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Claire Taylor

Publications and source records attributed to Claire Taylor.

11 recordsLinked to original sources
PubMed2006

Genetic and epigenetic analysis of von Hippel-Lindau (VHL) gene alterations and relationship with clinical variables in sporadic renal cancer.

Genetic and epigenetic changes in the von Hippel-Lindau (VHL) tumor suppressor gene are common in sporadic conventional renal cell carcinoma (cRCC). Further insight into the clinical significance of these changes may lead to increased biological understanding and identification of subgroups of patients differing prognostically or who may benefit from specific targeted treatments. We have comprehensively examined the VHL status in tissue samples from 115 patients undergoing nephrectomy, including 96 with sporadic cRCC. In patients with cRCC, loss of heterozygosity was found in 78.4%, mutation in 71%, and promoter methylation in 20.4% of samples. Multiplex ligation-dependent probe amplification identified intragenic copy number changes in several samples including two which were otherwise thought to be VHL-noninvolved. Overall, evidence of biallelic inactivation was found in 74.2% of patients with cRCC. Many of the mutations were novel and approximately two-thirds were potentially truncating. Examination of these and other published findings confirmed mutation hotspots affecting codons 117 and 164, and revealed a common region of mutation in codons 60 to 78. Gender-specific differences in methylation and mutation were seen, although not quite achieving statistical significance (P = 0.068 and 0.11), and a possible association between methylation and polymorphism was identified. No significant differences were seen between VHL subgroups with regard to clinicopathologic features including stage, grade, tumor size, cancer-free and overall survival, with the exception of a significant association between loss of heterozygosity and grade, although a possible trend for survival differences based on mutation location was apparent.

Adult↗
PubMed2005

The rising incidence of childhood type 1 diabetes in New South Wales, 1990-2002.

OBJECTIVES: To determine the incidence of childhood type 1 diabetes mellitus (T1DM) in New South Wales from 1997 to 2002; to compare with previously published rates (1990-1996); and to analyse trends in incidence from 1990 to 2002. DESIGN, SETTING AND PARTICIPANTS: Prospective population-based incidence study. Primary ascertainment of incident cases aged < 15 years was from the Australasian Paediatric Endocrine Group NSW children's diabetes register. Secondary ascertainment was from the National Diabetes Supply Scheme until 1999 and from the Australian Institute of Health and Welfare thereafter. Childhood population data were obtained from the Australian Bureau of Statistics. MAIN OUTCOME MEASURES: Age-standardised incidence; trends in incidence by calendar year, and sex and age at diagnosis. RESULTS: There were 3260 incident cases (1629 boys, 1631 girls) in the 13 years. Case ascertainment was 99.7% complete using the capture-recapture method. Mean age-standardised incidence per 100 000 person-years was 20.9 (95% CI, 19.9 to 21.9) from 1997 to 2002 compared with 17.8 (95% CI, 17.0 to 18.7) from 1990 to 1996; there was a plateau in incidence between 1997 and 2002. Overall, the incidence increased on average by 2.8% per year (95% CI, 1.9% to 3.8%, P < 0.001) and increased with age, being 12.2 (95% CI, 11.3 to 13.1) in 0-4 year olds; 18.9 (95% CI, 17.8 to 20.0) in 5-9 year olds and 26.7 (95% CI, 25.4 to 28.1) in 10-14 year olds. The increase per year in 0-4 year olds (3.9%) was not significantly higher than in older children. The mean incidence of T1DM was 19.8 (95% CI, 18.8 to 20.7) in girls and 18.8 (95% CI, 17.9 to 19.7) in boys (P = 0.02). CONCLUSIONS: The incidence of childhood-onset T1DM has increased significantly in all age groups in NSW since 1990. Resource planning in the management of childhood diabetes in NSW should take these findings into account.

Adolescent↗
PubMed2005

Resistance to the tubulin-binding agents in renal cell carcinoma: no mutations in the class I beta-tubulin gene but changes in tubulin isotype protein expression.

PURPOSE: The primary purpose of this study was to determine whether mutations of the class I beta-tubulin gene may be implicated in the inherent resistance to tubulin-binding agents (TBA) in renal cancer, with a small number of samples and cell lines also being examined for class I and III beta-tubulin isotype protein expression. EXPERIMENTAL DESIGN: DNA was extracted from 90 renal tumors and the class I beta-tubulin gene analyzed for mutations. For each sample, eight PCRs were used to cover the complete coding sequence with intronic primers ensuring highly homologous pseudogenes were not coamplified. Additionally, expression levels of class I and III beta-tubulin isotypes in 17 matched normal and malignant renal samples and a panel of renal cell carcinoma cell lines with differing intrinsic resistance to the TBAs was examined by Western blotting. RESULTS: Four polymorphic sequence changes of the class I beta-tubulin gene were identified with no mutations. Class I protein expression levels were higher in tumor tissue versus normal tissue, whereas class III expression showed no consistent change. In renal cancer cell lines, a significant correlation between class III isotype expression and vinblastine sensitivity was observed. CONCLUSIONS: These results do not support a role for mutations in the class I beta-tubulin gene in the intrinsic resistance of renal cancer to TBAs. Class III isotype expression may be implicated in resistance in vitro but in vivo, changes in class I isotype expression in renal cell carcinoma tissue may support a role in resistance to the TBAs and warrants further investigation.

Adult↗
PubMed2005

Prevalence of 9p21 deletions in UK melanoma families.

Although the CDKN2A gene has been shown to be the major genetic determinant governing high-penetrance susceptibility to melanoma, there remains a significant proportion of melanoma pedigrees in which germline mutations of CDKN2A have not been identified. We have therefore studied the prevalence of germline 9p deletions encompassing the CDKN2 locus in melanoma pedigrees, using multiplex ligation-dependent probe amplification. Germline deletions were found in 3 of 93 UK pedigrees, with no previously identified CDKN2A mutations. A hemizygous deletion of CDKN2A exon 1beta previously reported by this group was confirmed in one family and identified in a second. Microsatellite analysis determined that these two families were ancestrally related. In the third family, a novel p16 hemizygous deletion involving CDKN2A exons 1alpha, 2, and 3 was detected. An additional 9p21 deletion reported previously in a USA melanoma-neural system tumor family was shown to involve CDKN2A exon 1beta, and not p16. The CDKN2A exon 1beta deletions provide further evidence that this tumor suppressor gene is important in melanoma-neural system tumor susceptibility, but do not exclude the possibility of a novel gene or regulatory element also being deleted in this region. Deletions at 9p21 are rare and explain only a small proportion of melanoma susceptibility. This study is the first to comprehensively exclude deletions in melanoma-prone families with no previously identified CDKN2A mutations.

Chromosome Deletion↗
PubMed2005

Development of a human acute myeloid leukaemia screening panel and consequent identification of novel gene mutation in FLT3 and CCND3.

A study was undertaken to develop an acute myeloid leukaemia (AML) screening panel to uncover novel recurring gene mutations. Analysis was performed on six genes known to be mutated in AML (RUNX1, FLT3, KIT, CEBPA, PTPN11 and NRAS) and an additional two candidate genes (CCND3 and FES) in a panel of 175 primary human AML samples that included all French-American-British types except M3, and all cytogenetic risk groups. One hundred and fifteen mutations were identified in 97 (55%) patients comprising 81 patients (46%) with one mutation, 14 patients (8%) with two mutations and two patients (1%) with three mutations. Fifty-five of 88 (63%) patients with normal karyotype AML had at least one mutation. Correlation was observed between KIT mutation and 'favourable risk' cytogenetics (P <0.001), CEBPA mutation and 'intermediate risk' cytogenetics (P=0.045), and PTPN11 mutation and 'poor risk' disease (P <0.001). The frequency of individual gene mutation was in accordance with previously published studies. Three novel mutations of FLT3 were detected (Y589D, D839G, Y842H) that would have been overlooked by conventional gel electrophoresis. A 51-bp deletion was detected in CCND3 in a patient with normal karyotype AML. This validated panel now provides an important tool to evaluate other candidate genes in the genesis of myeloid malignancy.

Acute Disease↗
PubMed2005

No Evidence for BRAF as a melanoma/nevus susceptibility gene.

Somatic mutations of BRAF have been identified in both melanoma tumors and benign nevi. Germ line mutations in BRAF have not been identified as causal in families predisposed to melanoma. However, a recent study suggested that a BRAF haplotype was associated with risk of sporadic melanoma in men. Polymorphisms or other variants in the BRAF gene may therefore act as candidate low-penetrance genes for nevus/melanoma susceptibility. We hypothesized that promoter variants would be the most likely candidates for determinants of risk. Using denaturing high-pressure liquid chromatography and sequencing, we screened peripheral blood DNA from 184 familial melanoma cases for BRAF promoter variants. We identified a promoter insertion/deletion in linkage disequilibrium with the previously described BRAF polymorphism in intron 11 (rs1639679) reported to be associated with melanoma susceptibility in males. We therefore investigated the contribution of this BRAF polymorphism to melanoma susceptibility in 581 consecutively recruited incident cases, 258 incident cases in a study of late relapse, 673 female general practitioner controls, and the 184 familial cases. We found no statistically significant difference in either genotype or allele frequencies between cases and controls overall or between male and female cases for the BRAF polymorphism in the two incident case series. Our results therefore suggest that the BRAF polymorphism is not significantly associated with melanoma and the promoter insertion/deletion linked with the polymorphism is not a causal variant. In addition, we found that there was no association between the BRAF genotype and mean total number of banal or atypical nevi in either the cases or controls.

Alleles↗
PubMed2004

Sequence variation in the I-like domain of the beta1 integrin subunit in human oral squamous cell carcinomas.

We recently identified a heterozygous mutation in the beta1 integrin subunit of a squamous cell carcinoma (SCC) that maps to the I-like domain and activates ligand binding. To investigate the frequency of such mutations we screened 124 human oral SCCs. We identified six single nucleotide changes, all of which were also present in normal tissue, suggestive of polymorphisms. Two were in non-coding intronic sequences. Three were silent changes in exons. One caused a change in amino acid (A239V) that is unlikely to disturb integrin structure. We conclude that mutations in the beta1 I-like domain are uncommon in SCCs. However, population based studies of the polymorphisms we found may reveal an association with SCC development or prognosis.

Carcinoma, Squamous Cell↗
PubMed2003

Does the occurrence of certain rare cancers indicate an inherited cancer susceptibility?

We sought to determine whether rare cancers indicate an increased risk of inherited cancer susceptibility. We ascertained 77 individuals with rare cancers which occur with increased relative risk in carriers of germline BRCA1/BRCA2 (fallopian, young-onset pancreatic) or HNPCC (biliary, small intestinal, urothelial, gallbladder, young-onset pancreatic) mutations. Individuals with two primary neoplasms (7), or with a first- or two second-degree relatives with breast/ovarian cancer were tested for BRCA1/BRCA2 mutations (18); those with two primary HNPCC cancers or one first degree relative with an HNPCC-related cancer were tested for mutations in MLH1/MSH2 (19). Of these 77 individuals with cancer (19 fallopian, 8 gallbladder, 17 biliary, 17 pancreatic, 11 urothelial, 5 small intestinal), 39 (50.6%) had at least one first degree relative with cancer (excluding lung and skin); two conformed to Bethesda HNPCC criteria. No definitely pathogenic germline MLH1 and MSH2 mutations were found in 19 individuals, although 2 MSH2 variants were detected. A family history of breast/ovarian, HNPCC or colon cancer in a first degree relative was found in 40% of fallopian, 20% of biliary, 35% of pancreatic, 27% of urothelial and 20% of small bowel cancer patients. A BRCA1 frameshift mutation was detected in a woman with fallopian (54 y) and breast (39 y) cancers, and a BRCA2 nonsense mutation in a woman with biliary (48 y) and breast (45 y) cancers. This study supports the premise that the occurrence of rare (especially double primary) cancers does indicate an increased cancer susceptibility, although the numbers of cases ascertained were too small to draw firm conclusions.

Adult↗
PubMed2002

Mutation cluster region, association between germline and somatic mutations and genotype-phenotype correlation in upper gastrointestinal familial adenomatous polyposis.

Studies of adenomatous polyposis coli (APC) mutations in familial adenomatous polyposis (FAP) have focused on large bowel disease. It has been found that: 1) germline APC mutations around codon 1300 are associated with severe colorectal polyposis; 2) somatic APC mutations in colorectal tumors tend to cluster approximately between codons 1250 and 1450; and 3) patients with germline mutations close to codon 1300 tend to acquire somatic mutations (second hits) in their colorectal polyps by allelic loss, whereas the tumors of other FAP patients have truncating second hits. Using new and published data, we have investigated how germline and somatic APC mutations influence the pathogenesis of upper gastrointestinal polyps in FAP. We have compared the results with those from colorectal disease. We found that somatic mutations in upper gastrointestinal polyps cluster approximately between codons 1400 and 1580. Patients with germline APC mutations after codon 1400 tend to show allelic loss in their upper gastrointestinal polyps; the tumors of other patients have truncating somatic mutations after codon 1400. Finally, patients with germline mutations after codon 1400 tend to have more severe duodenal polyposis (odds ratio, 5.72; 95% confidence interval, 1.13 to 28.89; P = 0.035). Thus, in both upper gastrointestinal and colorectal tumors, a specific region of the APC gene is associated with severe disease, clustering of somatic mutations, and loss of the wild-type allele. However, the region concerned is different in upper gastrointestinal and colorectal disease. The data suggest that loss of all APC SAMP repeats is probably necessary for duodenal and gastric tumorigenesis in FAP, as it is in colonic tumors. Compared with colonic tumors, however, retention of a greater number of beta-catenin binding/degradation repeats is optimal for tumorigenesis in upper gastrointestinal FAP.

Adenomatous Polyposis Coli↗