c-Ki-ras gene mutations in dysplasia and carcinomas complicating ulcerative colitis

Bell, Sandra; Kelly, Sean; Hoyle, Jessica; Lewis, F A; Taylor, Graham R.; Thompson, Helen; Dixon, M. F.; Quirke, Philip

doi:10.1038/bjc.1991.264

Cited by 84 publications

(43 citation statements)

References 27 publications

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“…Genetic alterations in premalignant UC epithelia include p53 point mutations and loss of heterozygosity (39,40), Myc (41 ), and Src overexpression, and, rarely, ras mutations (42)(43)(44)(45). p53 inactivation and Src overexpression occur earlier in the histologic progression of neoplasia in UC than in sporadic colon cancer.…”

Section: Discussionmentioning

confidence: 99%

Elevated c-Src tyrosine kinase activity in premalignant epithelia of ulcerative colitis.

Cartwright¹,

Coad²,

Egbert³

1994

J. Clin. Invest.

126

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Ulcerative colitis (UC) is a chronic inflammatory disease of the colon with a high incidence of colon cancer. Dysplasia is a precursor to carcinoma and a predictor of malignant potential; epithelia containing high-grade or severe dysplasia is most likely to develop cancer. The cellular oncogene c-src and its viral homologue v-src (the transforming gene of Rous sarcoma virus) encode 60-kD cytoplasmic, membrane-associated protein tyrosine kinases. For the viral protein or transforming mutants of the cellular protein (Src), a close correlation exists between elevated tyrosine kinase activity and malignant transformation of cells. Previously, we and others observed elevated Src activity in sporadic colon carcinomas and benign adenomas at greatest risk for developing cancer (those with large size, villous architecture, and/or severe dysplasia). Here we report that Src activity and protein abundance are also elevated in neoplastic UC epithelia. Activity is highest in malignant and severely dysplastic epithelia, and 6-10-fold higher in mildly dysplastic than in nondysplastic epithelia. Thus, Src activity is elevated in premalignant UC epithelia, which is at greatest risk for developing cancer. The data suggest that activation of the src proto-oncogene is an early event in the genesis of UC colon cancer. (J.

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Section: Discussionmentioning

confidence: 99%

Elevated c-Src tyrosine kinase activity in premalignant epithelia of ulcerative colitis.

Cartwright¹,

Coad²,

Egbert³

1994

J. Clin. Invest.

126

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“…Matched control sections were con®rmed as tumor-free normal tissue by H and E staining before extraction. The sections were incubated for 24 h with Proteinase K (2 mg/ml, Sigma, Poole, Dorset, UK) and 1% SDS at 378C (Bell et al, 1991). This step was followed by extraction twice with phenol/chloroform/isoamyl alcohol (25 : 24 : 1) and precipitated with ethanol.…”

Section: Fish Mappingmentioning

confidence: 99%

Down-regulation of T1A12/mac25, a novel insulin-like growth factor binding protein related gene, is associated with disease progression in breast carcinomas

et al. 1998

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To de®ne genes that are essential to the initiation and progression of breast cancer we utilized subtractive hybridization and dierential display cloning techniques and isolated over 950 cDNAs from breast cell-lines derived from matched normal and tumor tissue. Of these, 102 cDNAs were characterized by DNA sequencing and Northern blot analysis. GenBank searches showed that one of these genes, T1A12 is identical to mac25, an insulin-like growth factor-binding protein related gene. Antibodies generated against the C-terminal region of the T1A12/mac25 protein were used to investigate its expression in 60 primary breast tissues. Sections of 12 benign, 16 ductal carcinoma in situ and 32 in®ltrating ductal carcinoma specimens were examined. Strong immunoperoxidase staining was observed in luminal epithelial cells of normal lobules and ducts, in apocrine cells of cysts and ®broadenomas. Moderate to weak protein expression was found in hyperplastic and DCIS cells, but no speci®c staining was detected in invasive carcinoma cells. FISH mapping using a PAC clone localized the T1A12/mac25 gene to 4q12-13. Microsatellite length polymorphism was studied using markers for 4q in paired normal and tumor breast tissues. Thirtythree per cent (10/30) of the samples were found to be polymorphic with D4S189 and D4S231 microsatellite markers and LOH was detected in 50% (5/10) of these informative samples. Our data indicate that T1A12/ mac25 expression is abrogated during breast cancer progression concomitant with loss of heterozygosity on chromosome 4q. T1A12/mac25 may therefore have a tumor suppressor-like function and its expression could indicate a disease with a more favorable status, having a better prognosis.

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“…Consequently, it has been considered that the state of genetic alterations, such as APC or K-ras mutations, may be different to some extent from that of sporadic colorectal carcinomas. Several investigations have been performed, focusing on APC or K-ras gene in UCAN, [12][13][14][15][16][17][18][19][20][21][22] but no conclusion has yet been reached. Therefore, we decided to examine the state of APC and K-ras genes in UCAN.…”

Section: U16-l3mentioning

confidence: 99%

“…The prevalence of adenomatous polyposis coli (APC) gene mutations in UCAN is low or equal to that of sporadic carcinomas, [12][13][14][15] and loss of heterozygosity (LOH) at the APC locus is seen in 25 to 40% of UCAN. 12,13,[16][17][18] UCAN has a low incidence of K-ras mutations, 19,20) but there are some reports of a relatively high incidence of Kras mutations among sporadic carcinomas. 13,14,21,22) However, there is still little information about the genetic alterations in UCAN and no clear conclusion has been reached.…”

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confidence: 99%

Genetic Alterations in Ulcerative Colitis‐associated Neoplasia Focusing on APC, K‐ras Gene and Microsatellite Instability

Umetani

Sasaki

Watanabe

et al. 1999

Japanese Journal of Cancer Research

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The status of genetic alterations in ulcerative colitis (UC)-associated neoplasia (UCAN) was investigated focusing on microsatellite instability (MSI) which is seen in a certain fraction of colorectal carcinomas, and adenomatous polyposis coli (APC) gene and K-ras gene, in which mutations occur in the early stage of sporadic colorectal tumorigenesis. Thirty-one UCAN from 15 UC patients who had undergone colorectal resection at our institution were investigated. There were 8 lesions of invasive carcinoma, 15 high-grade dysplasia (HGD) and 8 low-grade dysplasia (LGD). DNA was extracted from each neoplastic lesion and corresponding non-neoplastic tissue by a microdissection method. MSI status at 9 microsatellite loci, loss of heterozygosity (LOH) at the APC locus, and Kras codon 12 point mutation were examined. As for MSI, 4/31 (13%) UCAN (carcinoma: 1/8 (13%), HGD: 2/15 (13%), LGD: 1/8 (13%)) were MSI-high (3 or more unstable loci) and 12/31 (39%) UCAN (carcinoma: 3/8 (38%), HGD: 6/15 (40%), LGD: 3/8 (38%)) were MSI-low (1 or 2 unstable loci). LOH at the APC locus was not found in 9 UCAN from 6 informative (heterozygous) cases. The K-ras mutation rate of UCAN was 3/31 (9.7%) (carcinoma: 2/8 (25%), HGD: 1/15 (7%) and LGD: 0/8). MSI is relatively common in UCAN and is present at the early stage of tumorigenesis of UCAN, while the involvement of genetic alterations of the APC gene and K-ras gene is small. MSI may be one of the mechanisms of the increased neoplastic risk in UC, and UCAN may develop through a different carcinogenic pathway from sporadic carcinomas.

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c-Ki-ras gene mutations in dysplasia and carcinomas complicating ulcerative colitis

Cited by 84 publications

References 27 publications

Elevated c-Src tyrosine kinase activity in premalignant epithelia of ulcerative colitis.

Elevated c-Src tyrosine kinase activity in premalignant epithelia of ulcerative colitis.

Down-regulation of T1A12/mac25, a novel insulin-like growth factor binding protein related gene, is associated with disease progression in breast carcinomas

Genetic Alterations in Ulcerative Colitis‐associated Neoplasia Focusing on APC, K‐ras Gene and Microsatellite Instability

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