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1.
J Med Genet ; 39(7): 457-62, 2002 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-12114473

RESUMO

OBJECTIVE: To estimate the risk of malignant diseases in families of probands with the same mutation in the BRCA2 gene. DESIGN: A cohort study using record linkage of a breast cancer family resource and the Icelandic Cancer Registry. SETTING: Iceland. SUBJECTS: Families of 995 breast cancer patients, from which 887 were tested for a single founder 999del5 mutation; 90 had the mutation and 797 did not. RESULTS: Relatives of probands with the mutation had significantly increased relative risk (RR) of breast cancer. For first degree relatives, the RR was 7.55 (95% CI 6.04 to 9.03) but was 1.72 (95% CI 1.49 to 1.96) in first degree relatives of probands without the mutation. For prostate and ovarian cancer, the first and second degree relatives of probands with the mutation had a significantly increased RR, but in families of probands without the mutation no significant familial risk was found. CONCLUSIONS: The 999del5 mutation in the BRCA2 gene explains a substantial proportion of familial risk of breast cancer in Iceland, but significant familial risk remains in relatives of probands without the mutation. For prostate and ovarian cancer, the mutation accounts for most of the familiality observed in families of breast cancer patients.


Assuntos
Genes BRCA2 , Mutação/genética , Neoplasias/genética , Adulto , Idoso , Idoso de 80 Anos ou mais , Neoplasias da Mama/epidemiologia , Neoplasias da Mama/genética , Neoplasias da Mama Masculina/epidemiologia , Neoplasias da Mama Masculina/genética , Estudos de Coortes , Feminino , Efeito Fundador , Ligação Genética/genética , Humanos , Islândia , Neoplasias Renais/epidemiologia , Neoplasias Renais/genética , Masculino , Pessoa de Meia-Idade , Neoplasias/epidemiologia , Neoplasias Ovarianas/epidemiologia , Neoplasias Ovarianas/genética , Neoplasias Pancreáticas/epidemiologia , Neoplasias Pancreáticas/genética , Neoplasias da Próstata/epidemiologia , Neoplasias da Próstata/genética , Fatores de Risco , Neoplasias Gástricas/epidemiologia , Neoplasias Gástricas/genética
2.
Eur J Cancer ; 38(5): 728-35, 2002 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-11916557

RESUMO

The FHIT gene is a putative tumour suppressor gene. In this study, we analysed a set of 50 gastric tumours for alterations of FHIT, and found 38 of 45 tumours (84%) exhibiting loss of heterozygosity (LOH) within the FHIT gene. We used both nested Reverse Transcriptase Polymerase Chain Reaction (RT-PCR) and single step RT-PCR to analyse the FHIT transcripts and found 34 of 39 (87%) tumours and seven of the 11 (64%) corresponding non-cancerous tissues showed low or aberrant expression of FHIT mRNA and the appearance of the aberrant FHIT transcripts depended on the conditions of the RT-PCR. In these aberrant transcripts, frequent deletions and/or insertions were detected by direct sequencing. All breakpoints for deletions and insertions were at splicing sites. All insertions came from the adjacent introns, whose appearance was completely in accordance with the 'GU-AG' rule for pre-mRNA splicing. It may be suggested that an alternative splicing mechanism functions in the formation of these aberrant transcripts. The fragile nature of FRA3B within the FHIT gene could be responsible for the formation of the aberrant mRNA. Negative or reduced Fhit expression was detected in 39 of 50 tumours (78%). Moreover, an association was found between abnormal Fhit expression and positive node status (P=0.012). Thirteen of 48 tumours (27%) displayed microsatellite instability (MSI), among which 10 tumours also showed MSI within the FHIT gene. Furthermore, we detected an association between MSI and negative node status (P=0.02). We conclude that the abnormalities of FHIT, presumably associated with the unstable nature of FRA3B within the FHIT gene, are involved in the carcinogenesis of gastric cancer, and lack of mismatch repair (MMR) could possibly promote its alteration in a subset of gastric tumours.


Assuntos
Hidrolases Anidrido Ácido , Perda de Heterozigosidade , Repetições de Microssatélites/genética , Proteínas de Neoplasias/genética , Neoplasias Gástricas/genética , Sequência de Bases , Transformação Celular Neoplásica/genética , Análise Mutacional de DNA , DNA de Neoplasias/genética , Expressão Gênica , Marcadores Genéticos , Humanos , Metástase Linfática , Dados de Sequência Molecular , Proteínas de Neoplasias/análise , Polimorfismo Genético , RNA Mensageiro/genética , RNA Neoplásico/genética , Reação em Cadeia da Polimerase Via Transcriptase Reversa , Neoplasias Gástricas/química
3.
BMC Cancer ; 1: 16, 2001.
Artigo em Inglês | MEDLINE | ID: mdl-11747475

RESUMO

BACKGROUND: The E-cadherin-catenin complex plays a crucial role in epithelial cell-cell adhesion and in the maintenance of tissue architecture. Perturbation in the expression or function of this complex results in loss of intercellular adhesion, with possible consequent cell transformation and tumour progression. METHODS: We studied the alterations of E-cadherin and beta-catenin in a set of 50 primary gastric tumours by using loss of heterozygosity (LOH) analysis, gene mutation screening, detection of aberrant transcripts and immunohistochemistry (IHC). RESULTS: A high frequency (75%) of LOH was detected at 16q22.1 containing E-cadherin locus. Three cases (6%) showed the identical missense mutation, A592T. This mutation is not likely to contribute strongly to the carcinogenesis of gastric cancer, because a low frequency (1.6%) of this mutation was also found in 187 normal individuals. We also detected a low frequency (0.36%, 0%) of this mutation in 280 breast tumours and 444 other tumours, including colon and rectum, lung, endometrium, ovary, testis, kidney, thyroid carcinomas and sarcomas, respectively. We also analyzed the aberrant E-cadherin mRNAs in the gastric tumours and found that 7 tumours (18%) had aberrant mRNAs in addition to the normal mRNA. These aberrant mRNAs may produce abnormal E-cadherin molecules, resulting in weak cell-cell adhesion and invasive behaviour of carcinoma cells. Reduced expression of E-cadherin and beta-catenin was identified at the frequency of 42% and 28%, respectively. Specially, 11 tumours (22%) exhibited positive cytoplasmic staining for beta-catenin IHC. An association was found between reduced expression of E-cadherin and beta-catenin. Moreover, an association was detected between reduced expression of E-cadherin and diffuse histotype. CONCLUSION: Our results support the hypothesis that alterations of E-cadherin and beta-catenin play a role in the initiation and progression of gastric cancer.


Assuntos
Caderinas/genética , Proteínas do Citoesqueleto/genética , Mutação de Sentido Incorreto/genética , Neoplasias Gástricas/patologia , Transativadores/genética , Idade de Início , Idoso , Neoplasias da Mama/genética , Neoplasias da Mama/patologia , Caderinas/fisiologia , Adesão Celular/genética , Adesão Celular/fisiologia , Cromossomos Humanos Par 16/genética , Proteínas do Citoesqueleto/fisiologia , Análise Mutacional de DNA/métodos , DNA de Neoplasias/genética , Feminino , Regulação Neoplásica da Expressão Gênica/genética , Regulação Neoplásica da Expressão Gênica/fisiologia , Mutação em Linhagem Germinativa/genética , Mutação em Linhagem Germinativa/fisiologia , Humanos , Perda de Heterozigosidade/genética , Masculino , Mutação de Sentido Incorreto/fisiologia , Neoplasias da Próstata/genética , Neoplasias da Próstata/patologia , Neoplasias Cutâneas/genética , Neoplasias Cutâneas/patologia , Neoplasias Gástricas/genética , Transativadores/fisiologia , beta Catenina
4.
Eur J Hum Genet ; 9(10): 773-9, 2001 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-11781689

RESUMO

The 999del5 mutation is the single, strong BRCA2 founder mutation in Iceland and the most common BRCA1/2 founder mutation in Finland. To evaluate the origin and time since spreading of the 999del5 mutation in Iceland and in Finland, we constructed haplotypes with polymorphic markers within and flanking the BRCA2 gene in a set of 18 Icelandic and 10 Finnish 999del5 breast cancer families. All Icelandic families analysed shared a common core haplotype of about 1.7 cM. The common ancestors for the Icelandic families studied were estimated to trace back to 340-1000 years, not excluding the possibility that the mutation was brought to Iceland during the settlement of the country. Analysis of the Finnish families revealed two distinct haplotypes. A rare one, found in three families in the old settlement region in southwestern Finland, shared a four-marker (0.5 cM) core haplotype with the Icelandic 999del5 haplotype. A distinct approximately 6 cM haplotype was shared by seven 999del5 Finnish families estimated to have a common ancestry 140-300 years ago. These families cluster in two geographical regions in Finland, in the very same area as those with the rare haplotype and also in the most eastern, late settlement region of Finland. The results may indicate a common ancient origin for the 999del5 mutation in Iceland and in Finland, but distinct mutational events cannot be ruled out. The surprising finding of the same mutation in two completely different haplotypes in a sparsely populated area in Finland may suggest gene conversion.


Assuntos
Neoplasias da Mama/genética , Genes BRCA2 , Haplótipos/genética , Deleção de Sequência/genética , Etnicidade/genética , Feminino , Finlândia , Marcadores Genéticos , Geografia , Humanos , Islândia , Neoplasias Ovarianas/genética , Filogenia , Fatores de Tempo
5.
Proc Natl Acad Sci U S A ; 97(17): 9603-8, 2000 Aug 15.
Artigo em Inglês | MEDLINE | ID: mdl-10944226

RESUMO

A significant proportion of familial breast cancers cannot be explained by mutations in the BRCA1 or BRCA2 genes. We applied a strategy to identify predisposition loci for breast cancer by using mathematical models to identify early somatic genetic deletions in tumor tissues followed by targeted linkage analysis. Comparative genomic hybridization was used to study 61 breast tumors from 37 breast cancer families with no identified BRCA1 or BRCA2 mutations. Branching and phylogenetic tree models predicted that loss of 13q was one of the earliest genetic events in hereditary cancers. In a Swedish family with five breast cancer cases, all analyzed tumors showed distinct 13q deletions, with the minimal region of loss at 13q21-q22. Genotyping revealed segregation of a shared 13q21 germ-line haplotype in the family. Targeted linkage analysis was carried out in a set of 77 Finnish, Icelandic, and Swedish breast cancer families with no detected BRCA1 and BRCA2 mutations. A maximum parametric two-point logarithm of odds score of 2.76 was obtained for a marker at 13q21 (D13S1308, theta = 0.10). The multipoint logarithm of odds score under heterogeneity was 3.46. The results were further evaluated by simulation to assess the probability of obtaining significant evidence in favor of linkage by chance as well as to take into account the possible influence of the BRCA2 locus, located at a recombination fraction of 0.25 from the new locus. The simulation substantiated the evidence of linkage at D13S1308 (P < 0.0017). The results warrant studies of this putative breast cancer predisposition locus in other populations.


Assuntos
Neoplasias da Mama/genética , Deleção Cromossômica , Cromossomos Humanos Par 13/genética , Predisposição Genética para Doença/genética , Idoso , Proteína BRCA2 , Neoplasias da Mama/patologia , Mapeamento Cromossômico , Progressão da Doença , Feminino , Genes BRCA1/genética , Genoma Humano , Genótipo , Mutação em Linhagem Germinativa/genética , Haplótipos/genética , Humanos , Células Híbridas , Escore Lod , Masculino , Pessoa de Meia-Idade , Modelos Genéticos , Proteínas de Neoplasias/genética , Hibridização de Ácido Nucleico , Linhagem , Fatores de Transcrição/genética
6.
J Med Genet ; 37(5): 342-7, 2000 May.
Artigo em Inglês | MEDLINE | ID: mdl-10807692

RESUMO

Chromosomal losses involving the short arm of chromosome 8 are frequent in a variety of tumour types, including breast cancer, suggesting the presence of one or more tumour suppressor genes in this region. In this study, we have used 11 microsatellite markers to analyse loss of heterozygosity (LOH) at chromosome 8p in 151 sporadic breast tumours and 50 tumours from subjects carrying the BRCA2 999del5 mutation. Fifty percent of sporadic tumours compared to 78% of BRCA2 linked tumours exhibit LOH at one or more markers at 8p showing that chromosome 8p alterations in breast tumours from BRCA2 999del5 carriers are more pronounced than in sporadic breast tumours. The pattern of LOH is different in the two groups and a higher proportion of BRCA2 tumours have LOH in a large region of chromosome 8p. In the total patient material, LOH of 8p is associated with LOH at other chromosome regions, for example, 1p, 3p, 6q, 7q, 9p, 11p, 13q, 17p, and 20q, but no association is found between LOH at 8p and chromosome regions 11q, 16q, 17q, and 18q. Furthermore, an association is detected between LOH at 8p and positive node status, large tumour size, aneuploidy, and high S phase fraction. Breast cancer patients with LOH at chromosome 8p have a worse prognosis than patients without this defect. Multivariate analysis suggests that LOH at 8p is an independent prognostic factor. We conclude that chromosome 8p carries a tumour suppressor gene or genes, the loss of which results in growth advantage of breast tumour cells, especially in carriers of the BRCA2 999del5 mutation.


Assuntos
Neoplasias da Mama/genética , Cromossomos Humanos Par 8/genética , Perda de Heterozigosidade , Proteínas de Neoplasias/genética , Fatores de Transcrição/genética , Proteína BRCA2 , DNA de Neoplasias/análise , Feminino , Genes Supressores de Tumor , Mutação em Linhagem Germinativa , Humanos , Repetições de Microssatélites , Pessoa de Meia-Idade , Reação em Cadeia da Polimerase/métodos , Prognóstico , Deleção de Sequência
7.
Int J Oncol ; 16(1): 133-9, 2000 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-10601558

RESUMO

We have investigated microsatellite instability (MSI) in colorectal, gastric, endometrial and ovarian cancer as a result of mismatch repair (MMR) deficiency. We detected frameshift mutations in several genes that carry short repeated sequences and are important in cell fidelity and growth control; hMSH3, hMSH6, BAX, IGFIIR, TGFbetaIIR, E2F4 and BRCA2. Accumulation of mutations was heterogeneous and mainly restricted to tumours showing MSI at several loci (MSI-H). Both insertions and deletions were evident and occasional intratumour heterogeneity was evident with more than one different additional allele in the tumour. Most MSI-H tumours had acquired mutations in more than one gene and longer repeated sequences were more frequently targets for mutations. The TGFbetaIIR gene was mutated in 62%, the hMSH3 gene in 43%, the E2F4 gene in 35%, the hMSH6 in 32%, the BAX gene in 32%, the IGFIIR gene in 26%, and the BRCA2 gene in 2% of the MSI-H tumours. Homozygous mutations or mutation of both alleles were evident in all genes except BRCA2, in total 23/105 mutated cases, varying from 7% for BAX to 50% for E2F4. E2F4 mutations were exclusively found in colon tumours and E2F4 polymorphisms was found in 8% of cases. No difference in mutation prevalence was noted between cancer types apart from TGFbetaIIR mutations, which were frequently found in colon and gastric tumours but not in endometrial tumours, suggesting that endometrial tumours progress by a different route where TGFbetaIIR mutations are less favourable.


Assuntos
Pareamento Incorreto de Bases , Transformação Celular Neoplásica/genética , Neoplasias Colorretais Hereditárias sem Polipose/genética , DNA Ligases/metabolismo , Reparo do DNA , Repetições de Microssatélites/genética , Proteínas Associadas à Resistência a Múltiplos Medicamentos , Proteínas Proto-Oncogênicas c-bcl-2 , Idoso , Proteína BRCA2 , DNA Ligases/deficiência , Proteínas de Ligação a DNA/genética , Humanos , Pessoa de Meia-Idade , Proteína 3 Homóloga a MutS , Proteínas de Neoplasias/genética , Fenótipo , Proteínas Serina-Treonina Quinases , Proteínas Proto-Oncogênicas/genética , Receptor IGF Tipo 2/genética , Receptor do Fator de Crescimento Transformador beta Tipo II , Receptores de Fatores de Crescimento Transformadores beta/genética , Fatores de Transcrição/genética , Proteína X Associada a bcl-2
8.
Br J Cancer ; 81(7): 1103-10, 1999 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-10584868

RESUMO

We have studied a set of 40 human lobular breast cancers for loss of heterozygosity (LOH) at various chromosome locations and for mutations in the coding region plus flanking intron sequences of the E-cadherin gene. We found a high frequency of LOH (100%, 31/31) at 16q21-q22.1. A significantly higher level of LOH was detected in ductal breast tumours at chromosome arms 1p, 3p, 9p, 11q, 13q and 18q compared to lobular breast tumours. Furthermore, we found a significant association between LOH at 16q containing the E-cadherin locus and lobular histological type. Six different somatic mutations were detected in the E-cadherin gene, of which three were insertions, two deletions and one splice site mutation. Mutations were found in combination with LOH of the wild type E-cadherin locus and loss of or reduced E-cadherin expression detected by immunohistochemistry. The mutations described here have not previously been reported. We compared LOH at different chromosome regions with E-cadherin gene mutations and found a significant association between LOH at 13q and E-cadherin gene mutations. A significant association was also detected between LOH at 13q and LOH at 7q and 11q. Moreover, we found a significant association between LOH at 3p and high S phase, LOH at 9p and low ER and PgR content, LOH at 17p and aneuploidy. We conclude that LOH at 16q is the most frequent chromosome alteration and E-cadherin is a typical tumour suppressor gene in lobular breast cancer.


Assuntos
Neoplasias da Mama/genética , Caderinas/genética , Aberrações Cromossômicas/genética , Transtornos Cromossômicos , Mapeamento Cromossômico , Feminino , Humanos , Imuno-Histoquímica , Perda de Heterozigosidade , Mutação , Reação em Cadeia da Polimerase , Polimorfismo Conformacional de Fita Simples , Análise de Sequência de DNA
9.
Anticancer Res ; 19(3A): 1821-6, 1999.
Artigo em Inglês | MEDLINE | ID: mdl-10470121

RESUMO

Instability of microsatellite DNA or replication error (RER) is characteristic of tumours caused by mismatch repair (MMR) deficiency. Germline mutations in MMR genes are associated with Hereditary non-polyposis colorectal carcinoma (HNPCC) and somatic mutations in these genes are also found in a substantial fraction of colorectal cancers (CRC). In this study we concurrently screened colorectal tumours for the RER phenotype and loss of heterozygosity (LOH) at MMR gene loci. The RER phenotype was evident in 47/197 (24%) tumours. RER was more commonly detected in young patients (< 50 years) and in tumours located in the proximal colon. RER was positively associated with LOH at the hMSH2/hMSH6 loci on chromosome 2p, where LOH was observed in 46% of the RER+ tumours. LOH at hMLH1 and hPMS1 loci was more frequent in the younger patients (< 50 years). RER was not associated with clinicopathological parameters, such as Duke's stage and tumour differentiation (grade). The RER phenotype was associated with better overall survival, but there was a trend towards significance when multivariate analysis was used. This indicates that loss of MMR genes generate a less aggressive phenotype, and raises the question about RER being a useful indicator of prognosis for CRC patients.


Assuntos
Adenosina Trifosfatases , Neoplasias Colorretais/genética , Enzimas Reparadoras do DNA , Reparo do DNA/genética , Proteínas de Ligação a DNA , Perda de Heterozigosidade , Repetições de Microssatélites , Proteínas de Neoplasias/genética , Proteínas de Saccharomyces cerevisiae , Proteínas Adaptadoras de Transdução de Sinal , Adulto , Idade de Início , Idoso , Proteínas de Transporte , Diferenciação Celular , Neoplasias Colorretais/mortalidade , Neoplasias Colorretais/patologia , Neoplasias Colorretais Hereditárias sem Polipose/genética , Neoplasias Colorretais Hereditárias sem Polipose/mortalidade , Neoplasias Colorretais Hereditárias sem Polipose/patologia , Análise Mutacional de DNA , Replicação do DNA , DNA de Neoplasias/biossíntese , DNA de Neoplasias/genética , Feminino , Seguimentos , Proteínas Fúngicas/genética , Predisposição Genética para Doença , Genótipo , Humanos , Islândia/epidemiologia , Masculino , Pessoa de Meia-Idade , Endonuclease PMS2 de Reparo de Erro de Pareamento , Proteína 1 Homóloga a MutL , Proteínas MutL , Proteína 2 Homóloga a MutS , Estadiamento de Neoplasias , Proteínas Nucleares , Fenótipo , Prognóstico , Proteínas Proto-Oncogênicas/genética , Estudos Retrospectivos , Análise de Sobrevida
10.
Br J Cancer ; 79(9-10): 1468-74, 1999 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-10188892

RESUMO

The distal half of chromosome 1p was analysed with 15 polymorphic microsatellite markers in 683 human solid tumours at different locations. Loss of heterozygosity (LOH) was observed at least at one site in 369 cases or 54% of the tumours. LOHs detected ranged from 30-64%, depending on tumour location. The major results regarding LOH at different tumour locations were as follows: stomach, 20/38 (53%); colon and rectum, 60/109 (55%); lung, 38/63 (60%); breast, 145/238 (61%); endometrium, 18/25 (72%); ovary, 17/31 (55%); testis, 11/30 (37%); kidney, 22/73 (30%); thyroid, 4/14 (29%); and sarcomas, 9/14 (64%). High percentages of LOH were seen in the 1p36.3, 1p36.1, 1p35-p34.3, 1p32 and 1p31 regions, suggesting the presence of tumour-suppressor genes. All these regions on chromosome 1p show high LOH in more than one tumour type. However, distinct patterns of LOH were detected at different tumour locations. There was a significant separation of survival curves, with and without LOH at chromosome 1p, in the breast cancer patients. Multivariate analysis showed that LOH at 1p in breast tumours is a better indicator for prognosis than the other variables tested in our model, including nodal metastasis.


Assuntos
Cromossomos Humanos Par 1/genética , Perda de Heterozigosidade , Neoplasias/genética , Neoplasias/mortalidade , Análise de Variância , Distribuição de Qui-Quadrado , Mapeamento Cromossômico , Feminino , Marcadores Genéticos , Humanos , Masculino , Repetições de Microssatélites/genética , Neoplasias/patologia , Análise de Sobrevida
11.
Oncol Rep ; 6(1): 117-22, 1999.
Artigo em Inglês | MEDLINE | ID: mdl-9864413

RESUMO

Replication errors (RER) at microsatellite repeats indicate genomic instability in hereditary nonpolyposis colorectal cancer (HNPCC) and in some sporadic cancers. We have studied genomic instability in 313 sporadic breast tumors and in 106 tumors from BRCA2, 999del5 carriers at 43 genomic loci on 13 chromosomes. RER was observed in 8/419 (1.9%) of the cases at one or more chromosomal loci. The frequencies of type I and type II RER were similar. The majority of RER+ tumors showed ER+, PgR+, high S-phase fraction, tumor size >2 cm and LOH at 2p, 2q and 3p. All 8 RER+ tumors were of the ductal histotype. The breast cancer cases with RER are not part of an HNPCC syndrome and a family history of colorectal cancer growth is not detected in relatives, with the exception of one case. However, four of the RER+ cases are from individuals carrying the BRCA2, 999del5 mutation. We conclude that RER is a rare somatic event during human breast carcinogenesis and may be associated with progression of breast carcinomas.


Assuntos
Neoplasias da Mama/genética , Replicação do DNA , Repetições de Microssatélites , Proteínas de Neoplasias/genética , Fatores de Transcrição/genética , Adulto , Idade de Início , Idoso , Idoso de 80 Anos ou mais , Aneuploidia , Proteína BRCA2 , Neoplasias da Mama/epidemiologia , Neoplasias da Mama/patologia , Carcinoma Ductal de Mama/genética , Carcinoma Ductal de Mama/patologia , Cromossomos Humanos/genética , Cromossomos Humanos/ultraestrutura , DNA de Neoplasias/genética , Estrogênios , Saúde da Família , Feminino , Heterozigoto , Humanos , Islândia/epidemiologia , Perda de Heterozigosidade , Masculino , Pessoa de Meia-Idade , Neoplasias/epidemiologia , Neoplasias/genética , Neoplasias Hormônio-Dependentes/genética , Neoplasias Hormônio-Dependentes/patologia , Reação em Cadeia da Polimerase , Progesterona , Deleção de Sequência
12.
Cancer Res ; 58(19): 4421-5, 1998 Oct 01.
Artigo em Inglês | MEDLINE | ID: mdl-9766673

RESUMO

Germ-line mutation in the BRCA2 gene confers an increased risk of breast cancer. An elevation of additional genetic defects in tumors of patients with germ-line mutation in the BRCA2 gene compared with sporadic breast tumors has been reported. To evaluate the nature of the difference, we did detailed mapping of chromosomes 1p, 3p, 6q, 11, 13q, 16q, 17, and 20q, using microsatellite markers. We found that the frequency of loss of heterozygosity was similar at some chromosomal regions in the BRCA2 999del5 and sporadic tumors but significantly different at others. These others include chromosomal arms 3p, 6q, 11p, 11q, 13q, and 17p. Loss of heterozygosity mapping suggests that the same chromosome regions are involved in both tumor groups but at elevated frequencies in BRCA2 999del5 tumors. This higher frequency of genetic aberrations could pinpoint genes that selectively promote tumor progression in individuals predisposed to breast cancer due to the BRCA2 999del5 germ-line mutation. Accumulation of somatic genetic changes during tumor progression may follow a specific and more aggressive pathway of chromosome damage in these individuals.


Assuntos
Neoplasias da Mama/genética , Mapeamento Cromossômico , Marcadores Genéticos , Heterozigoto , Perda de Heterozigosidade , Proteínas de Neoplasias/genética , Deleção de Sequência , Fatores de Transcrição/genética , Proteína BRCA2 , Cromossomos Humanos , Feminino , Triagem de Portadores Genéticos , Humanos , Repetições de Microssatélites
13.
J Natl Cancer Inst ; 90(15): 1138-45, 1998 Aug 05.
Artigo em Inglês | MEDLINE | ID: mdl-9701363

RESUMO

BACKGROUND: We have previously demonstrated that breast cancers associated with inherited BRCA1 and BRCA2 gene mutations differ from each other in their histopathologic appearances and that each of these types differs from breast cancers in patients unselected for family history (i.e., sporadic cancers). We have now conducted a more detailed examination of cytologic and architectural features of these tumors. METHODS: Specimens of tumor tissue (5-microm-thick sections) were examined independently by two pathologists, who were unaware of the case or control subject status, for the presence of cell mitosis, lymphocytic infiltration, continuous pushing margins, and solid sheets of cancer cells; cell nuclei, cell nucleoli, cell necrosis, and cell borders were also evaluated. The resulting data were combined with previously available information on tumor type and tumor grade and further evaluated by multifactorial analysis. All statistical tests are two-sided. RESULTS: Cancers associated with BRCA1 mutations exhibited higher mitotic counts (P = .001), a greater proportion of the tumor with a continuous pushing margin (P<.0001), and more lymphocytic infiltration (P = .002) than sporadic (i.e., control) cancers. Cancers associated with BRCA2 mutations exhibited a higher score for tubule formation (fewer tubules) (P = .0002), a higher proportion of the tumor perimeter with a continuous pushing margin (P<.0001), and a lower mitotic count (P = .003) than control cancers. CONCLUSIONS: Our study has identified key features of the histologic phenotypes of breast cancers in carriers of mutant BRCA1 and BRCA2 genes. This information may improve the classification of breast cancers in individuals with a family history of the disease and may ultimately aid in the clinical management of patients.


Assuntos
Neoplasias da Mama/genética , Neoplasias da Mama/patologia , Genes BRCA1 , Mutação , Proteínas de Neoplasias/genética , Fatores de Transcrição/genética , Adulto , Fatores Etários , Idoso , Proteína BRCA2 , Feminino , Humanos , Pessoa de Meia-Idade , Análise Multivariada
14.
Anticancer Res ; 18(2A): 1031-6, 1998.
Artigo em Inglês | MEDLINE | ID: mdl-9615760

RESUMO

Human primary breast cancers were analysed for somatic loss of heterozygosity (LOH) at chromosome 18 with 15 polymorphic microsatellite markers. LOH was observed in 148 of the 228 cases analyzed, (65%). Three smallest common deletion regions (SCDR) were detected on the long arm of chromosome 18. The marker D18S51 at the region 18q22 showed the highest LOH (42%). Tumors with and without LOH at 18q were tested for association with clinico-pathological features of the tumors, such as estrogen and progesterone receptor content, age at diagnosis, tumor size, node status, histological type, S-phase fraction, DNA ploidy and LOH at other chromosomal regions. A significant association was found between LOH at 18q and high S-phase fraction (99.9% confidence interval) and low progesterone receptor content (99% confidence interval). Furthermore, an association was found between LOH at 18q and LOH at 1p, 7q, 9p, 13q and 17q. We conclude that there are three separate LOH target regions at chromosome 18q, and that inactivation of one or more genes at these regions might be important for human breast carcinogenesis.


Assuntos
Neoplasias da Mama/genética , Cromossomos Humanos Par 18 , Perda de Heterozigosidade , Receptores de Progesterona/análise , Fase S , Neoplasias da Mama/química , Neoplasias da Mama/patologia , Feminino , Humanos , Prognóstico
15.
J Med Genet ; 35(6): 446-9, 1998 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-9643283

RESUMO

The majority of breast cancer in high risk families is believed to result from a mutation in either of two genes named BRCA1 and BRCA2. A germline defect in either gene is usually followed by chromosomal deletion of the normal allele in the tumour. In Iceland two recurrent mutations have been identified, 999del5 BRCA2 and G5193A BRCA1. In this study, randomly selected pairs of sisters diagnosed with breast cancer at the age of 60 years or younger were analysed to evaluate the proportion of breast cancer resulting from BRCA1 and BRCA2. Genotypes and allele loss in tumour tissue from 42 sister pairs were compared using markers within and around the BRCA1 and BRCA2 genes. Eleven sister pairs were highly suggestive of BRCA2 linkage, and no obvious BRCA1 linkage was seen. Screening for the G5193A BRCA1 and 999del5 BRCA2 mutations showed the 999del5 mutation in the 11 BRCA2 suggestive pairs plus three pairs less indicative of linkage, and the G5193A BRCA1 mutation in one pair. When known mutation carriers are removed from the group, no indication of further linkage to BRCA1 or BRCA2 is seen. The results of our studies suggest that a large proportion of familial breast cancer in Iceland is the result of the 999del5 BRCA2 mutation, and it is unlikely that BRCA1 and BRCA2 germline mutations other than 999del5 and G5193A play a significant role in hereditary breast cancer in Iceland. Furthermore it can be concluded that most families with BRCA1 or BRCA2 linkage are easily identified by studying LOH around the defective gene in as few as two affected relatives.


Assuntos
Proteína BRCA1/genética , Neoplasias da Mama/genética , Deleção de Genes , Genes BRCA1 , Mutação , Proteínas de Neoplasias/genética , Núcleo Familiar , Mutação Puntual , Fatores de Transcrição/genética , Fatores Etários , Proteína BRCA1/análise , Proteína BRCA2 , Feminino , Triagem de Portadores Genéticos , Marcadores Genéticos , Humanos , Pessoa de Meia-Idade , Proteínas de Neoplasias/análise , Fatores de Transcrição/análise
16.
Eur J Cancer ; 34(1): 142-7, 1998 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-9624249

RESUMO

Our previous studies have indicated that genetic aberrations in the 3p14 region are more frequent in malignant tumours from hereditary breast cancer patients than sporadic breast cancers. The main purpose of this study was to test if BRCA2 susceptibility alleles contribute to imbalance in the 3p14 region. We mapped allelic imbalance at 3p14 in tumours from Icelandic sisters affected with breast cancer using a set of 10 microsatellite markers (tel-D3S1295-D3S1234-D3S1300-D3S1600-D3S1233+ ++-D3S1217-D3S1261-D3S1296-D3S1210- D3S1284-cen). The patients were of known carrier status with respect to the 999del5 mutation in BRCA2 which is the most common cause of hereditary breast cancer in Iceland. Of 103 patients, 32 in the group were mutation carriers. A high degree of imbalance was observed in tumours from BRCA2 mutation carriers, ranging from 44 to 88% for individual markers. This was significantly higher than the percentage of imbalance in tumours from non-carriers, where the frequency ranged from 25 to 43%. In both groups, we noted elevated 3p14 imbalance in patients with bilateral disease. Allelic imbalance was most commonly observed near the marker D3S1210 (3p14.1-p12) and the FHIT gene (3p21.1-p14.2) for both groups. We conclude that genomic aberrations in 3p14 are especially frequent in tumours with BRCA2 gene defects, and suggest that this is caused by regional loss of chromosome stability rather than selection.


Assuntos
Neoplasias da Mama/genética , Cromossomos Humanos Par 3/genética , Mutação , Proteínas de Neoplasias/genética , Fatores de Transcrição/genética , Proteína BRCA2 , Fragilidade Cromossômica , Feminino , Predisposição Genética para Doença , Humanos , Perda de Heterozigosidade , Pessoa de Meia-Idade
17.
Breast Cancer Res Treat ; 47(2): 121-7, 1998 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-9497100

RESUMO

Inheritance is believed to play a major role in 5-10% of breast cancer. The breast cancer susceptibility genes BRCA1 and BRCA2 are estimated to account for more than half of these cases. Recent studies have suggested that breast cancers associated with BRCA1 germline mutations are of higher grade than sporadic cases. The purpose of this investigation was to determine if there are significant pathologic and biologic differences between hereditary BRCA2 related breast carcinomas and non-hereditary breast cancers. Forty cases of hereditary breast cancer from families associated with a specific 999del5 BRCA2 mutation were compared with regard to histologic and biologic factors to an age matched control group. Thirty-four patients (85%) had ductal carcinoma, two had lobular carcinoma, and one patient had medullary carcinoma. Compared to the control group, the BRCA2 tumors had less tubule formation (p = 0.02), more nuclear pleomorphism (p = 0.02), and higher mitotic rates (p = 0.002), and were thus of higher histologic grade (p = 0.003). By flow cytometry the BRCA2 tumors also had significantly higher S-phase fractions than the control tumors (p = 0.02). Significant differences in axillary lymph-node involvement or ploidy status were not detected. According to the results of this study, hereditary breast cancers associated with the 999del5 BRCA2 mutation are high grade tumors with a rapid proliferation rate. Other or additional factors than the defining BRCA2 mutation are involved in determining the tumor type.


Assuntos
Neoplasias da Mama/genética , Carcinoma Ductal de Mama/genética , Proteínas de Neoplasias/genética , Fatores de Transcrição/genética , Adulto , Idoso , Proteína BRCA2 , Mama/patologia , Mama/ultraestrutura , Neoplasias da Mama/patologia , Carcinoma Ductal de Mama/patologia , Feminino , Marcadores Genéticos , Humanos , Pessoa de Meia-Idade , Mutação
18.
Oncogene ; 16(1): 21-6, 1998 Jan 08.
Artigo em Inglês | MEDLINE | ID: mdl-9467939

RESUMO

Breast tumours from BRCA1 and BRCA2 mutation carriers are genetically instable and display specific patterns of chromosomal aberrations, suggestive of distinct genetic pathways in tumour progression. The frequency of abnormalities affecting chromosome 17p and the TP53 gene was determined in 27 breast tumours from 26 female patients carrying the Icelandic BRCA2 founder mutation (999del5). Loss of heterozygosity (LOH) was detected in 23 of the 27 tumours (85%). The majority of tumours manifesting LOH had lost a large region on 17p, although a more restricted loss, including the TP53 locus was seen in a few tumours. Positive p53 immunostaining was observed in 18 of 26 tumours (69%). However, mutations in the TP53 gene were detected in only three tumours (11%), including a missense (codon 139) and a nonsense mutation (codon 306) in two tumours with moderate p53 expression and a frameshift deletion (codon 182) in a tumour with no detectable p53 expression. Positive p53 immunostaining, mainly weak, was observed in 16 of the 24 tumours (66%) without TP53 mutation. The high frequency of LOH at chromosome 17p13 suggests that one or more genes from this region are involved in the development of BRCA2-induced breast cancer. The frequent finding of weak overexpression of, presumably wild type p53 protein, suggests an alternative mechanism of TP53 involvement specific to these tumours.


Assuntos
Neoplasias da Mama/genética , Cromossomos Humanos Par 17 , Heterozigoto , Perda de Heterozigosidade , Proteínas de Neoplasias/genética , Fatores de Transcrição/genética , Proteína BRCA2 , Cromossomos Humanos Par 13 , Cromossomos Humanos Par 7 , DNA Satélite , Marcadores Genéticos , Humanos , Imuno-Histoquímica , Proteína Supressora de Tumor p53/metabolismo
20.
Eur J Cancer ; 34(13): 2076-81, 1998 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-10070314

RESUMO

Several chromosome regions exhibit loss of heterozygosity (LOH) in human breast carcinoma and are thought to harbour tumour suppressor genes (TSG). At chromosome 13q, two TSGs have been identified, RB1 at 13q14 and BRCA2 at 13q12-q13. In this study, 139 sporadic breast tumours were analysed with 18 polymorphic microsatellite markers for detailed mapping of LOH at chromosome 13q and evaluation of an association with known progression factors. LOH with at least one marker was observed in 71 (51%) of the tumours analysed. The deletion mapping indicated three LOH target regions, 13q12-q13, 13q14 and 13q31-q34. LOH at chromosome 13q12-q13 was associated with low progesterone receptor content, a high S phase fraction and aneuploidy. Multivariate analysis adjusting for lymph node involvement and S phase fraction showed that patients with tumours exhibiting LOH at 13q12-q13 have a 3-4-fold increased risk of recurrence and death compared with other patients. Our results suggest there are at least three separate LOH target regions at chromosome 13q and inactivation of one or more genes at chromosome 13q12-q13 results in poor prognosis for breast cancer patients.


Assuntos
Neoplasias da Mama/genética , Cromossomos Humanos Par 13/genética , Perda de Heterozigosidade/genética , Proteínas de Neoplasias/genética , Fatores de Transcrição/genética , Aneuploidia , Proteína BRCA2 , Neoplasias da Mama/metabolismo , Mapeamento Cromossômico , Intervalo Livre de Doença , Feminino , Deleção de Genes , Humanos , Repetições de Microssatélites , Prognóstico , Receptores de Progesterona/metabolismo , Fase S/genética
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