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I Tomlinson

Publications and source records attributed to I Tomlinson.

13 recordsLinked to original sources
PubMed1998

A serine/threonine kinase gene defective in Peutz-Jeghers syndrome.

Studies of hereditary cancer syndromes have contributed greatly to our understanding of molecular events involved in tumorigenesis. Here we investigate the molecular background of the Peutz-Jeghers syndrome (PJS), a rare hereditary disease in which there is predisposition to benign and malignant tumours of many organ systems. A locus for this condition was recently assigned to chromosome 19p. We have identified truncating germline mutations in a gene residing on chromosome 19p in multiple individuals affected by PJS. This previously identified but unmapped gene, LKB1, has strong homology to a cytoplasmic Xenopus serine/threonine protein kinase XEEK1, and weaker similarity to many other protein kinases. Peutz-Jeghers syndrome is therefore the first cancer-susceptibility syndrome to be identified that is due to inactivating mutations in a protein kinase.

AMP-Activated Protein Kinase Kinases↗
PubMed1998

Peutz-Jeghers disease: most, but not all, families are compatible with linkage to 19p13.3.

A locus for Peutz-Jeghers syndrome (PJS) was recently mapped to chromosome 19p13.3. Each of 12 families studied was compatible with linkage to the marker D19S886. We have analysed 20 further families and found that the majority of these are consistent with a PJS gene on 19p13.3. Three families were, however, unlinked to 19p13.3 and none of the available PJS polyps from these families showed allele loss at D19S886. There were no obvious clinicopathological or ethnic differences between the 19p13.3 linked and unlinked families. There appears, therefore, to be a major PJS locus on chromosome 19p13.3 and the possibility exists of a minor locus (or loci) elsewhere.

Chromosomes, Human, Pair 19↗
PubMed1997

Reciprocity between membranous and nuclear expression of beta-catenin in colorectal tumours.

beta-Catenin has a central role not only in linking the cadherin-mediated cell adhesion system but also in the intercellular signalling pathway. To investigate alterations of beta-catenin in the development of colorectal carcinoma, the pattern of beta-catenin expression was studied using immunohistochemistry in 74 sporadic colorectal adenomas, in histologically normal mucosa adjacent to 65 of these adenomas, and in 52 carcinomas arising in adenomas. All normal epithelia displayed cell boundary staining for beta-catenin. Adenomas and carcinomas showed varying degrees of membranous staining. However, some tumours also showed nuclear staining of beta-catenin protein. Decreased membranous and increased nuclear beta-catenin staining were associated with increasing degrees of dysplasia in adenomas (P < 0.005, P < 0.05, respectively). Carcinomas manifested significantly reduced membranous, but enhanced nuclear beta-catenin expression compared with their associated adenomas (P < 0.001, P < 0.005, respectively). An inverse correlation was found between decreased membranous and increased nuclear staining of beta-catenin in both adenomas and carcinomas (P < 0.025, P < 0.05, respectively). The data confirm that reduced membranous and increased nuclear expression of beta-catenin is associated with the progression of colorectal adenomas to carcinomas. Our results also suggest that decreased membranous expression of beta-catenin may result from aberrant localisation of the protein in the cell nucleus.

Adenoma↗
PubMed1997

Molecular genetics of colon cancer.

Colorectal cancer remains a major health problem. Few therapies are effective apart from surgery, and survival has increased little in recent years. This is despite the fact that screening by colonoscopy can potentially remove nearly all colorectal tumours before they become malignant. Molecular genetics has identified some inherited mutations (such as at APC and the mismatch repair loci) that predispose to colon cancer and some somatic mutations (such as at APC and p53) that cause sporadic colon tumours. We review the likely role of these and other genes in colorectal tumorigenesis. We also highlight areas of relative ignorance in colon cancer and emphasise that many important genes, especially those that cause invasion and metastasis, remain to be identified. Colorectal cancer is, however, a well characterised tumour, as regards both its natural history and its histopathology; there are consequently good prospects for advances in colon cancer genetics, with probable benefits for its treatment. We anticipate: (a) that new genes predisposing to colon tumours, including those conferring relatively minor risks, will be characterised; (b) genes and proteins important in invasion and metastasis will be identified; (c) the network of protein interactions in which molecules such as APC are involved will be elucidated; (d) large-scale studies of somatic mutations in tumours will provide accurate predictions of prognosis and suggest optimal therapeutic regimens; and (e) new potential targets for therapy will be identified. Whilst molecular genetics is by no means sufficient for progress in preventing and treating colon cancer, it is a necessary and central part of such advances.

Adenoma↗
PubMed1997

Localization of a susceptibility locus for Peutz-Jeghers syndrome to 19p using comparative genomic hybridization and targeted linkage analysis.

Many human cancer susceptibility genes have been successfully mapped by genetic linkage studies. One that has so far eluded researchers is that for Peutz-Jeghers (P-J) syndrome, a condition characterized by intestinal hamartomatous polyposis and melanin spots of the lips, buccal mucosa and digits. A dramatically elevated risk of malignancy has also been documented. Gastrointestinal tumours as well as cancers of the breast, ovary, testis and uterine cervix appear to be overrepresented in families with this syndrome. The nature of hamartomatous polyps is equivicol. Hamartomas are usually considered histologically benign, but in the case of Peutz-Jeghers patients, there are reports of adenomatous and malignant changes in the polyps, and the possibility of a hamartoma-carcinoma sequence has been discussed. A search for a putative tumour suppressor locus was made using comparative genomic hybridization (CGH) of Peutz-Jeghers polyps, combined with loss of heterozygosity (LOH) study. Genetic linkage analysis in 12 families using markers from a deletion site demonstrated the presence of a high-penetrance locus in distal 19p with a multipoint lod score of 7.00 at marker D19S886 without evidence of genetic heterogeneity. The study demonstrates the power of CGH combined with LOH analysis in identifying putative tumour suppressor loci, and provides molecular evidence of malignant potential in hamartomas.

Adenocarcinoma↗
PubMed1996

Population genetics of tumours.

The available evidence suggests that cancer is essentially a somatic evolutionary process involving a series of mutations. Each mutation gives some advantage to a selected clone, and expansion then occurs within that selected clone. The advantages are associated with both growth rate and factors leading to independent growth. The aim of this paper is first to give some background information on genetic changes in tumours, using colorectal cancer as an example. We will then introduce a mathematical model that explains many phenomena associated with the development of benign tumours and the long lag periods that are characteristic of the development of human tumours. The model addresses populations of cells and not populations of people.

Apoptosis↗
PubMed1996

A pericentric inversion of chromosome six in a patient with Peutz-Jeghers' syndrome and the use of FISH to localise the breakpoints on a genetic map.

Karyotypic analysis in a patient with Peutz-Jeghers' syndrome demonstrated a pericentric inversion on chromosome 6. Further investigation was undertaken using fluorescence in situ hybridisation (FISH) with yeast artificial chromosome clones selected to contain genetic markers from chromosome 6, and a probe for the centromeric alphoid repeat array. This analysis located one inversion breakpoint within the alphoid array, in a 1-cM interval between D6S257 and D6S402, and the other in a 4-cM interval between D6S403 and D6S311. The oestrogen receptor gene locus (ESR) is excluded from the latter interval.

Adult↗
PubMed1993

NHS rationing.

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Attitude of Health Personnel↗
PubMed1989

The consequences of heterogamy and homogamy on the similarity between spouses.

Humans in many societies are known to mate, or marry, assortatively for a number of characters such as eye colour, height, IQ and place of birth. In this assortment an element of active choice may be involved. It is not known whether this choice is genetic. Two models of human mate choice are examined in which both males and females can express a mating preference. In the first, 'sexual' preferences can be expressed for any phenotype not necessarily one's own; in the second, preferences are only expressed for an individual's own phenotype. The results of the examination indicate how much active choice would be needed to account for the observed correlations between human mates, and suggest whether human mating preferences are more likely to be sexual or assorting.

Choice Behavior↗
PubMed1984

A fibrinolytic defect in chronic back pain syndromes.

Blood fibrinolytic activity was measured in 18 subjects with severe chronic back pain and 18 age and sex matched controls. The patients showed evidence of defective fibrinolysis--namely, significant prolongation of the euglobulin clot-lysis time, reduction in fibrin-plate lysis-area and plasminogen levels, and increase in levels of the fibrinolytic inhibitors, alpha 2 antiplasmin and alpha 2 macroglobulin. This defect could be associated with fibrin deposition and scar formation and be responsible for the development and/or perpetuation of chronic inflammation and scarring at sites of damage in the spine. Enhancement of fibrinolytic activity may offer a new approach to the management of these back problems, and a double-blind controlled trial is in progress.

Adult↗
PubMed1984

Starch synovitis.

Three patients with unexplained synovial inflammation were found to have an ulcerative, granulomatous synovitis on biopsy. Maize starch was identified in giant cells within the granulomata. Starch synovitis has clinical and histological similarities to starch peritonitis, which is thought to be an example of a cell mediated immune response.

Adult↗
PubMedDate not supplied

Reduced expression of molecules of the cadherin/catenin complex in the transition from colorectal adenoma to carcinoma.

E-cadherin is crucial to the intercellular adherens junctions which are involved in the organisation and maintenance of epithelial structure and suppression of tumour invasion. E-cadherin is associated with the actin cytoskeleton via cytoplasmic proteins, including alpha-, beta- and gamma-catenins, which together form the cadherin/catenin complex. To evaluate changes of the molecules of the cadherin/catenin complex in colorectal carcinogenesis, seventy-four sporadic adenomas, samples of histologically normal epithelium adjacent to 65 adenomas, and 52 carcinomas arising in adenomas were investigated by immunohistochemistry. All normal epithelial cells showed a uniform membranous staining pattern for E-cadherin, alpha-, beta-, and gamma-catenin. Decreased expression of all 4 proteins occurred in parallel in adenomas and carcinomas (in all cases, p < 10(-5). Decreased expression of the cadherin/catenin complex in adenomas was associated with increasing severity of dysplasia (p < 0.001, for E-cadherin, alpha-, and gamma-catenin, p < 0.005 for beta-catenin). Carcinomas displayed significantly reduced expression of the cadherin/catenin complex compared with their associated adenomas (all p < 0.001). The results directly confirm that colorectal tumour progression and invasion is associated with disruption of the cadherin/catenin complex and suggest that the genetic changes and transcriptional modulation of catenins underlying this progression may affect all members of the complex.

Adenoma↗