APC, K‐ras codon 12 mutations and <i>p53</i> gene expression in carcinoma and adenoma of the gall‐bladder suggest two genetic pathways in gall‐bladder carcinogenesis

Itoi, Takao; Watanabe, Hidenobu; Ajioka, Yoichi; Oohashi, Yasuhiro; Takei, Kohtaro; Nishikura, Ken; Nakamura, Yusuke; Horii, Akira; Saito, Toshihiko

doi:10.1111/j.1440-1827.1996.tb03618.x

Cited by 79 publications

(58 citation statements)

References 31 publications

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“…The minimum overlapping region was 12p12, which corresponds to the chromosomal locus of the K-ras gene (12p12.1). Although it is well known that K-ras mutation is frequent in biliary tract cancers [3, 4, 5, 6, 7, 8], there are only a few reports of K-ras gene amplification in cancers [28, 29]. Accordingly, it is likely that the gain at 12p12 is attributable to an increase in the copy number of gene(s) other than K-ras in biliary tract cancer.…”

Section: Discussionmentioning

confidence: 98%

“…However, existing genetic information concerning biliary tract cancers is very limited, although several genes, such as K-ras [3, 4, 5, 6, 7, 8], p53 [8, 9, 10, 11]and c-erbB-2 [11, 12, 13], have been reported to be involved in the development and/or progression of biliary tract cancers. Frequent inactivation of p16 INK4 /CDKN2 and loss of heterozygosity at 3p, 5p and 9p have also been shown in biliary tract cancers [7, 9].…”

Section: Introductionmentioning

confidence: 99%

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Genetic Aberrations Detected by Comparative Genomic Hybridization in Biliary Tract Cancers

et al. 1999

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In order to elucidate cytogenetic changes characteristic of biliary tract cancer, we examined the genetic imbalances in 18 biliary tract cancers using comparative genomic hybridization (CGH). The most common sites of increases in copy number, in order of frequency, were 17q (33% of the cases), 5p (28%), 3q (22%), 7p (22%), 8q (22%), and 12p (22%), whereas copy number decreases of 6q (28%), 18q (28%), 4q (22%), 5q (22%), and 9p (22%) were frequent. The average number of chromosomal aberrations was significantly greater in stage IV than in stage III tumors (7.9 vs. 2.2/tumor, p < 0.05). The frequent aberrations detected in this study may be related to the development and/or progression of biliary tract cancers. This is the first report on CGH of biliary tract cancers.

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Section: Discussionmentioning

confidence: 98%

Section: Introductionmentioning

confidence: 99%

Genetic Aberrations Detected by Comparative Genomic Hybridization in Biliary Tract Cancers

et al. 1999

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“…To improve the preoperative diagnostic rate in biliary malignancy, many assays to detect genetic alternations have been investigated, including p53, 12-15 K-ras, [16][17][18][19][20] and telomerase. 21 A group of centrosome abnormalities, detected in cells obtained from the bile or pancreatic juice, could be another modality for the biological diagnosis of biliary malignancy.…”

Section: Discussionmentioning

confidence: 99%

Centrosome abnormalities in human carcinomas of the gallbladder and intrahepatic and extrahepatic bile ducts

et al. 2000

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During mitosis, 2 centrosomes ensure accurate assembly of bipolar spindles and fidelity of the chromosomal segregation. The presence of more than 2 copies of centrosomes during mitosis can result in the formation of multipolar spindles, unbalanced chromosome segregation, and aneuploidy. Recent studies have provided evidence that centrosome hyperamplification plays a pivotal role in carcinogenesis. Using immunofluorescence analysis with ␥-tubulin and pericentrin antibodies, paraffin-embedded sections from 40 malignant biliary diseases including gallbladder cancers (GC; n ‫؍‬ 13), intrahepatic cholangiocellular carcinoma (CCC; n ‫؍‬ 19), and extrahepatic bile duct cancers (BDC; n ‫؍‬ 8) were examined. Thirty-seven benign biliary diseases including chronic cholecystitis, gallbladder adenoma, hepatolithiasis, and choledochal cyst were included as benign controls. The frequencies of the centrosome abnormalities were 70% for GC, 58% for CCC, and 50% for BDC, respectively. The frequencies of centrosome abnormalities in malignant biliary diseases were significantly higher than in their benign counterparts (GC, CCC, BDC; P ‫؍‬ .001, .002, and .001, respectively). The results of current study also indicated that biliary malignancy in the advanced stage (III-IV) displayed a higher frequency of centrosome abnormalities than in the early stage (I-II) (P F .001). We conclude that abnormalities in size, number, and shape of the centrosome are frequently observed in biliary tract malignancy. Centrosome abnormalities started to occur in the early stage of biliary malignancy and became very frequent in the advanced stage. This implies that centrosome abnormality might relate to the transition from early to advanced malignancy in biliary malignancy. (HEPATOLOGY 2000;31:59-64.)

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“…9 Recent evidence from a variety of other cancer models has indicated that telomere shortening may also contribute to carcinoma progression, although this has not been previously examined in biliary tract carcinoma. [10][11][12] For example, telomere shortening appears to be an early and common event in precursors to invasive prostatic and pancreatic cancer.…”

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confidence: 99%

Telomere length variation in biliary tract metaplasia, dysplasia, and carcinoma

et al. 2006

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Biliary tract carcinoma, including carcinoma of the gallbladder, intrahepatic bile ducts (cholangiocarcinoma), and extrahepatic bile ducts, affects 7500 people in the United States annually, and has an overall 32% 5-year survival rate for disease limited to the mucosa, and a dismal 10% 5-year survival for more advanced disease. The identification of factors involved in the pathogenesis and progression of biliary tract carcinoma is critical for devising effective methods of screening and treatment. Recent evidence suggests that reduction of the length of telomeres, which normally help maintain chromosomal stability, may promote the development and progression of a variety of carcinomas. Using a novel, recently validated telomere fluorescence in situ hybridization method, we examined telomere length in normal and inflamed gallbladder epithelium, metaplasia and dysplasia of the gallbladder, and biliary tract carcinoma to determine whether telomere shortening is associated with neoplastic progression in the biliary tract. Although normal and inflamed gallbladder epithelium demonstrated uniform normal telomere lengths, over half of all metaplastic lesions demonstrated shortened telomeres, supporting prior evidence that metaplastic lesions of the gallbladder are pre-neoplastic. Dysplastic epithelium and invasive carcinomas demonstrated almost universally abnormally short telomeres, indicating that telomere shortening occurs at an early, preinvasive stage of cancer development. In addition, invasive adenocarcinoma of the biliary tract frequently demonstrated intratumoral heterogeneity of telomere lengths. We conclude that telomere shortening is a consistent and early finding in the development of biliary tract carcinoma.

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APC, K‐ras codon 12 mutations and p53 gene expression in carcinoma and adenoma of the gall‐bladder suggest two genetic pathways in gall‐bladder carcinogenesis

Cited by 79 publications

References 31 publications

Genetic Aberrations Detected by Comparative Genomic Hybridization in Biliary Tract Cancers

Genetic Aberrations Detected by Comparative Genomic Hybridization in Biliary Tract Cancers

Centrosome abnormalities in human carcinomas of the gallbladder and intrahepatic and extrahepatic bile ducts

Telomere length variation in biliary tract metaplasia, dysplasia, and carcinoma

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