Epithelial and stromal genetic instability linked to tumor suppressor genes in ulcerative colitis-associated tumorigenesis

Yagishita, Hiroko; Yoshida, Tsutomu; Ishiguro, K; Numata, Yoshiko; Okayasu, Isao

doi:10.1080/00365520701817419

Cited by 17 publications

(18 citation statements)

References 20 publications

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“…Moreover, whereas MMR-mediated MSI commonly manifests as a ''widening'' of electropherogram stutter peaks, indicative of a large number of length variants simultaneously present within a sample (34), the rare polyguanine mutations we identified were predominantly the result of single slipped alleles. While there have been reports of ''low-level'' MSI in UC-derived adenocarcinomas and occasionally in surrounding nondysplastic tissue (29,35,36), microsatellite slippage events are expected to be occasionally witnessed in any clonally derived population (22,37), and the latter may best explain our findings. Nevertheless, it is possible that a moderately increased rate of slippage may occur in UC.…”

supporting

confidence: 61%

Clonal expansions in ulcerative colitis identify patients with neoplasia

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Risques

et al. 2009

Proc. Natl. Acad. Sci. U.S.A.

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Chronic inflammation predisposes to a variety of human cancers. Affected tissues slowly accumulate mutations, some of which affect growth regulation and drive successive waves of clonal evolution, whereas a far greater number are functionally neutral and serve only to passively mark expanding clones. Ulcerative colitis (UC) is an inflammatory bowel disease, in which up to 10% of patients eventually develop colon cancer. Here we have mapped mutations in hypermutable intergenic and intronic polyguanine tracts in patients with UC to delineate the extent of clonal expansions associated with carcinogenesis. We genotyped colon biopsies for length altering mutations at 28 different polyguanine markers. In eight patients without neoplasia, we detected only two mutations in a single individual from among 37 total biopsies. In contrast, for 11 UC patients with neoplasia elsewhere in the colon, we identified 63 mutations in 51 nondysplastic biopsies, and every patient possessed at least one mutant clone. A subset of clones were large and extended over many square centimeters of colon. Of these, some occurred as isolated populations in nondysplastic tissue, considerably distant from neoplastic lesions. Other large clones included regions of cancer, suggesting that the tumor arose within a preexisting clonal field. Our results demonstrate that neutral mutations in polyguanine tracts serve as a unique tool for identifying fields of clonal expansions, which may prove clinically useful for distinguishing a subset of UC patients who are at risk for developing cancer.field effect ͉ lineage mapping ͉ neoplastic evolution

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supporting

confidence: 61%

Clonal expansions in ulcerative colitis identify patients with neoplasia

Salk

Salipante

Risques

et al. 2009

Proc. Natl. Acad. Sci. U.S.A.

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“…LOH (Fig. 3), microsatellite instability, consistent cytogenetic abnormalities, and/or telomere attrition in stroma have been independently described by many different investigators for a broad variety of solid tumors and nonmalignant conditions, such as head and neck squamous cell carcinomas, colorectal adenomas and carcinomas, Barrett esophagus and esophageal adenocarcinomas, esophageal squamous cell carcinomas, and carcinomas of the cervix, ovary, bladder, and prostate, as well as inflammatory bowel disease (10)(11)(12)(13)(14)(15)(16)(17)(18)(19)(20)(21)(22). However, do these genomic alterations in the stroma have any clinical implications for patients with cancers?…”

Section: Somatic Genomic Alterations In Tumor Stroma Of Different Typmentioning

confidence: 99%

Genomic Alterations in Tumor Stroma

et al. 2009

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It was traditionally believed that the tumor was the seed that lay in the passive soil of the microenvironment, with the latter providing ''permissive elements'' for the tumor to grow and invade. Subsequently, it was recognized that both neoplasia and its microenvironment interacted as equal partners. Recent advances addressing genomic alterations in the tumor microenvironment, relevant to clinical outcome and treatment choices, are summarized. These include microenvironmental genomic alterations not only in different solid tumors, but also, rather surprisingly, in inflammatory bowel disease. These observations promise new biomarkers of prognosis and a new compartment to target therapy.

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“…Previously, we demonstrated that not only epithelial but also stromal elements exhibit genomic instability in both sporadic and ulcerative colitis-associated colorectal adenocarcinomas with a background of chronic inflammation, and provided evidence that such stromal alteration might influence tumorigenesis [9][10][11][12]. Furthermore, genomic alterations in stromal elements were found consistently in early stages of colorectal carcinogenesis, especially in ulcerative colitis-associated tumors, accompanied by stepwise increase in genetic instability of the epithelium with duration of illness.…”

Section: Introductionmentioning

confidence: 97%

“…Our results suggest a role for microenvironmental changes with gene alterations in stromal cells [10]. In this study, we focused on increasing risk of carcinogenesis in the colorectum with aging, analyzing MSI and LOH with microsatellite markers recommended by the National Cancer Institute (NCI) [11], markers on chromosome 17 (Chr.17, close to the p53 gene, the p53 gene locus and the BRCA1 gene) [12,13], and tumor suppressor gene (TSG)-related markers (D9S161, close to p16 INK4A ; D7S486, close to ST-7; D13S268, close to Rb; D18S474, close to Smad4 and DCC; D3S1300, close to FHIT; and D11S904, close to WT1) [14]. For this purpose, we applied laser-captured microdissection of both epithelial and stromal elements in normal-appearing colorectal mucosa in patients with sporadic colorectal cancer.…”

Section: Introductionmentioning

confidence: 99%