatellite instability of cancers of the papilla of vater and their precursor lesions. 1925 34

We hypothesized that in a comprehensive analysis of colorectal carcinomas (CRC) the three currently known major molecular mechanisms of carcinogenesis (i.e., chromosomal instability, microsatellite instability, and CpG island methylator phenotype, CIMP) would associate with the molecular features indicative of these pathways, allowing a molecular classification. A prospectively collected clinicopathologically well-characterized series of 130 CRCs was tested for chromosomal instability (DNA-flow cytometry and analysis of allelic imbalance with microsatellite markers 5q21, 8p21, 9q21, 17p13, and 18q21), microsatellite instability (Bethesda panel), CIMP (MethyLight), and mutations of K-ras, B-raf, APC, and p53. Morphology was reviewed, and nuclear beta-catenin translocation was assessed by immunohistochemistry. Based on the molecular features, sporadic high-degree microsatellite instable tumours, tumours of the hereditary non-polyposis coli carcinoma syndrome, and 'sporadic standard-type' CRC could be delineated (14, 4, and 55, respectively). However, overlap between classes was seen for 46 of the remaining tumours where widespread or occasional methylations (excluding MLH1) were observed, and the majority had chromosomal instability. Importantly, a group of 11 tumours was observed without either microsatellite or chromosomal instability, nor any methylation. Morphologically, these tumours were without any distinguishing features, all had tumour budding and 10 showed nuclear beta-catenin translocation. Overall, the data give an overview of the molecular classes in CRC that should be taken into account in studies on carcinogenesis and clinicopathological studies. Specifically, the absence of CIN, MSI, and CIMP in an 8.46% fraction of tumours delineates a group to be aware of.
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PMID:Chromosomally and microsatellite stable colorectal carcinomas without the CpG island methylator phenotype in a molecular classification. 1957 46

Hexavalent chromium [Cr(VI)] is a well-recognized human lung carcinogen. In order to gain further insight into Cr(VI)-induced carcinogenesis, we have established an adequate in vitro cellular model for the study of this process. To this end, BEAS-2B cells were used. Chronic exposure of cells to 1 microM Cr(VI) induced changes in the cells' ploidy and a decrease in cloning efficiency, although cultures continued to progress to confluence. After prolonged exposure (12 passages), the culture became heterogeneous, exhibiting areas where apparently normal epithelial cells and morphologically altered cells coexisted. Subsequent culture at a very low density strongly accentuated the Cr(VI)-induced changes in morphology and pattern of growth. Three individual colonies were then ring-cloned and expanded into three subclonal aneuploid cell lines. These subclonal cell lines showed changes in growth pattern and morphology, as well as a karyotype drift concomitant with the overexpression of genes commonly involved in malignant transformation (c-MYC, EGFR, HIF-1alpha and LDH-A). Moreover, when one of these cell lines (RenG2) was injected into nude mice, it showed the ability to induce tumors. This cell line revealed no microsatellite instability (MSI), which points to the expression of a functional MLH1 protein and an active mismatch repair (MMR) system. Therefore, the progression to malignancy of the BEAS-2B cells involved Cr(VI)-induced transformants that retained the ability to repair DNA damage, suggesting that genotoxicity underlies the ongoing carcinogenic process.
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PMID:Human bronchial epithelial cells malignantly transformed by hexavalent chromium exhibit an aneuploid phenotype but no microsatellite instability. 1961 15

More than one million patients will manifest colorectal cancer (CRC) this year of which, conservatively, approximately 3% (approximately 30,700 cases) will have Lynch syndrome (LS), the most common hereditary CRC predisposing syndrome. Each case belongs to a family with clinical needs that require genetic counseling, DNA testing for mismatch repair genes (most frequently MLH1 or MSH2) and screening for CRC. Colonoscopy is mandated, given CRC's proximal occurrence (70-80% proximal to the splenic flexure). Due to its early age of onset (average 45 years of age), colonoscopy needs to start by age 25, and because of its accelerated carcinogenesis, it should be repeated every 1 to 2 years through age 40 and then annually thereafter. Should CRC occur, subtotal colectomy may be necessary, given the marked frequency of synchronous and metachronous CRC. Because 40-60% of female patients will manifest endometrial cancer, tailored management is essential. Additional extracolonic cancers include ovary, stomach, small bowel, pancreas, hepatobiliary tract, upper uroepithelial tract, brain (Turcot variant) and sebaceous adenomas/carcinomas (Muir-Torre variant). LS explains only 10-25% of familial CRC.
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PMID:Review of the Lynch syndrome: history, molecular genetics, screening, differential diagnosis, and medicolegal ramifications. 1965 56

Epigenetic changes have been proposed as mediators of the field defect in colorectal carcinogenesis, which has implications for risk assessment and cancer prevention. As a test of this hypothesis, we evaluated the methylation status of eight genes (MINT1, 2, 31, MLH1, p16, p14, MGMT, and ESR1), as well as BRAF and KRAS mutations, in 57 multiple colorectal neoplasias (M-CRN) and compared these to 69 solitary colorectal cancers (S-CRC). There were no significant differences in methylation between M-CRNs and S-CRCs except for p14 and MGMT that was significantly higher in M-CRNs than S-CRCs (16.1% versus 9.3%; 26.5% versus 17.3%, respectively; P < 0.05). We found significant (P < 0.05) correlations for MINT1 (r = 0.8), p16 (r = 0.8), MLH1 (r = 0.9), and MGMT (r = 0.6) methylation between tumors pairs of the same site (proximal/proximal and distal/distal). KRAS showed no concordance in mutations. BRAF mutation showed concordance in proximal site pairs but was discordant in different site pairs. Histologically, eight of 10 paired cancers with similar locations were concordant for a cribriform glandular configuration. We conclude that synchronous colorectal tumors of the same site are highly concordant for methylation of multiple genes, BRAF mutations, and a cribriform glandular configuration, all consistent with a patient-specific predisposition to particular subtypes of colorectal cancers. Screening for and secondary prevention of colon cancer should take this fact into account.
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PMID:Concordant DNA methylation in synchronous colorectal carcinomas. 1973 82

Aberrant DNA methylation affects carcinogenesis of colorectal cancer. Folate metabolizing enzymes may influence the bioavailability of methyl groups, whereas DNA and histone methyltransferases are involved in epigenetic regulation of gene expression. We studied associations of genetic variants of folate metabolizing enzymes (MTHFR, MTR, and MTRR), DNA methyltransferase DNMT3b, and histone methyltransferases (EHMT1, EHMT2, and PRDM2), with colorectal cancers, with or without the CpG island methylator phenotype (CIMP), MLH1 hypermethylation, or microsatellite instability. Incidence rate ratios were calculated in case-cohort analyses, with common homozygotes as reference, among 659 cases and 1,736 subcohort members of the Netherlands Cohort Study on diet and cancer (n = 120,852). Men with the MTHFR 677TT genotype were at decreased colorectal cancer risk (incidence rate ratio, 0.49; P = 0.01), but the T allele was associated with increased risk in women (incidence rate ratio, 1.39; P = 0.02). The MTR 2756GG genotype was associated with increased colorectal cancer risk (incidence rate ratio, 1.58; P = 0.04), and inverse associations were observed among women carrying DNMT3b C-->T (rs406193; incidence rate ratio, 0.72; P = 0.04) or EHMT2 G-->A (rs535586; incidence rate ratio, 0.76; P = 0.05) polymorphisms. Although significantly correlated (P < 0.001), only 41.5% and 33.3% of CIMP tumors harbored MLH1 hypermethylation or microsatellite instability, respectively. We observed inverse associations between MTR A2756G and CIMP among men (incidence rate ratio, 0.58; P = 0.04), and between MTRR A66G and MLH1 hypermethylation among women (incidence rate ratio, 0.55; P = 0.02). In conclusion, MTHFR, MTR, DNMT3b, and EHMT2 polymorphisms are associated with colorectal cancer, and rare variants of MTR and MTRR may reduce promoter hypermethylation. The incomplete overlap between CIMP, MLH1 hypermethylation, and microsatellite instability indicates that these related "methylation phenotypes" may not be similar and should be investigated separately.
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PMID:Genetic variants of methyl metabolizing enzymes and epigenetic regulators: associations with promoter CpG island hypermethylation in colorectal cancer. 1984 71

Microsatellite unstable cancers account for up to 15% of sporadic colon cancers and are predominantly located in the proximal colon. These cancers commonly show MLH1 promoter methylation and the CpG island methylator phenotype (CIMP). A potential precursor of sporadic unstable cancers, the proximal hyperplastic polyp, is also reported to have CIMP and MLH1 methylation. However, this latter finding is not supported by MLH1 protein expression studies. To help resolve this apparent discrepancy, we determined MLH1 promoter methylation and CIMP by quantitative real-time PCR for 29 proximal hyperplastic polyps, 23 distal hyperplastic polyps, and 11 sporadic microsatellite unstable colon cancers. BRAF V600E mutation status was also determined. Positive methylation was defined as the percentage of methylated reference (PMR) >10. Only 1 of 29 proximal hyperplastic polyps showed positive MLH1 methylation (PMR of 13.0). Neither this polyp nor seven other proximal polyps with PMR values between 0 and 10 showed loss of MLH1 protein expression by immunohistochemistry. In contrast, all 11 microsatellite unstable cancers showed high degrees of MLH1 methylation, with PMR values >30. Fourteen of twenty-nine (48%) of the proximal hyperplastic polyps and 1 of 23 (4%) of the distal hyperplastic polyps showed CIMP (P<0.001). Of the unstable cancers, 10 of 11 showed CIMP. The PMR values in the CIMP-positive proximal hyperplastic polyps were significantly lower than those of the unstable cancers for 4 of the 5 CIMP markers (P<0.05). BRAF V600E mutations were seen in 83% of proximal and 74% of distal hyperplastic polyps. Quantitative analysis of MLH1 methylation does not support earlier reports of MLH1 methylation in proximal hyperplastic polyps. However, these lesions do harbor promoter methylation at other CIMP loci, although at a lower level than that seen in unstable cancers. If these polyps are the precursor for sporadic microsatellite unstable cancers, then MLH1 methylation and higher degrees of promoter methylation in general occur at a later stage of carcinogenesis.
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PMID:Quantitative evaluation of CpG island methylation in hyperplastic polyps. 1985 73

Squamous cell carcinomas of head and neck (HNSCC) are a result of multiple genetic and epigenetic alterations. Epigenetic inactivation of tumor suppressor genes is an important event in head and neck carcinogenesis. Here we analyzed the promoter methylation of 15 genes (RASSF1A, p16, MGMT, DAPK, RARbeta, MLH1, CDH1, GSTP1, RASSF2, RASSF4, RASSF5, MST1, MST2, LATS1, LATS2) in 54 HNSCC and in matching 23 normal tissues. Methylation of these tumor-related genes (TRG) was significantly more frequent in HNSCC (42%) compared to normal samples (23%; p<0.05). Particularly, methylation of p16 (60%), MGMT (53%), DAPK (67%), RARbeta (75%), MLH1 (69%), CDH1 (43%), RASSF5 and MST1 (96%) was often found in HNSCC. Methylation of RASSF1A (18%), GSTP1 (4%), RASSF4 (13%), MST2 (4%), LATS1 (24%) and LATS2 (8%) was less frequently detected. A trend of increased TRG methylation in more advanced tumor stages and less differentiated HNSCC was observed. Methylation of p16 was significantly higher in poorly differentiated HNSCC (p=0.037) and RASSF5 methylation occurred preferentially in advanced tumor stages (p<0.05). Methylation of RASSF4 was higher in patients with recurrent HNSCC (23%) than patients without relapse (0%; p=0.033). Methylation of TRG in head and neck cancer cell lines was observed at similar frequency as in primary HNSCC. In summary, frequent hyper-methylation of tumor-related genes in HNSCC was detected and this epigenetic silencing event may have an essential role in head and neck carcinogenesis.
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PMID:Frequent promoter hypermethylation of tumor-related genes in head and neck squamous cell carcinoma. 1988 8

To understand the importance of frequent deletion of 3p22.3 in cervical carcinogenesis, alterations (deletion/methylation/expression) of the candidate genes STAC, MLH1, ITGA9, and RBSP3, located in the region, were analyzed in 24 cervical intraepithelial neoplasia (CIN) and 137 uterine cervical carcinoma (CACX) samples. In CIN, RBSP3 deletion (48%) and methylation (26%) were high compared with the other genes (4-9%). In CACX, alterations of these genes were as follows: deletion: STAC (54%) > MLH1 (46%) > RBSP3 (45%) > ITGA9 (41%), methylation: RBSP3 (25%) > ITGA9 (24%) > STAC (19%) > MLH1 (13%). Overall, alterations of RBSP3 showed association with CIN, whereas for STAC and MLH1, this frequency increased significantly from CIN --> Stage I/II and for ITGA9 from CIN --> Stage I/II and also from Stage I/II --> Stage III/IV. Quantitative mRNA expression analysis showed differential reduced expression of these genes in CACX concordant to their molecular alterations. The more active RBSP3B splice variant was underexpressed in CACX. RB1 was infrequently deleted in CACX. Concordance was seen between (i) inactivation of RBSP3 and intense p-RB1 nuclear immunostaining and (ii) low/absence of MLH1 expression and its molecular alterations in CACX. In normal cervical epithelium, p-RB1 immunostaining was low in differentiated cells, whereas MLH1 staining was seen in both nucleus and cytoplasm irrespective of differentiation stage. Alterations of the genes were significantly associated with poor prognosis. High parity (>or=5)/early sexual debut (<or=19 years) coupled with RBSP3 alterations/RB1 deletion predicted worst prognosis. Thus, inactivation of RBSP3 might be one of the early events in cervical carcinogenesis.
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PMID:RBSP3 is frequently altered in premalignant cervical lesions: clinical and prognostic significance. 1988 27


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