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Query: UMLS:C0596263 (carcinogenesis)
 64,820 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Herein, we describe the clinical, pathologic, immunohistochemical, and molecular features of 3 unique patients with long standing inflammatory bowel disease, all of whom developed numerous discrete hyperplastic/serrated colonic polyps similar to those described in the hyperplastic/serrated polyposis syndrome. The 3 patients (2 with ulcerative colitis and 1 with Crohn ileo-colitis) were evaluated for a variety of clinical, histologic (including the type, location and number of polyps in the colon), and immunohistochemical features [MLH-1, MSH-2, MGMT (O(6)-methylguanine-DNA methyltransferase), beta-catenin, and p53]. KRAS and BRAF mutation analysis was also performed on a subset of polyps from 2 patients. All patients had moderate-severe pancolitis of more than 10 years duration and had >20 colonic polyps. None had polyps in the upper gastrointestinal tract. Pathologically, a combination of conventional hyperplastic polyps and sessile serrated polyps (adenomas) were present in the 3 cases. In addition, serrated adenomas were present in 2 and conventional adenomas in 1. Two patients also had synchronous adenocarcinoma. All 3 cases showed retention of MLH-1 and MSH-2, and a membranous beta-catenin staining pattern. However, 2 cases showed loss of MGMT in several serrated polyps, and one also in adjacent colitic mucosa. KRAS mutations were detected in 5/11 serrated polyps. However, BRAF mutations were not present in any of the polyps tested. These findings suggest the possibility of a serrated pathway of carcinogenesis in inflammatory bowel disease characterized by silencing of MGMT, most likely by gene promoter methylation, KRAS mutations, and possibly other, as yet, uncharacterized molecular alterations, resulting eventually in progression to adenocarcinoma.
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PMID:Hyperplastic/serrated polyposis in inflammatory bowel disease: a case series of a previously undescribed entity. 1822 33

The pulmonary adenoma susceptibility 1 (Pas1) gene affects susceptibility to the development of lung adenomas in mice with a subset of the adenomas progressing to adenocarcinoma (ADC). In this study, genotype distributions for 10 polymorphisms in the human counterparts for three mouse candidate Pas1 genes, KRAS, CASC1/LAS1 and LRMP, were examined in a hospital-based case-control study consisting of 364 lung ADC cases and 253 controls. All the ADC cases were subjected to lobectomy and subsequent pathological investigation of atypical adenomatous hyperplasia (AAH), a putative precursor for peripheral lung ADC, including bronchioloalveolar carcinoma, in the resected lobes. Eighty-one (22%) of the ADC cases carried at least one AAH lesion in addition to the primary ADC and 34 (9%) of them carried multiple AAH lesions. None of the 10 polymorphisms examined showed significant associations with overall lung ADC risk (P > 0.05). However, minor allele carriers for two polymorphisms in the KRAS gene, KRAS-1 and -6, showed significantly increased odds ratios (ORs) for ADC accompanied by multiple AAHs [OR = 3.0; 95% confidence interval (CI) = 1.4-6.2, P = 0.004 and OR = 2.4; 95% CI = 1.1-4.7, P = 0.02, respectively]. Minor haplotypes including the minor allele for the KRAS-6 polymorphism showed increased ORs for ADC accompanied by multiple AAHs, and KRAS transcripts from the minor allele for this polymorphism were more abundantly detected in lung tissues than those from the major allele. Thus, KRAS polymorphisms were indicated to be involved in risk for the development of AAHs that progress to ADC by causing differential KRAS oncogene expression in the lungs.
Carcinogenesis 2008 May
PMID:Association of KRAS polymorphisms with risk for lung adenocarcinoma accompanied by atypical adenomatous hyperplasias. 1829 80

The Comet-FISH technique is a useful tool to detect overall and region-specific DNA damage and repair in individual cells. It combines two well-established methods, the Comet assay (single cell gel electrophoresis) and the technique of fluorescence in situ hybridization (FISH). Whereas the Comet assay allows separating fragmented from non-fragmented DNA, FISH helps to detect specifically labelled DNA sequences of interest, including whole chromosomes. Thus the combination of both techniques has been applied in particular for detection of site-specific breaks in DNA regions which are relevant for development of different diseases. This paper reviews the relevant literature and presents three examples on how Comet-FISH was used for studying the induction of DNA damage by genotoxic compounds related to oxidative stress in colon cancer-relevant genes (TP53, APC, KRAS) of a colon adenoma cell line. The accumulated evidence on relative sensitivity of these genes in comparison to global damage allows a more definite conclusion on the possible contribution of the genotoxic factors during colorectal carcinogenesis. Telomere fragility was compared in different cell lines treated with cytostatic agents, and revealed new patterns of biological activities through the drugs and different sensitivities of the cell lines that were found to be associated with their tumour origin. A third example relates to measuring repair of specific gene regions using Comet-FISH, a method that can be developed to biomarker application. Taken together, available data suggests that Comet-FISH helps to get further insights into sensitivity of specific DNA regions and consequently in mechanisms of carcinogenesis. Although the nature of the measured Comet-FISH endpoint precludes us from stating basically that damage and repair are occurring within the specific gene, it is at least possible to evaluate whether the damage and repair are occurring within the vicinity of the gene of interest.
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PMID:Use of Comet-FISH in the study of DNA damage and repair: review. 1830 59

The accepted view of ovarian carcinogenesis is that carcinoma begins in the ovary, undergoes progressive "dedifferentiation" from a well to a poorly differentiated tumor, and then spreads to the pelvic and abdominal cavities before metastasizing to distant sites. It has therefore been reasoned that survival for this highly lethal disease could be improved by developing screening methods that detect disease when it is confined to the ovary. To date, however, no prospective randomized trial of any ovarian cancer screening test(s) has demonstrated a decrease in mortality. We believe that one of the main reasons for this is that the dogma underlying ovarian carcinogenesis is flawed. Based on studies performed in our laboratory during the last decade, we have proposed a model of ovarian carcinogenesis that takes into account the diverse nature of ovarian cancer and correlates the clinical, pathological, and molecular features of the disease. In this model, ovarian tumors are divided into 2 groups designated type I and type II. Type I tumors are slow growing, generally confined to the ovary at diagnosis, and develop from well-established precursor lesions that are termed "borderline" tumors. Type I tumors include low-grade micropapillary serous carcinoma, mucinous, endometrioid, and clear cell carcinomas. They are genetically stable and are characterized by mutations in a number of different genes including KRAS, BRAF, PTEN, and beta-catenin. Type II tumors are rapidly growing highly aggressive neoplasms for which well-defined precursor lesions have not been described. Type II tumors include high-grade serous carcinoma, malignant mixed mesodermal tumors (carcinosarcomas), and undifferentiated carcinomas. This group of tumors has a high level of genetic instability and is characterized by mutation of TP53. The model helps to explain why current screening techniques, aimed at detecting stage I disease, have not been effective. Tumors that remain confined to the ovary for a long period belong to the type I group, but they account for only 25% of the malignant tumors. Most of what is considered ovarian cancer belongs to the type II category, and these are only rarely confined to the ovary. Although the reasons for this are not entirely clear, possible explanations include rapid spread from the ovary early in carcinogenesis and development of carcinoma in extra ovarian sites, notably, the peritoneum and fallopian tube, with secondary involvement of the ovary. The latter tumors are advanced stage at their inception. Therefore, a more realistic end point for the early detection of ovarian cancer is volume and not stage of disease. The model does not replace the histopathologic classification but, by drawing attention to the molecular genetic events that play a role in tumor progression, sheds light on new approaches to early detection and treatment.
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PMID:Pathogenesis of ovarian cancer: lessons from morphology and molecular biology and their clinical implications. 1831 28

Mutations on the KRAS gene occur early during pancreatic duct cell carcinogenesis and have been identified in up to 90% of ductal adenocarcinoma. However, the functional role of KRAS mutations in the malignant transformation of normal pancreatic duct epithelial cells into cancer cells remains unknown. We have developed an in vitro model for KRAS transformation using near-normal HPV-16E6E7-immortalized human pancreatic ductal epithelial (HPDE-E6E7) cells. The expression of mutant KRAS(G12V) in HPDE cells by retroviral transduction resulted in weak tumorigenic transformation, with tumors formed in 50% of immune-deficient scid mice implanted by these KRAS-transformed cells. The model provides an opportunity to dissect further the molecular and cellular mechanisms associated with human pancreatic duct cell carcinogenesis.
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PMID:Human pancreatic duct epithelial cell model for KRAS transformation. 1837 52

The goal of ovarian cancer screening is to detect disease when confined to the ovary (stage I) and thereby prolong survival. We believe this is an elusive goal because most ovarian cancer, at its earliest recognizable stage, is probably not confined to the ovary. We propose a new model of ovarian carcinogenesis based on clinical, pathological, and molecular genetic studies that may enable more targeted screening and therapeutic intervention to be developed. The model divides ovarian cancer into 2 groups designated type I and type II. Type I tumors are slow growing, generally confined to the ovary at diagnosis and develop from well-established precursor lesions so-called borderline tumors. Type I tumors include low-grade micropapillary serous carcinoma, mucinous, endometrioid, and clear cell carcinomas. They are genetically stable and are characterized by mutations in a number of different genes including KRAS, BRAF, PTEN, and beta-catenin. Type II tumors are rapidly growing, highly aggressive neoplasms that lack well-defined precursor lesions; most are advanced stage at, or soon after, their inception. These include high-grade serous carcinoma, malignant mixed mesodermal tumors (carcinosarcomas), and undifferentiated carcinomas. The type II tumors are characterized by mutation of TP53 and a high level of genetic instability. Screening tests that focus on stage I disease may detect low-grade type I neoplasms but miss the more aggressive type II tumors, which account for most ovarian cancers. A more rational approach to early detection of ovarian cancer should focus on low volume rather than low stage of disease.
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PMID:Early detection and treatment of ovarian cancer: shifting from early stage to minimal volume of disease based on a new model of carcinogenesis. 1839 29

Hereditary non-polyposis colorectal carcinoma (Lynch syndrome) is among the most common hereditary cancers in man and a model of cancers arising through deficient DNA mismatch repair (MMR). Lynch syndrome patients are predisposed to different cancers in a non-random fashion, the basis of which is poorly understood. We addressed this issue by determining the molecular profiles for different tumors from a nationwide cohort of Lynch syndrome families (approximately 150 tumors in total). We focused on some less prevalent cancers, affecting the brain (n = 7) and urinary tract (five bladder and five ureter uroepithelial cancers and four kidney adenocarcinomas), and compared their molecular characteristics to those of the most common cancers, colorectal, gastric and endometrial adenocarcinomas, from the same families. Despite origin from verified MMR gene mutation carriers, the frequency of high-level microsatellite instability in tumors varied between high (100-96% for ureter, stomach and colon), intermediate (63-60% for endometrium and bladder) and low (25-0% for kidney and brain). In contrast to gastrointestinal and endometrial carcinomas, active (nuclear) beta-catenin was rare and KRAS mutations were absent in brain and urological tumors. Compared with other tumors, frequent stabilization of p53 protein characterized urinary tract cancers. Promoter methylation of tumor suppressor genes discriminated the tumors in an organ-specific manner. Our findings suggest that different Lynch syndrome tumors develop along different routes. Uroepithelial cancers of the ureter (and bladder to lesser extent) share many characteristics of MMR deficiency-driven tumorigenesis, whereas brain tumors and kidney adenocarcinomas follow separate pathways.
Carcinogenesis 2008 Jul
PMID:Differential cancer predisposition in Lynch syndrome: insights from molecular analysis of brain and urinary tract tumors. 1855 May 72

A subset of colorectal cancers with CpG island methylator phenotype-high (CIMP-H) is frequently associated with MSI and BRAF V600E mutation. Since limited data are available on different histological types of colorectal polyps, we compared the pattern and the frequency of promoter methylation, CIMP-H, MSI, KRAS and BRAF V600E mutations and the relationship among these molecular parameters and the clinicopathologic characteristics in 110 serrated polyps (48 hyperplastic polyps, 32 sessile serrated adenomas and 30 serrated adenomas) and 32 tubular adenomas using 7 commonly used tumor-associated gene loci. No significant difference in the frequency of overall methylation frequency (86% vs. 100%) and CIMP-H (39% vs. 28%) between serrated polyps and tubular adenomas was observed, but proximally located serrated polyps showed more frequent methylation at 5 of 7 loci examined, and were more likely to be CIMP-H (62% vs. 22%). MGMT methylation was more common in tubular adenomas while MLH1 and HIC1 were more frequently methylated in serrated polyps. BRAF mutation was frequently present in all types of serrated polyps (80%), but was absent in tubular adenomas and was not associated with CIMP or MSI status. These results show comparable frequencies of promoter methylation of tumor-associated genes and CIMP-H, but distinct differences in gene-specific or colonic site-specific methylation profiles occur in serrated polyps and tubular adenomas. BRAF mutation occurs independently of CIMP and MSI in all types of serrated polyps and may serve as a marker of serrated pathway of colorectal carcinogenesis.
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PMID:Distinct CpG island methylation profiles and BRAF mutation status in serrated and adenomatous colorectal polyps. 1879 61

Genome-wide DNA hypomethylation plays has an important role in genomic instability and colorectal carcinogenesis. However, the relationship between cellular DNA methylation level and patient outcome remains uncertain. Using 643 colon cancers in two independent prospective cohorts, we quantified DNA methylation in repetitive long interspersed nucleotide element-1 (LINE-1) elements using pyrosequencing, which is a good indicator of global DNA methylation level. We used Cox proportional hazard models to calculate hazard ratios (HRs) of colon cancer-specific and overall mortality, adjusting for patient and tumoral features, including CpG island methylator phenotype (CIMP). Statistical tests were two-sided. LINE-1 hypomethylation was linearly associated with a statistically significant increase in colon cancer-specific mortality (for a 30% decrease in LINE-1 methylation: multivariable HR = 2.37, 95% confidence interval [CI] = 1.42 to 3.94; P(trend) < .001) and overall mortality (multivariable HR = 1.85, 95% CI = 1.25 to 2.75; P(trend) = .002). The association was consistent across the two independent cohorts and strata of clinical and molecular characteristics, including sex, age, tumor location, stage, and CIMP, microsatellite instability, KRAS, BRAF, p53, and chromosomal instability status. In conclusion, tumoral LINE-1 hypomethylation is independently associated with shorter survival among colon cancer patients.
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PMID:A cohort study of tumoral LINE-1 hypomethylation and prognosis in colon cancer. 1903 68

Activating point mutations of the mouse Kras2 oncogene or its human homologue, KRAS, are critical for lung adenocarcinoma genesis, independent of the species. Significantly, in the mouse, several polymorphic Kras2 alleles have been identified, which cosegregate with genetic susceptibility to chemical induction of lung tumors. Moreover, a major lung tumor susceptibility locus, the Pas1 (Pulmonary adenoma susceptibility 1), was found to colocalize with Kras2 on distal chromosome 6 on linkage analysis. The Kras2 may thus be involved in both cellular transformation and genetic control of tumor susceptibility. In this review, the focus is on current knowledge regarding the relationship between Kras2 and experimental mouse lung carcinogenesis, especially from the aspect of disease predisposition. Because mouse and human lung tumors share considerable similarities, the experimental information should provide clues to personalized medicine in the human setting.
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PMID:The Kras2 oncogene and mouse lung carcinogenesis. 1910 9


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