Muir Torre syndrome and MSH2 mutations: the importance of dermatological awareness.
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Anus Neoplasms↗
Biomedical subjects
W D Foulkes
Publications and source records attributed to W D Foulkes.
Extensive DNA methylation in normal colorectal mucosa in hyperplastic polyposis.
BACKGROUND: Hyperplastic polyposis of the colorectum is a precancerous condition that has been linked with DNA methylation. The polyps in this condition have been distinguished from typical small hyperplastic polyps and renamed sessile serrated adenomas. Sessile serrated adenomas also occur sporadically and appear to be indistinguishable from their counterparts in hyperplastic polyposis. AIMS AND METHODS: The existence of distinguishing molecular features was explored in a series of serrated polyps and matched normal mucosa from patients with and without hyperplastic polyposis by assessing mutation of BRAF, DNA methylation in 14 markers (MINTs 1, 2 and 31, p16, MGMT, MLH1, RASSF1, RASSF2, NORE1 (RASSF5), RKIP, MST1, DAPK, FAS, and CHFR), and immunoexpression of MLH1. RESULTS: There was more extensive methylation in sessile serrated adenomas from subjects with hyperplastic polyposis (p<0.0001). A more clearcut difference in patients with hyperplastic polyposis was the finding of extensive DNA methylation in normal mucosa from the proximal colon. CONCLUSIONS: A genetic predisposition may underlie at least some forms of hyperplastic polyposis in which the earliest manifestation may be hypermethylation of multiple gene promoters in normal colorectal mucosa. Additionally, some of the heterogeneity within hyperplastic polyposis may be explained by different propensities for MLH1 inactivation within polyps.
Adaptor Proteins, Signal Transducing↗
Is the E133K allele of VG5Q associated with Klippel-Trenaunay and other overgrowth syndromes?
BACKGROUND: It has been reported that the activating mutation, E133K, in the angiogenic factor VG5Q (formally named AGGF1) causes Klippel-Trenaunay Syndrome (KTS), a rare vascular disease associated with asymmetric overgrowth. This proposal followed from the observation that five out of 130 KTS patients were constitutionally heterozygous for VG5Q, E133K. OBJECTIVE: To explore the possibility that VG5Q, and specifically E133K, is implicated in other mosaic overgrowth syndromes. RESULTS: 24 patients were analysed for this sequence change. One patient was constitutionally heterozygous for E133K. Analysis of both parents revealed that the patient's mother, who was healthy, also carried E133K. An analysis of 275 healthy controls showed that 3.3% (9/275) of the population were carriers of E133K. CONCLUSIONS: The findings bring into question the assertion that VG5Q, E133K is a mutation and that it causes KTS.
Amino Acid Substitution↗
Transforming growth factor-beta pathway disruption and infiltration of colorectal cancers by intraepithelial lymphocytes.
AIMS: Colorectal cancers deficient in DNA mismatch repair (MMR) are often characterized by the presence of numerous intraepithelial lymphocytes (IELs). These CD8+ T cells selectively express CD103, which is upregulated locally by transforming growth factor (TGF)-beta, and adhere to E-cadherin expressed by mucosal epithelia. Many of these cancers also possess inactivating mutations in the type II TGF-beta receptor and are believed to be insensitive to TGF-beta. The present study aimed to explore whether such refractoriness to TGF-beta is an independently contributing factor to IEL retention. METHODS AND RESULTS: A panel of colorectal cancers enriched for DNA MMR deficiency was examined by immunohistochemistry to explore the expression levels and localization of various components in the TGF-beta signalling pathway. Logistic regression was then carried out in order to identify predictors of elevated lymphocytic infiltration independent of DNA MMR status. Increases in Smad4 expression, tumour cell proliferation and TGF-beta secretion each emerged as independent predictors of marked lymphocyte infiltration. CONCLUSIONS: These results strongly support the hypothesis that refractoriness to normal TGF-beta signalling in colorectal cancers plays a role in the retention of lymphocytes within tumour epithelium. Since IEL infiltration is an independent predictor of favourable prognosis, the TGF-beta pathway may represent an important therapeutic target.
Adenocarcinoma↗
Multiple primary malignancies in a patient with situs ambiguus.
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Female↗
Application of BRCA1 and BRCA2 mutation carrier prediction models in breast and/or ovarian cancer families of French Canadian descent.
The BRCAPRO, Couch, Myriad I and II, Ontario Family History Assessment Tool (FHAT), and Manchester models have been used to predict BRCA1 or BRCA2 mutation carrier status of women at high risk for developing the heritable form of breast and ovarian cancers. We have evaluated these models for their accuracy in classifying 224 French Canadian families with at least three cases of breast cancer (diagnosed before the age of 65 years), ovarian cancer, or male breast cancer where mutation status was known for an index affected case used to assess the model. This series includes 44 BRCA1 and 52 BRCA2 mutation-positive families. Using receiver operator characteristics analyses, the C-statistics were found to be 0.81, 0.80, 0.79, and 0.74 for the BRCAPRO, FHAT, Manchester, and Myriad II models, respectively, when incorporating both BRCA1 and BRCA2 mutation carrier predictions. For the BRCAPRO model, 75% scored greater than a 0.43 probability in the mutation-positive group and 75% scored less than 0.50 in the mutation-negative group. Only 38 of 128 (30%) mutation-negative group had a probability greater than 0.43 with the BRCAPRO model. While all models were highly predictive of carrier status, the BRCAPRO model was the most accurate where a cut-off of 10% would have eliminated 60 of 128 (47%) mutation-negative families for genetic testing and only miss 10 of 96 (10%) mutation-positive families. A review of the cancer phenotypes with high BRCAPRO probabilities showed that significantly more metachronous bilateral breast cancer cases occurred in BRCA1/2 mutation carrier families in comparison to mutation-negative families, a feature which is not discriminated in the BRCAPRO model.
BRCA1 Protein↗
Disruption of an exon splicing enhancer in exon 3 of MLH1 is the cause of HNPCC in a Quebec family.
BACKGROUND: A 3 bp deletion located at the 5' end of exon 3 of MLH1, resulting in deletion of exon 3 from RNA, was recently identified. HYPOTHESIS: That this mutation disrupts an exon splicing enhancer (ESE) because it occurs in a purine-rich sequence previously identified as an ESE in other genes, and ESEs are often found in exons with splice signals that deviate from the consensus signals, as does the 3' splice signal in exon 3 of MLH1. DESIGN: The 3 bp deletion and several other mutations were created by polymerase chain reaction mutagenesis and tested using an in vitro splicing assay. Both mutant and wild type exon 3 sequences were cloned into an exon trapping vector and transiently expressed in Cos-1 cells. RESULTS: Analysis of the RNA indicates that the 3 bp deletion c.213_215delAGA (gi:28559089, NM_000249.2), a silent mutation c.216T-->C, a missense mutation c.214G-->C, and a nonsense mutation c.214G-->T all cause varying degrees of exon skipping, suggesting the presence of an ESE at the 5' end of exon 3. These mutations are situated in a GAAGAT sequence 3 bp downstream from the start of exon 3. CONCLUSIONS: The results of the splicing assay suggest that inclusion of exon 3 in the mRNA is ESE dependent. The exon 3 ESE is not recognised by all available motif scoring matrices, highlighting the importance of RNA analysis in the detection of ESE disrupting mutations.
Adaptor Proteins, Signal Transducing↗
Cyclin E expression in breast cancer: predicting germline BRCA1 mutations, prognosis and response to treatment.
BACKGROUND: Elevated levels of the cell cycle protein cyclin E, and low levels of its inhibitor, p27(Kip1), have been associated with a poor prognosis following breast cancer. Some studies have found that germline mutations in the breast cancer susceptibility gene, BRCA1, are also associated with an inferior survival rate. The relationship between cyclin E/p27(Kip1) levels, BRCA1 status and outcome has not been studied in detail. PATIENTS AND METHODS: We analyzed a historical cohort of 288 Ashkenazi Jewish women who were diagnosed with breast cancer between 1980 and 1995 and were previously tested for BRCA1/2 mutations. Protein levels of cyclin E and p27(Kip1) were assessed by immunohistochemistry. Breast cancer-specific survival (BCSS) was the main outcome measured. RESULTS: The median follow-up was 8 years. Thirty tumors carried germline BRCA1 mutations. These tumors were more likely to have high cyclin E protein levels [odds ratio (OR) 9.5; P <0.001] and low p27(Kip1) protein levels (OR 2.8; P=0.03) than tumors from patients without BRCA1/2 mutations. High cyclin E expression level was the strongest predictor of BRCA1 germline mutations (multivariate OR 4.7; P=0.004). On univariate analysis, high cyclin E protein levels [relative risk (RR) 2.6; P <0.001] and low p27(Kip1) protein levels (RR 2.3; P=0.006) were significant prognostic factors for a poorer BCSS. In Cox multivariate models, high cyclin E levels remained an independent indicator of poor outcome only in the subgroup of patients who did not receive chemotherapy (P=0.002). CONCLUSIONS: In this ethnically restricted cohort, a high level of cyclin E is a characteristic of BRCA1-related breast cancer, and is a marker of poor prognosis following breast cancer, particularly in the absence of adjuvant chemotherapy.
Adult↗
Novel genomic insertion-- deletion in MLH1: possible mechanistic role for non-homologous end-joining DNA repair.
Hereditary non-polyposis colorectal cancer (HNPCC) is an inherited cancer syndrome caused by a defect in the mismatch repair pathway. The majority of HNPCC mutations have been detected in MLH1 and MSH2. Most reported mutations are substitutions, small insertions and deletions, but standard methods of mutation analysis do not detect large rearrangements. It is now established that large deletions, insertions and rearrangements account for a significant proportion of MLH1 and MSH2 mutations. We report an unusual rearrangement resulting in the deletion of exons 6, 7 and 8 of MLH1, with the retention of part of intron 6 and insertions of two nucleotides each flanking the retained sequence. The 349-bp-retained sequence is made up of two closely spaced Alu sequences. The mutation was initially detected by protein truncation test and cDNA sequencing. Multiplex ligation-dependent probe amplification confirmed the deletion of three exons. PCR and sequencing were used to characterize the breakpoint. Despite the high density of Alu elements in MLH1, there is no homology at the deletion breakpoints or insertion junctions in this case to suggest that homologous recombination has occurred. We propose a mechanism involving non-homologous end joining to explain the occurrence of this complex deletion.
Adaptor Proteins, Signal Transducing↗
BRCA1:185delAG found in the San Luis Valley probably originated in a Jewish founder.
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Base Sequence↗
The HNPCC associated MSH2*1906G-->C founder mutation probably originated between 1440 CE and 1715 CE in the Ashkenazi Jewish population.
The MSH2*1906G-->C mutation was recently shown to be a rare yet highly penetrant mutation leading to colorectal cancer. The mutation was only found among Ashkenazi Jewish individuals and lies on an extended haplotype that is common in that population. This study determined that the mutation probably arose between 11 and 22 generations ago, during the time when the Ashkenazim were living in eastern Europe.
Alleles↗
Mutation analysis of the tumor suppressor PTEN and the glypican 3 (GPC3) gene in patients diagnosed with Proteus syndrome.
Proteus syndrome is a complex hamartomatous disorder characterized by asymmetrical gigantism, epidermal nevi, vascular malformations, hamartomas, lipomas, and hyperostosis. Since the syndrome was first described, many hypotheses have been proposed to explain its occurrence. The most plausible is Happle's somatic mosaic hypothesis, but no somatic mutations in candidate genes have been reported to be clearly involved in Proteus syndrome. However, germ-line PTEN mutations have been reported in patients with Proteus and in "Proteus-like disorders." Other studies of patients with Proteus syndrome have not supported these findings. In this study, affected and unaffected tissue from six patients diagnosed with Proteus syndrome were screened by direct sequencing of genomic DNA to determine if there might be an association between germ-line or somatic mutations in PTEN or GPC3 and the development of Proteus syndrome. No intra-exonic mutations were identified, indicating that neither PTEN nor GPC3 are likely to have major roles in the etiology of Proteus syndrome in our series of patients.
DNA↗
Breast-feeding and the risk of breast cancer in BRCA1 and BRCA2 mutation carriers.
BACKGROUND: Several studies have reported that the risk of breast cancer decreases with increasing duration of breast-feeding. Whether breast-feeding is associated with a reduced risk of hereditary breast cancer in women who carry deleterious BRCA1 and BRCA2 mutations is currently unknown. METHODS: We conducted a case-control study of women with deleterious mutations in either the BRCA1 or the BRCA2 gene. Study participants, drawn from an international cohort, were matched on the basis of BRCA mutation (BRCA1 [n = 685] or BRCA2 [n = 280]), year of birth (+/-2 years), and country of residence. The study involved 965 case subjects diagnosed with breast cancer and 965 control subjects who had no history of breast or ovarian cancer. Information on pregnancies and breast-feeding practices was derived from a questionnaire administered to the women during the course of genetic counseling. Conditional logistic regression analyses were used to estimate odds ratios (ORs) for the risk of breast cancer. All statistical tests were two-sided. RESULTS: Among women with BRCA1 mutations, the mean total duration of breast-feeding was statistically significantly shorter for case subjects than for control subjects (6.0 versus 8.7 months, respectively; mean difference = 2.7 months, 95% confidence interval [CI] = 1.4 to 4.0; P<.001). The total duration of breast-feeding was associated with a reduced risk of breast cancer (for each month of breast-feeding, OR = 0.98, 95% CI = 0.97 to 0.99; P(trend)<.001). Women with BRCA1 mutations who breast-fed for more than 1 year were less likely to have breast cancer than those who never breast-fed (OR = 0.55, 95% CI = 0.38 to 0.80; P =.001), although no such association was seen for BRCA2 (OR = 0.95, 95% CI = 0.56 to 1.59; P =.83). CONCLUSIONS: Women with deleterious BRCA1 mutations who breast-fed for a cumulative total of more than 1 year had a statistically significantly reduced risk of breast cancer.
Adult↗
Germline truncating mutations in both MSH2 and BRCA2 in a single kindred.
There has been interest in the literature in the possible existence of a gene that predisposes to both breast cancer (BC) and colorectal cancer (CRC). We describe the detailed characterisation of one kindred, MON1080, with 10 cases of BC or CRC invasive cancer among 26 first-, second- or third-degree relatives. Linkage analysis suggested that a mutation was present in BRCA2. DNA sequencing from III: 22 (diagnosed with lobular BC) identified a BRCA2 exon 3 542G>T (L105X) mutation. Her sister (III: 25) had BC and endometrial cancer and carries the same mutation. Following immunohistochemical and microsatellite instability studies, mutation analysis by protein truncation test, cDNA sequencing and quantitative real-time PCR revealed a deletion of MSH2 exon 8 in III: 25, confirming her as a double heterozygote for truncating mutations in both BRCA2 and MSH2. The exon 8 deletion was identified as a 14.9 kb deletion occurring between two Alu sequences. The breakpoint lies within a sequence of 45 bp that is identical in both Alu sequences. In this large BC/CRC kindred, MON1080, disease-causing truncating mutations are present in both MSH2 and BRCA2. There appeared to be no increased susceptibility to the development of colorectal tumours in BRCA2 mutation carriers or to the development of breast tumours in MSH2 mutation carriers. Additionally, two double heterozygotes did not appear to have a different phenotype than would be expected from the presence of a mutation in each gene alone.
Adult↗
Prevention and genetic testing for breast cancer: variations in medical decisions.
The discovery linking the genes BRCA1&2 to familial breast cancer played an important role in the clinical practice of geneticists and physicians. The availability of genetic tests for BRCA gene mutations prompted cancer geneticists to give information about genetic risk and to assess many women with a personal or family history of breast or ovarian cancer to inform them of preventive measures. These consist mainly of breast self-examination, mammography screening, chemoprevention and prophylactic surgery (mastectomy, oophorectomy). This paper examines clinical practices related to hereditary breast cancer testing and introduces a number of results from a survey carried out, between 1996 and 1998, in three clinics located in Montreal (Quebec, Canada), Marseilles (France) and Manchester (Great Britain). Results show substantial differences in the way cancer geneticists deal with environmental risk factors, breast and ovarian cancer testing, and chemoprevention and prophylactic surgery. Differences across cities persist in the multivariate analysis, suggesting that attitudes towards preventive measures may be partially explained by cultural factors. Different dimensions of culture are discussed including the social representation of health and risk, the interpretation of scientific evidence and the role of innovation leadership.
Adolescent↗
Putative common origin of two MLH1 mutations in Italian-Quebec hereditary non-polyposis colorectal cancer families.
Hereditary non-polyposis colorectal cancer (HNPCC) is one of the most common inherited cancer syndromes, accounting for 3-5% of all cases of colorectal cancer. In most HNPCC families, the disease is caused by a germline mutation in MLH1 or MSH2. In some populations, founder mutations appear to explain a substantial fraction of HNPCC. We report here the identification and preliminary characterization of two putative MLH1 founder mutations. The mutation MLH1c.1831delAT was shown to segregate in two Quebec families of Italian origin who fulfilled the Amsterdam criteria for HNPCC. Haplotype analysis using five intragenic microsatellite/single nucleotide polymorphism markers spanning MLH1 on chromosome 3 showed that these two unrelated families share an identical haplotype. In addition, two other Italian kindred whose affected members carry MLH1g.IVS6 + 3A>G also share a common haplotype, suggesting that, similarly, the latter mutation has a common origin. These mutations are the first putative founder MLH1 mutations to be identified in HNPCC kindred of Italian origin.
Adaptor Proteins, Signal Transducing↗
BRCA1 functions as a breast stem cell regulator.
BRCA1 is an important susceptibility gene for breast cancer, which confers substantial lifetime risks of breast cancer, particularly in the pre-menopausal age group. Typically, carriers of BRCA1 mutations develop breast tumours that grow rapidly and are high grade and oestrogen receptor negative. They also possess a basal epithelial phenotype, as defined by cytokeratin expression, that is not present in most breast cancers. It has recently been proposed that the adult breast stem cell expresses only basal keratins. Others have indicated a CD44 positive, CD24 negative phenotype for breast cancer stem cells. In this paper, I argue that the biology of human BRCA1 and its rodent homologues and the clinicopathological features of breast cancer related to BRCA1 support the notion that one of the key functions of BRCA1 is to act as a stem cell regulator. This has implications for the management of carriers of mutations of BRCA1, in part because support for the role of BRCA1 as a stem cell regulator would emphasise the distinct nature of breast cancer related to BRCA1.
Animals↗
Ratio of female to male offspring of women tested for BRCA1 and BRCA2 mutations.
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Adult↗