Chromosome 5 allele loss in human colorectal carcinomas

Solomon, Ellen; Voss, R.; Hall, Victoria L.; Bodmer, W F; Jass, Jeremy R.; Jeffreys, Alec J.; Lucibello, Frances C.; Patel, I.; Rider, Susan H.

doi:10.1038/328616a0

Cited by 523 publications

(142 citation statements)

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“…It has been reported that the genes encoding two key enzymes in cholesterol synthesis are located in chromosome 5 (44,45), which has been shown to be the location of one of the genes involved in the adenoma-carcinoma sequence (46,47). It is possible that deletions in genes on chromosome 5 lead both to decreased cholesterol synthesis and to the progression of adenoma to cancer.…”

Section: Discussionmentioning

confidence: 99%

Tissue metabolomic fingerprinting reveals metabolic disorders associated with human gastric cancer morbidity

Wang²,

Liu³

et al. 2011

Oncol Rep

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Abstract. the principal way to improve the outcome of gastric cancer (GC) is to predict carcinogenesis and metastasis at an early stage. the aims of the present study were to test the hypothesis that distinct metabolic profiles are reflected in GC tissues and to further explore potential biomarkers for GC diagnosis. Gas chromatography/mass spectrometry (GC/Ms) was utilized to analyze tissue metabolites from 30 GC patients. A diagnostic model for GC was constructed using orthogonal partial least squares discriminant analysis (OpLs-DA), and the metabolomic data were analyzed using the non-parametric Wilcoxon rank sum test to identify the metabolic tissue biomarkers for GC. Over 100 signals were routinely detected in one single total ion current (tIC) chromatogram, and the OPLS-DA model generated from the metabolic profile of the tissues adequately discriminated the GC tissues from the normal mucosae. Among the low-molecular-weight endogenous metabolites, a total of 41 compounds, such as amino acids, organic acids, carbohydrates, fatty acids and steroids, were detected, and 15 differential metabolites were identified with significant difference (p<0.05). A total of 20 variables were noted which contributed to a great extent in the discriminating OpLs-DA model (VIp value >1.0), among which 12 metabolites were identified using both VIP values (VIP >1) and the Wilcoxon test (p<0.05). In conclusion, the identification of the metabolites associated with GC morbidity potentially revealed perturbations of glycolysis, fatty acid β-oxidation, cholesterol and amino acid metabolism. these results suggest that tissue metabolic profiles have great potential in detecting GC and may aid in understanding its underlying mechanisms.

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Section: Discussionmentioning

confidence: 99%

Tissue metabolomic fingerprinting reveals metabolic disorders associated with human gastric cancer morbidity

Wang²,

Liu³

et al. 2011

Oncol Rep

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“…When tumours form while retaining the chromosome carrying the wild-type Apc allele, the expression of the Apc polypeptide is attenuated (¢gure 3). This loss of expression is not accompanied by any known mutation of the Apc gene: the wild-type DNA sequence at the Min site is retained, and no chain-terminating mutations of Apc are detected (A. R. Shoemaker, unpublished data scenario is currently mysterious, with several conceivable explanations: (i) the wild-type allele might be silenced by a stable epigenetic change, along lines initially suggested by Solomon, Bodmer and their colleagues (Solomon et al 1987); (ii) a speci¢c epigenetic mechanism, hypermethylation of the Apc promoter, might attenuate Apc expression (Hiltunen et al 1997); or (iii) a second locus that regulates the expression of Apc might be somatically mutated (Haber et al 1990). Consistent with this last possibility, the incidence of tumours retaining but not expressing an apparently normal Apc allele is increased by appropriately timed ENU treatment of AKRÁMin mice (A. R. Shoemaker, unpublished data).…”

Section: The Centrality Of the Apc Regulatormentioning

confidence: 91%

The intestinal epithelium and its neoplasms: genetic, cellular and tissue interactions

Dove

Cormier

Gould

et al. 1998

Phil. Trans. R. Soc. Lond. B

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The Min (multiple intestinal neoplasia) strain of the laboratory mouse and its derivatives permit the fundamental study of factors that regulate the transition between normal and neoplastic growth. A gene of central importance in mediating these alternative patterns of growth is Apc, the mouse homologue of the human adenomatous polyposis coli (APC) gene. When adenomas form in the Min mouse, both copies of the Apc gene must be inactivated. One copy is mutated by the nonsense Apc allele carried in heterozygous form in this strain. The other copy can be silenced by any of several mechanisms. These range from loss of the homologue bearing the wild-type Apc allele; to interstitial deletions surrounding the wild-type allele; to intragenic mutation, including nonsense alleles; and ¢nally, to a reduction in expression of the locus, perhaps owing to mutation in a regulatory locus. Each of these proposed mechanisms may constitute a two-hit genetic process as initially posited by Knudson; however, apparently the two hits could involve either a single locus or two loci. The kinetic order for the transition to adenoma may be still higher than two, if polyclonal adenomas require stronger interactions than passive fusion.The severity of the intestinal neoplastic phenotype of the Min mouse is strongly dependent upon loci other than Apc. One of these, Mom1, has now been rigorously identi¢ed at the molecular level as encoding an active resistance conferred by a secretory phospholipase. Mom1 acts locally within a crypt lineage, not systemically. Within the crypt lineage, however, its action seems to be non-autonomous: when tumours arise in Mom1 heterozygotes, the active resistance allele is maintained in the tumour (MOH or maintenance of heterozygosity). Indeed, the secretory phospholipase is synthesized by post-mitotic Paneth cells, not by the proliferative cells that presumably generate the tumour. An analysis of autonomy of modi¢er gene action in chimeric mice deserves detailed attention both to the number of genetic factors for which an animal is chimeric and to the clonal structure of the tissue in question.Beyond Mom1, other loci can strongly modify the severity of the Min phenotype. An emergent challenge is to ¢nd ways to identify the full set of genes that interact with the intestinal cancer predisposition of the Min mouse strain. With such a set, one can then work, using contemporary mouse genetics, to identify the molecular, cellular and organismal strategies that integrate their functions. Finally, with appropriately phenotyped human families, one can investigate by a candidate approach which modifying factors in£uence the epidemiology of human colon cancer. Even if a candidate modi¢er does not explain any of the genetic epidemiology of colon cancer in human populations, modi¢er activities discovered by mouse genetics provide candidates for chemopreventive and/or therapeutic modalities in the human.

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“…The presumption would then be that some fraction of non-hereditary colon cancers should show loss of heterozygosity for syntenic markers, the idea being that a somatic mutation had occurred at one copy of the gene, and a gross chromosomal event such as deletion, chromosomal loss or recombination had led to loss of the other normal copy. Solomon et al (1987) reported such loss at a frequency of 23%, or perhaps higher. Other investigators have since reported frequencies in the range of 19-36% (Law et al, 1988;Vogelstein et al, 1988 There is no information about the location of the nonpolyposis colon cancer, but one may begin by assuming that it is not on Sq.…”

Section: Wilms' Tumour and Rhabdomyosarcomamentioning

confidence: 96%

The ninth Gordon Hamilton-Fairley memorial lecture: Hereditary cancers: clues to mechanisms of carcinogenesis

1989

Br J Cancer

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The study of hereditary cancer in humans, notably retinoblastoma, has identified a category of cancer genes that is different from that of the oncogenes. Whereas the latter group of genes exerts its effect through expression, the former does so as a result of failure of normal expression. Primary oncogene abnormality seems to play a crucial initiating role in certain neoplasms, particularly leukaemias, lymphomas and some sarcomas. In contrast, anti-oncogenes (tumour suppressor genes) appear to be important in the initiation of several solid tumours of children, as well as some common carcinomas of adults. Both classes are apparently involved in tumour progression and metastasis. Virtually every kind of cancer can occur in hereditary form, so the role of anti-oncogenes in the origin of human cancers may be considerable. The prototypic anti-oncogene has been that for retinoblastoma. For this tumour the recessive mechanism has been demonstrated by molecular means, and the gene has been cloned. The possibility has been suggested that gene (or gene product) replacement therapy could be accomplished.

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Chromosome 5 allele loss in human colorectal carcinomas

Cited by 523 publications

References 0 publications

Tissue metabolomic fingerprinting reveals metabolic disorders associated with human gastric cancer morbidity

Tissue metabolomic fingerprinting reveals metabolic disorders associated with human gastric cancer morbidity

The intestinal epithelium and its neoplasms: genetic, cellular and tissue interactions

The ninth Gordon Hamilton-Fairley memorial lecture: Hereditary cancers: clues to mechanisms of carcinogenesis

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