Nomenclature for factors of the HLA system, 1996.
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Alleles↗
Biomedical subjects
W F Bodmer
Publications and source records attributed to W F Bodmer.
Nomenclature for factors of the HLA system, 1996.
Explore the source record for details and available documents.
Alleles↗
The mutation rate and cancer.
The selection of advantageous mutations underlies tumorigenesis. The growth of a tumor is therefore a form of evolution at the somatic level, in which the population is comprised of individual cells within the tumor. Models of tumorigenesis have considered the relative importance of mutation and selection. We show that selection is more important than an increased mutation rate in the growth of a tumor. Some cancers may acquire a "mutator phenotype," probably leading to faster growth, but mutator phenotypes are not necessary for carcinogenesis.
Biological Evolution↗
Selection for beta 2-microglobulin mutation in mismatch repair-defective colorectal carcinomas.
Novel peptide antigens complexed with human leukocyte antigen (HLA) and beta 2-microglobulin (beta 2M) molecules are presented at the cell surface to cytotoxic T lymphocytes (CTLs), provoking lysis of the antigen-presenting cell [1]. In tumor cells, genetically altered or abnormally expressed proteins provide a source of peptides that can be presented to CTLs; the resulting anti-tumour CTL responses may provide part of the body's defence against cancer. Disabling mutations in the HLA and beta 2M proteins required for peptide presentation allow a tumour cell to escape destruction by CTLs. Cells with deficient DNA mismatch repair have high spontaneous mutation rates [2] and produce many altered proteins that are a potential source of numerous unique peptides. Mutator tumour cells might therefore be particularly vulnerable to immune surveillance and CTL attack. Mutator phenotypes [3,4] and loss of beta 2M (or HLA) expression [5,6] are both relatively common among sporadic colorectal tumours. We have compared the frequency of beta 2M mutations in sporadic colorectal and other tumours with and without a mutator phenotype. Mutations were more frequent among colorectal tumours with the microsatellite instability indicative of a defect in DNA mismatch repair. The inactivating beta 2M mutations were predominantly frameshifts, which is consistent with the underlying mismatch repair defects. Evasion of immune surveillance by acquiring beta 2M mutations therefore occurs at high frequency in tumour cells with a mutator phenotype due to defective DNA mismatch repair.
Colorectal Neoplasms↗
Polyclonal origin of colonic adenomas in an XO/XY patient with FAP.
It is widely accepted that tumors are monoclonal in origin, arising from a mutation or series of mutations in a single cell and its descendants. The clonal origin of colonic adenomas and uninvolved intestinal mucosa from an XO/XY mosaic individual with familial adenomatous polyposis (FAP) was examined directly by in situ hybridization with Y chromosome probes. In this patient, the crypts of the small and large intestine were clonal, but at least 76 percent of the microadenomas were polyclonal in origin.
Adenomatous Polyposis Coli↗
Expression of a single-chain HLA class I molecule in a human cell line: presentation of exogenous peptide and processed antigen to cytotoxic T lymphocytes.
We have synthesized a recombinant gene encoding a single-chain HLA-A2/beta 2-microglobulin (beta 2m) molecule by linking beta 2m through its carboxyl terminus via a short peptide spacer to HLA-A2 (A*0201). This gene has been expressed in the beta 2m-deficient colorectal tumor cell line DLD-1. Transfection of this cell with the single-chain construct was associated with conformationally correct cell surface expression of a class I molecule of appropriate molecular mass. The single-chain HLA class I molecule presented either exogenously added peptide or (after interferon-gamma treatment) endogenously processed antigen to an influenza A matrix-specific, HLA-A2-restricted cytotoxic T-lymphocyte line. The need for interferon gamma for the processing and presentation of endogenous antigen suggests that DLD-1 has an antigen-processing defect that can be up-regulated, a feature that may be found in other carcinomas. Our data indicate that single-chain HLA class I constructs can form functional class I molecules capable of presenting endogenously processed antigens. Such molecules should be of use for functional studies, as well as providing potential anticancer immunotherapeutic agents or vaccines.
Amino Acid Sequence↗
Clinico-pathological features and p53 expression in left-sided sporadic colorectal cancers with and without microsatellite instability.
Defects in mismatch repair (MMR) can result in the development of a 'mutator phenotype', manifest as an increase in DNA replication errors (RERs). Patients with hereditary non-polyposis colorectal cancer (HNPCC) have germline mutations in MMR genes. These patients develop carcinomas of the colon and other specific sites at a significantly earlier age than patients with sporadic carcinomas. RERs are found in the cancers from patients with HNPCC and have been demonstrated in 10-20 per cent of sporadic colorectal cancers (CRCs). Loss of MMR may simply accelerate tumour development, but it is also possible that these tumours follow a different carcinogenetic pathway from tumours with intact MMR. In particular, it has been suggested that p53 mutations occur less often in RER-positive (RER+) sporadic colorectal cancers. In this study, the clinico-pathological features and frequency of p53 overexpression in 17 left-sided RER+ CRCs were compared with 35 left-sided RER- CRCs. No differences were found in the age and tumour stage at presentation, mucinous differentiation, or Jass prognostic grouping between these two types of CRC. Thirteen out of 17 (76 per cent) RER+ and 19/35 (54 per cent) RER- tumours showed overexpression of p53, a non-significant difference (chi 2 test). Although some previous studies have suggested differences in the clinico-pathological features and p53 expression of RER+ and RER- right-sided CRCs, our results show that these differences do not exist in left-sided cancers.
Aged↗
The frequency and mechanism of loss of heterozygosity on chromosome 11q in breast cancer.
Loss of heterozygosity (LOH, allele loss) occurs frequently on the long arm of chromosome 11 in breast cancer. Seventy-one paired tumour/normal DNA samples from breast cancer patients under 50 years old were studied for allele loss at four microsatellite loci on 11q: D11S29 (11q23.3), NCAM (11q22-q23), D11S968 (11qtel), and D11S1313 (11qcen). The maximum frequency of LOH (approximately 35 per cent) was found at the D11S29 and NCAM loci. This result is consistent with previous studies and the frequency of allele loss is moderate to high compared with the usual baseline of 0-20 per cent. In most of the cases studied, LOH on chromosome 11q could be accounted for by one of two mechanisms. Either chromosomal non-disjunction had occurred, or sequences stretching from the telomere at least as far as NCAM had undergone deletion or mitotic recombination. These results suggest that a putative tumour suppressor gene is most likely to exist near 11q22-q23. There was a very low frequency of microsatellite instability in the tumours. An association was found between lack of progesterone receptor (PgR) expression and LOH at NCAM, suggesting that deletion of sequences on 11q may prevent high levels of PgR expression in some cases.
Adult↗
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↗
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↗
Allele loss on chromosome 11q and microsatellite instability in malignant melanoma.
Loss of heterozygosity (allele loss, LOH) occurs frequently on the long arm of chromosome 11 in several types of cancer. We analysed 32 melanomas (almost all metastatic lesions) for allele loss at eight loci along the length of chromosome 11 (ptel-D11S922-D11S899-D11S1324-D11S1313-++ +D11S901-NCAM-D11S29-D11S968-qtel). The highest frequency of loss (38%) was at D11S29 (11q23.3). Of 13 melanomas which had lost an allele at one or more loci, all but one showed LOH at either D11S29 or NCAM (11q22). The region between these two loci is the most likely location of any tumour suppressor gene. Low frequencies of LOH occurred on 11p and there was little evidence for tumour suppressor loci outside the 11cen-q23.3 region. Unusually for melanomas, widespread microsatellite instability, with slippage of several repeat units, was observed in two of 32 tumours studied (and four other tumours showed new microsatellite alleles that differed by just one repeat unit from their normal counterparts). However, no mutations of the mismatch repair genes hMSH2 and hMLH1 were detected in these two tumours, and the observed replication errors may result from mutations in other genes involved in mismatch repair or DNA replication. LOH on 11q and replication errors appear to comprise part of the genetic pathways of several tumour types, including melanomas.
Adult↗
Allele loss occurs frequently at hMLH1, but rarely at hMSH2, in sporadic colorectal cancers with microsatellite instability.
Mutations at the hMSH2 and hMLH1 mismatch repair loci have been implicated in the pathogenesis of colorectal cancer. Tumours with two allelic mutations at a mismatch repair locus develop replication errors (RERs). In the hereditary non-polyposis colorectal cancer (HNPCC) syndrome, one mutation is inherited and the other acquired somatically: in RER+ sporadic colorectal cancers, both mutations are somatic. RER+ tumours tend to have a low frequency of allele loss, presumably because they acquire most mutations through RERs. However, before a second mismatch repair mutation has occurred somatically, there is no reason to suppose that allele loss occurs less frequently in tumours that are to become RER+. Indeed, this second mutation might itself occur by allele loss. We have searched for allele loss at the hMSH2 and hMLH1 loci in RER+ and RER- sporadic colorectal cancers. Loss occurred at the hMLH1 locus in 7/17 (41%) RER+ tumours, compared with 6/40 (15%) RER- cancers (chi2=3.82, P approximately 0.05). At hMSH2, 2/22 RER+ sporadic cancers (9%) had lost an allele, compared with 2/40 (5%) RER- cancers (chi2=0.03, P>0.5). Taken together with previous studies which focused on colorectal cancers from HNPCC families, the data suggest that allele loss at hMLH1, but not at hMSH2, contributes to defective mismatch repair in inherited and sporadic colorectal cancer.
Adaptor Proteins, Signal Transducing↗
Variants at the secretory phospholipase A2 (PLA2G2A) locus: analysis of associations with familial adenomatous polyposis and sporadic colorectal tumours.
The Min mouse is a model for human familial adenomatous polyposis (FAP), an autosomal dominant disease characterised by multiple adenomatous gastrointestinal polyps. The severity of the Min phenotype is modified by a locus (Mom1) on mouse chromosome 4, at a position syntenic with human chromosome 1p35-p36. The secretory phospholipase A2 (Pla2s) gene is a candidate for this modifier locus and there is evidence that a locus on human chromosome 1p35-p36 acts to modify the severity of human duodenal FAP. We have analysed the human secretory phospholipase A2 locus (PLA2G2A) for variants that could directly influence the FAP phenotype. We found no PLA2G2A variants predicted to result in functional variation in the phospholipase A2 protein. Two PLA2G2A polymorphisms were, however, discovered, one a 'silent' base change in exon 3 and another in a noncoding region. Three other variants (possible mutations) were found in non-coding regions. In 70 FAP patients from 20 families, no associations were found between the severity of duodenal polyposis and any PLA2G2A variant. One allele at the exon 3 polymorphic site did, however, occur more often then expected in patients with relatively severe colonic FAP. Although of borderline statistical significance, this association, if genuine, is likely to result from linkage disequilibrium between the PLA2G2A alleles studied and undetected genetic variation at a closely linked locus. The frequency of the alleles at both polymorphic sites has also been determined in the germ line of patients with sporadic colorectal adenomas and carcinomas and in random controls, but no differences were found among these groups. Our results suggest that PLA2G2A variants do not influence inherited or sporadic colonic tumours. A linked locus may be a modifier of human FAP, but does not influence the risk of colorectal tumours in the general population.
Adenomatous Polyposis Coli↗
Testing candidate loci on chromosomes 1 and 6 for genetic linkage to Peutz-Jeghers' disease.
Peutz-Jeghers' syndrome (PJS) is a disease with autosomal dominant inheritance, which is characterised by gastrointestinal hamartomata and characteristic melanin pigmentation. Three candidate sites for a PJS locus have recently been proposed, chromosomes 1p31-p32, 6q25 and 6p11-cen. At the first of these sites, a multipoint LOD score of 4.00 had been found, strongly suggesting genetic linkage to PJS. The last two candidate sites were suggested by the chromosomal breakpoints of a patient with an inv(6) and PJS. We have analysed up to 34 families in order to test each of the three candidate sites for linkage to PJS. No evidence was found in support of a Peutz-Jeghers' syndrome locus on chromosome 1p31-p32. The candidate region on 6q25 was also excluded. The region close to the centromere of chromosome 6 has not been excluded and there is some evidence of linkage to a marker near 6cen, although genetic heterogeneity in PJS must be proposed to account for a gene at this site.
Chromosomes, Human, Pair 1↗
Chromosome 11q in sporadic colorectal carcinoma: patterns of allele loss and their significance for tumorigenesis.
AIMS: To analyse the frequency of loss of heterozygosity (allele loss, LOH) in a large sample of colorectal carcinomas using highly informative markers along chromosome 11q. METHODS: One hundred paired samples of colorectal cancer and normal tissue were genotyped at six microsatellite markers on chromosome 11q (cen-D11S1313-D11S901-DRD2/NCAM-D11S29- D11S968-tel). The high levels of heterozygosity at these markers allow allele loss to be determined in about 80% of cases at any one locus. The frequency of replication errors (RERs, microsatellite instability) has also been determined. RESULTS: LOH was found at frequencies of 25% and 29% at the distal D11S968 (11qter) and D11S29 (11q23.3) loci, slightly above the accepted baseline of 0-20%. Allele loss at NCAM, DRD2, D11S901, and D11S1313 was not raised above baseline levels. The probable genetic mechanism of allele loss--chromosomal non-disjunction, mitotic recombination, deletion, or gene conversion--seemed to vary between tumours and no consistent mechanism of mutation was found. Microsatellite instability was found in 23 (23%) tumours. No associations were found between LOH and clinical data (patient sex, age at presentation, tumour site, and Duke's stage). CONCLUSIONS: Although gene(s) on 11q may have a role in the development of a minority of colorectal carcinomas, this study provides evidence against the general importance of allele loss on chromosome 11q in the pathogenesis of colorectal cancer. The results also have implications for the importance of 11q in other cancers: it seems less likely that a single tumour supressor gene at this location promotes the growth of all types of tumour when lost. Rather, one or more genes with tissue specific effects may be involved.
Age Factors↗
A modifying locus for familial adenomatous polyposis may be present on chromosome 1p35-p36.
Mutations of the APC gene cause familial adenomatous polyposis (FAP) in humans and multiple intestinal neoplasia (Min) in laboratory mouse strains. A dominant modifying gene (Mom1), which partially suppresses the min phenotype, has been mapped to mouse chromosome 4. This region is syntenic with human chromosome 1p35-p36. The phospholipase A2 (Pla2s) locus is an excellent candidate for Mom1 and the equivalent human locus PLA2G2A is found on chromosome 1p35. It does not necessarily follow, however, than any modifier of mouse polyposis also influences human disease. In order to test whether a locus on 1p modifies FAP, subjects from 28 FAP families have been typed at microsatellite loci on this chromosome arm. The severity of their duodenal polyposis has also been assessed by endoscopy. Pedigree (lod score) linkage analysis found no evidence of a simple, dominant modifying gene, comparable with the action of Mom1 in inbred mouse strains. Given the more complex genetic and environmental interactions likely to exist in outbred human populations, it is probably more appropriate to use tests which do not specify a mode of inheritance. Using these methods of analysis, the data suggest that a locus on chromosome 1p35-p36 may influence the severity of duodenal FAP.
Adenomatous Polyposis Coli↗
Genetic mapping of hereditary mixed polyposis syndrome to chromosome 6q.
Hereditary mixed polyposis syndrome (HMPS) is characterized by atypical juvenile polyps, colonic adenomas, and colorectal carcinomas. HMPS appears to be inherited in an autosomal dominant manner. Genetic linkage analysis has been performed on a large family with HMPS. Data did not support linkage to the APC locus or to any of the loci for hereditary nonpolyposis colorectal cancer. Evidence that the HMPS locus lies on chromosome 6q was, however, provided by significant two-point LOD scores for linkage between HMPS and the D6S283 locus. Analysis of recombinants and multipoint linkage analysis suggested that the HMPS locus lies in a 4-cM interval containing the D6S283 locus and flanked by markers D6S468 and D6S301.
Adenoma↗
Bcl-2 expression in colorectal tumors: evidence of different pathways in sporadic and ulcerative-colitis-associated carcinomas.
Colorectal cancers (CRCs) differ in their age at presentation, distribution, histological features, and prognosis. If tumor biology reflects genetic events, these tumors might be expected to show differences in their genetic pathways. In this study, we investigated the role of Bcl-2 in the development of three different tumor groups. Using markers at eight different microsatellite locl, we characterized one group of 34 left-sided sporadic CRCs as replication error negative (RER-) and another group of 18 left-sided sporadic CRCs as replication error positive (RER+). These tumors, together with a third group of 22 left-sided ulcerative-colitis-associated CRCs (UCACRCs), were then examined by immunohistochemistry for Bcl-2 overexpression. Of 34 of the RER- tumors, 21 (62%) and 10 of 18 (56%) of the RER+ tumors were positive for Bcl-2 overexpression. In contrast, only 5 of 22 (23%) of the UCACRCs showed similar overexpression. Our results show a significantly lower frequency of Bcl-2 overexpression in UCACRCs as compared with sporadic CRCs (P < 0.005) but no difference between sporadic left-sided RER+ and RER- CRCs. These data provide additional evidence that UCACRCs may develop along a pathway that is different from that of sporadic CRCs.
Carcinoma↗