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N Hamel

Publications and source records attributed to N Hamel.

At least 19 recordsLinked to original sources
PubMed2005

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↗
PubMed2004

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↗
PubMed2003

Glomeruloid microvascular proliferation is associated with p53 expression, germline BRCA1 mutations and an adverse outcome following breast cancer.

Glomeruloid microvascular proliferation (GMP) in breast cancer independently adversely affected survival (relative risk 1.9, 95% CI: 1.2-3.0), particularly among women who received adjuvant chemotherapy (10-year survival 27 vs 69%, P=0.0003), and was significantly associated with p53 overexpression and BRCA1 germline mutations. The presence of GMP may influence treatment decisions.

Adult↗
PubMed2002

The founder mutation MSH2*1906G-->C is an important cause of hereditary nonpolyposis colorectal cancer in the Ashkenazi Jewish population.

Hereditary nonpolyposis colorectal cancer (HNPCC) is caused by mutations in the mismatch-repair genes. We report here the identification and characterization of a founder mutation in MSH2 in the Ashkenazi Jewish population. We identified a nucleotide substitution, MSH2*1906G-->C, which results in a substitution of proline for alanine at codon 636 in the MSH2 protein. This allele was identified in 15 unrelated Ashkenazi Jewish families with HNPCC, most of which meet the Amsterdam criteria. Genotype analysis of 18 polymorphic loci within and flanking MSH2 suggested a single origin for the mutation. All colorectal cancers tested showed microsatellite instability and absence of MSH2 protein, by immunohistochemical analysis. In an analysis of a population-based incident series of 686 Ashkenazi Jews from Israel who have colorectal cancer, we identified 3 (0.44%) mutation carriers. Persons with a family history of colorectal or endometrial cancer were more likely to carry the mutation than were those without such a family history (P=.042), and those with colorectal cancer who carried the mutation were, on average, younger than affected individuals who did not carry it (P=.033). The mutation was not detected in either 566 unaffected Ashkenazi Jews from Israel or 1,022 control individuals from New York. In hospital-based series, the 1906C allele was identified in 5/463 Ashkenazi Jews with colorectal cancer, in 2/197 with endometrial cancer, and in 0/83 with ovarian cancer. When families identified by family history and in case series are included, 25 apparently unrelated Ashkenazi Jewish families have been found to harbor this mutation. Although this pathogenic mutation is not frequent in the Ashkenazi Jewish population (accounting for 2%-3% of colorectal cancer in those whose age at diagnosis is <60 years), it is highly penetrant and accounts for approximately one-third of HNPCC in Ashkenazi Jewish families that fulfill the Amsterdam criteria.

Alanine↗
PubMed2002

Haplotype analysis of a BRCA1: 185delAG mutation in a Chilean family supports its Ashkenazi origins.

At least 25% of Ashkenazi Jewish families with two or more cases of premenopausal breast cancers are attributable to one of three founder mutations in BRCA1 or BRCA2. As these three founder mutations are common in the Ashkenazi Jewish population ( approximately 2.5%) and can easily be tested for in a multiplex assay, establishing ethnicity can expedite genetic testing. It is not always possible, however, to conclusively establish ethnicity before offering testing. We report here the occurrence of a founder Ashkenazi Jewish BRCA1 mutation, 185delAG (also known as 187delAG), in a non-Jewish Chilean family with no reported Jewish ancestry. The linked haplotype present in this family was identical to that identified in the Ashkenazi Jewish population. This case report not only illustrates the problem of the definition of ethnicity but also points to the possibility of further studies of the frequency of founder Ashkenazi Jewish mutations in populations not generally considered to be of Ashkenazi Jewish origin.

Adult↗
PubMed2002

An MLH1 haplotype is over-represented on chromosomes carrying an HNPCC predisposing mutation in MLH1.

BACKGROUND: The mismatch repair gene, MLH1, appears to occur as two main haplotypes at least in white populations. These are referred to as A and G types with reference to the A/G polymorphism at IVS14-19. On the basis of preliminary experimental data, we hypothesised that deviations from the expected frequency of these two haplotypes could exist in carriers of disease associated MLH1 germline mutations. METHODS: We assembled a series (n=119) of germline MLH1 mutation carriers in whom phase between the haplotype and the mutation had been conclusively established. Controls, without cancer, were obtained from each contributing centre. Cases and controls were genotyped for the polymorphism in IVS14. RESULTS: Overall, 66 of 119 MLH1 mutations occurred on a G haplotype (55.5%), compared with 315 G haplotypes on 804 control chromosomes (39.2%, p=0.001). The odds ratio (OR) of a mutation occurring on a G rather than an A haplotype was 1.93 (95% CI 1.29 to 2.91). When we compared the haplotype frequencies in mutation bearing chromosomes carried by people of different nationalities with those seen in pooled controls, all groups showed a ratio of A/G haplotypes that was skewed towards G, except the Dutch group. On further analysis of the type of each mutation, it was notable that, compared with control frequencies, deletion and substitution mutations were preferentially represented on the G haplotype (p=0.003 and 0.005, respectively). CONCLUSION: We have found that disease associated mutations in MLH1 appear to occur more often on one of only two known ancient haplotypes. The underlying reason for this observation is obscure, but it is tempting to suggest a possible role of either distant regulatory sequences or of chromatin structure influencing access to DNA sequence. Alternatively, differential behaviour of otherwise similar haplotypes should be considered as prime areas for further study.

Adaptor Proteins, Signal Transducing↗
PubMed2001

TP53 mutations in breast cancer associated with BRCA1 or BRCA2 germ-line mutations: distinctive spectrum and structural distribution.

Several groups have studied the molecular pathology of inherited breast cancer. By combining several such studies, we show in this study that somatic TP53 abnormalities are more common in breast cancer associated with BRCA1 or BRCA2 germ-line mutations than in sporadic breast cancers (odds ratio, 2.8; P = 0.0003). Then, we compared the spectrum of TP53 mutations for breast cancers in the IARC TP53 mutation database with the 82 mutations reported in BRCA1/2-associated breast cancers. The spectrum differed significantly both in distribution (P < 1 x 10(-6)) and in base changes (P = 0.025). Mutations at A:T bp were more common in BRCA1/2-associated tumors and strand bias suggesting DNA repair abnormalities was found. Changes were common at TP53 codons that are not mutation hotspots. Structural modeling showed that most of these p53 non-hotspot amino acids characterized in breast tumors isolated from patients with deficient BRCA1/2 function are distributed in a region of the protein on the opposite side of the p53 DNA-binding surface. Our results suggest that BRCA1/2 mutations influence the type and distribution of TP53 mutations seen in breast cancer.

BRCA2 Protein↗
PubMed2001

Double primary cancers of the breast and thyroid in women: molecular analysis and genetic implications.

Multiple primary cancers are characteristic of hereditary cancer syndromes. A familial association between breast and thyroid cancer has been suggested, but a genetic basis for this association has not yet been established. To determine the extent to which double primary cancers of the breast and thyroid are due to common hereditary factors, we conducted a registry- and hospital-based study in Ontario and Quebec. We obtained family histories of 74 women diagnosed with both cancer of the breast and thyroid before 70 years of age. Cancer histories were obtained for the 533 first- degree relatives of these women. The observed cancer rate in the relatives was compared with the expected number, based on age- standardized Canadian cancer incidence rates, and relative risks were estimated. A total of 87 cancers were observed in the relatives, compared to 93.7 expected cancers, giving a relative risk of 0.9 (95% confidence interval (CI): 0.7-1.1). The risk for breast cancer was 1.1 (95% CI: 0.6-1.7) and the risk for thyroid cancer was 0.7 (95% CI: 0-3.8). Blood samples were collected on 53 patients for mutational analysis of the BRCA1, BRCA2, and PTEN genes. One woman was found to be a carrier of a BRCA1 mutation (exon 11 3227delT). Our findings do not support the hypothesis that a significant proportion of double primary cancers of the breast and thyroid are due to hereditary factors.

Adult↗
PubMed2001

Prevalence of founder BRCA1 and BRCA2 mutations in unselected French Canadian women with breast cancer.

The frequency of BRCA1 and BRCA2 mutations in women with breast cancer varies according to the age at diagnosis, family history of cancer, and ethnicity/country of origin. We set out to estimate the frequency of seven previously described founder mutations in BRCA1 and BRCA2 in all eligible French Canadian women diagnosed with invasive breast cancer at one Montreal hospital over a 20-month period. One hundred and ninety-two patients were eligible and 127 (66.2%) provided blood for genetic testing. We identified 4 women who carried a founder mutation (3.1%, 95% confidence interval 0.9-7.9%) in this population. Interestingly, all the mutations were in BRCA2. The mean age at diagnosis for mutation carriers was 51.2 years (range 49.1-53.5). Two of these 4 cases were lobular invasive carcinomas and 2 were ductal carcinomas, histological grade 1 or 2. Despite a small tumor size (< or =20 mm), axillary nodal involvement was present in 3 women. Estrogen receptors were strongly expressed in all cases. Two of the 4 cases reported a strong family history of breast cancer, but a family history of site-specific breast cancer was a relatively poor indicator of the presence of BRCA2 mutations. The absence of BRCA1 mutations may be a result of chance, but may also reflect different geographical origins of the most common BRCA1 mutations within the French Canadian population.

Adult↗
PubMed2001

A link between diabetes and atherosclerosis: Glucose regulates expression of CD36 at the level of translation.

Both the risk and the rate of development of atherosclerosis are increased in diabetics, but the mechanisms involved are unknown. Here we report a glucose-mediated increase in CD36 mRNA translation efficiency that results in increased expression of the macrophage scavenger receptor CD36. Expression of CD36 was increased in endarterectomy lesions from patients with a history of hyperglycemia. Macrophages that were differentiated from human peripheral blood monocytes in the presence of high glucose concentrations showed increased expression of cell-surface CD36 secondary to an increase in translational efficiency of CD36 mRNA. We obtained similar data from primary cells isolated from human vascular lesions, and we found that glucose sensitivity is a function of ribosomal reinitiation following translation of an upstream open reading frame (uORF). Increased translation of macrophage CD36 transcript under high glucose conditions provides a mechanism for accelerated atherosclerosis in diabetics.

5' Untranslated Regions↗
PubMed2000

No association between P53 codon 72 polymorphism and risk of squamous cell carcinoma of the head and neck.

An initial report suggested that patients homozygous for the arginine allele at codon 72 of P53 were at increased risk for human papillomavirus (HPV)-related cervical cancer, but other groups have not confirmed this finding. Since approximately 18-36% of head and neck cancers are HPV-related, we examined the genotypic frequencies at that locus in 163 cases with squamous cell carcinoma of the head and neck (SCCHN) and 163 ethnically matched controls. We found no significant excess of arginine homozygotes in cases compared to controls (P= 0.50). No significant differences in allele frequencies were observed when the data were stratified by tobacco exposure or by cancer site. These findings suggest a limited role, if any, for this P53 polymorphism in SCCHN.

Base Sequence↗
PubMed2000

Polymorphisms in GSTM1, GSTT1 and CYP1A1 and risk of pancreatic adenocarcinoma.

A prospective study of 149 unselected incident cases of pancreatic adenocarcinoma and 146 ethnically-matched controls found no associations between GSTM1 (adjusted odds ratio (AOR) 1.14), GSTT1 (AOR: 1.19) and CYP1A1 (AOR: 1.08) polymorphisms and pancreatic cancer susceptibility. Smoking and drinking status did not affect results. These polymorphisms do not appear to be important gene modifiers in pancreatic cancer.

Adenocarcinoma↗