| 1. |
- Arver, Brita, et al.
(författare)
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First BRCA1 and BRCA2 gene testing implemented in the health care system of Stockholm
- 2001
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Ingår i: Genetic Testing. - : Mary Ann Liebert Inc. - 1557-7473 .- 1090-6576. ; 5:1, s. 41282-41282
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Tidskriftsartikel (refereegranskat)abstract
- The aim of the study was to optimize the criteria for the BRCA1 and BRCA2 gene testing and to improve oncogenetic counseling in the Stockholm region. Screening for inherited breast cancer genes is laborious and a majority of tested samples turn out to be negative. The frequencies of mutations in the BRCA1 and BRCA2 genes differ across populations. Between 1997 and 2000, 160 families with breast and/or ovarian cancer were counseled and screened for mutations in the two genes. Twenty-five BRCA1 and two BRCA2 disease-causing mutations were found. Various factors associated with the probability of finding a BRCA1 mutation in the families were estimated. Age of onset in different generations and other malignancies were also studied. Families from our region in which both breast and ovarian cancer occur were likely to carry a BRCA1 mutation (34%). In breast-only cancer families, mutations were found only in those with very early onset. All breast-only cancer families with a mutation had at least one case of onset before 36 years of age and a young median age of onset (< 43 years). Other malignancies than breast and ovarian cancers did not segregate in the BRCA1 families and surveillance for other malignancies is not needed, in general. Decreasing age of onset with successive generations was common and must be taken into account when surveillance options are considered.
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| 2. |
- Bergthorsson, J.T., et al.
(författare)
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BRCA1 and BRCA2 mutation status and cancer family history of Danish women affected with multifocal or bilateral breast cancer at a young age
- 2001
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Ingår i: Journal of Medical Genetics. - : BMJ. - 0022-2593 .- 1468-6244. ; 38:6, s. 361-368
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Tidskriftsartikel (refereegranskat)abstract
- Introduction - A small fraction of breast cancer is the result of germline mutations in the BRCA1 and BRCA2 cancer susceptibility genes. Mutation carriers frequently have a positive family history of breast and ovarian cancer, are often diagnosed at a young age, and may have a higher incidence of double or multiple primary breast tumours than breast cancer patients in general. Objectives - To estimate the prevalence and spectrum of BRCA1 and BRCA2 mutations in young Danish patients affected with bilateral or multifocal breast cancer and to determine the relationship of mutation status to family history of cancer. Subjects - From the files of the Danish Breast Cancer Cooperative Group (DBCG), we selected 119 breast cancer patients diagnosed before the age of 46 years with either bilateral (n=59) or multifocal (n=61) disease. Methods - DNA from the subjects was screened for BRCA1 and BRCA2 mutations using single strand conformation analysis (SSCA) and the protein truncation test (PTT). Observed and expected cancer incidence in first degree relatives of the patients was estimated using data from the Danish Cancer Registry. Results - Twenty four mutation carriers were identified (20%), of whom 13 had a BRCA1 mutation and 11 carried a BRCA2 mutation. Two mutations in BRCA1 were found repeatedly in the material and accounted for seven of the 24 (29%) mutation carriers. The mutation frequency was about equal in patients with bilateral (22%) and multifocal breast cancer (18%). The incidence of breast and ovarian cancer was greatly increased in first degree relatives of BRCA1 and BRCA2 mutation carriers, but to a much lesser degree in relatives of non-carriers. An increased risk of cancer was also noted in brothers of non-carriers. Conclusions - A relatively broad spectrum of germline mutations was observed in BRCA1 and BRCA2 and most of the mutations are present in other populations. Our results indicate that a diagnosis of bilateral and multifocal breast cancer is predictive of BRCA1 and BRCA2 mutation status, particularly when combined with information on the patients' age at diagnosis and family history of breast/ovarian cancer.
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| 3. |
- Borg, Åke
(författare)
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Hereditary prostate cancer: a new piece of the puzzle.
- 2001
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Ingår i: Nature Medicine. - : Springer Science and Business Media LLC. - 1546-170X .- 1078-8956. ; 7:2, s. 153-155
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Tidskriftsartikel (refereegranskat)abstract
- An eagerly awaited prostate cancer susceptibility gene has been announced. But does the candidate live up to expectations?
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| 4. |
- Borg, Åke
(författare)
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Molecular and pathological characterization of inherited breast cancer.
- 2001
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Ingår i: Seminars in Cancer Biology. - : Elsevier BV. - 1096-3650 .- 1044-579X. ; 11:5, s. 375-385
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Tidskriftsartikel (refereegranskat)abstract
- The two major breast cancer susceptibility genes, BRCA1 and BRCA2, account for the majority of familial breast–ovarian cancer, but only a modest proportion of breast cancer families without ovarian or male breast cancer. Search for additional breast cancer genes with traditional linkage analysis has so far been unsuccessful, probably due to genetic heterogeneity. Pooling of families of different ethnical, cultural, and geographical origin proved to be a useful approach when identifying BRCA1 and BRCA2, but for genes mutated only in specific populations it is important not to introduce locus heterogeneity by pooling. Genetic heterogeneity can possibly be circumvented by using objective means, such as tumour histopathology or gene expression profiling, for subclassification of families prior to linkage analysis. Also, additional breast cancer genes can be identified by further characterization of the function of BRCA1 and BRCA2 and their interacting proteins.
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| 5. |
- Esteller, Manel, et al.
(författare)
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DNA methylation patterns in hereditary human cancers mimic sporadic tumorigenesis
- 2001
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Ingår i: Human Molecular Genetics. - : Oxford University Press (OUP). - 0964-6906 .- 1460-2083. ; 10:26, s. 3001-3007
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Tidskriftsartikel (refereegranskat)abstract
- Cancer cells have aberrant patterns of DNA methylation including hypermethylation of gene promoter CpG islands and global demethylation of the genome. Genes that cause familial cancer, as well as other genes, can be silenced by promoter hypermethylation in sporadic tumors, but the methylation of these genes in tumors from kindreds with inherited cancer syndromes has not been well characterized. Here, we examine CpG island methylation of 10 genes (hMLH1, BRCA1, APC, LKB1, CDH1, p16(INK4a), p14(ARF), MGMT, GSTP1 and RARbeta2) and 5-methylcytosine DNA content, in inherited (n = 342) and non-inherited (n = 215) breast and colorectal cancers. Our results show that singly retained alleles of germline mutated genes are never hypermethylated in inherited tumors. However, this epigenetic change is a frequent second "hit", associated with the wild-type copy of these genes in inherited tumors where both alleles are retained. Global hypomethylation was similar between sporadic and hereditary cases, but distinct differences existed in patterns of methylation at non-familial genes. This study demonstrates that hereditary cancers "mimic" the DNA methylation patterns present in the sporadic tumors.
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| 6. |
- Gentile, Massimiliano, et al.
(författare)
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Deletion mapping of chromosome segment 11q24-q25, exhibiting extensive allelic loss in early onset breast cancer
- 2001
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Ingår i: International Journal of Cancer. - 0020-7136 .- 1097-0215. ; 92:2, s. 208-213
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Tidskriftsartikel (refereegranskat)abstract
- Frequent allelic deletions at chromosome 11q24-q25 have been described in both early and late onset breast cancers, suggesting the existence of a gene locus implicated in the initiation and/or progression of the disease. In the present study we fine mapped this region further by loss of heterozygosity (LOH) analysis in a population of early onset breast cancer cases (n = 102, 22 to 36 years old). Loss of chromosomal material was assessed for possible association with patient survival as well as Nottingham histologic grade (NHG). Additionally, we investigated the involvement of the 11q24-q25 locus in a group of familial breast cancer cases with no detectable BRCA1 or BRCA2 gene alterations (n = 32, ages 28 to 40 years). Among the consecutive patients, extensive LOH was observed for all markers at 11q24-q25, with frequencies ranging from 42% to 54%. Deletion at the D11S4125 marker was found to be associated with reduced survival (p = 0.026), whereas the adjacent D11S387 marker correlated with higher histologic grade (p = 0.042). In the familial cases, the most telomeric markers showed substantially lower proportions of LOH, ranging from 10% to 21%. Comparison of the two patient groups demonstrated that this difference in LOH frequency was statistically significant for the D11S4098, D11S968, D11S387 and D11S4125 markers (p = 0.020, p = 0.029, p = 0.0070 and p = 0.0030, respectively). We conclude that 11q25 may harbor a gene implicated in early onset breast cancer. Our data suggest that the most probable position for this locus is defined by the markers D11S387 and D11S4125 and furthermore that it may play a less significant role in familial breast cancer cases not linked to either of the BRCA genes.
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| 7. |
- Gruvberger, Sofia, et al.
(författare)
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Estrogen receptor status in breast cancer is associated with remarkably distinct gene expression patterns
- 2001
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Ingår i: Cancer Research. - 1538-7445. ; 61:16, s. 5979-5984
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Tidskriftsartikel (refereegranskat)abstract
- To investigate the phenotype associated with estrogen receptor alpha (ER) expression in breast carcinoma, gene expression profiles of 58 node-negative breast carcinomas discordant for ER status were determined using DNA microarray technology. Using artificial neural networks as well as standard hierarchical clustering techniques, the tumors could be classified according to ER status, and a list of genes which discriminate tumors according to ER status was generated. The artificial neural networks could accurately predict ER status even when excluding top discriminator genes, including ER itself. By reference to the serial analysis of gene expression database, we found that only a small proportion of the 100 most important ER discriminator genes were also regulated by estradiol in MCF-7 cells. The results provide evidence that ER+ and ER- tumors display remarkably different gene-expression phenotypes not solely explained by differences in estrogen responsiveness.
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| 8. |
- Grönberg, Henrik, et al.
(författare)
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BRCA2 mutation in a family with hereditary prostate cancer
- 2001
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Ingår i: Genes, Chromosomes and Cancer. - 1045-2257. ; 30:3, s. 299-301
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Tidskriftsartikel (refereegranskat)abstract
- Hereditary prostate cancer is a genetically heterogeneous disease, and so far four different susceptibility loci have been identified. Reports of associated cancers are few, and it is generally considered a sire-specific disease. However, some reports have shown an elevated risk for prostate cancer among BRCA2 mutation carriers. In this report, we present a family in which the father and four of his sons were diagnosed with prostate cancer at exceptionally early ages (51, 52, 56, 58, and 63 years, respectively). In addition, three daughters were diagnosed with breast cancer between the ages of 47 and 61. In this family, a truncating mutation in exon 11, 6051delA of the BRCA2 gene, leading to an early termination of the protein (codon 1962), was identified. Although BRCA2 is probably responsible only for a very small fraction of hereditary prostate cancers, this finding supports previous reports of an increased risk of prostate cancer in BRCA2 mutation carriers.
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| 9. |
- Hashemi, J, et al.
(författare)
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Haplotype analysis and age estimation of the 113insR CDKN2A founder mutation in Swedish melanoma families.
- 2001
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Ingår i: Genes, chromosomes & cancer. - : Wiley. - 1045-2257 .- 1098-2264. ; 31:2, s. 107-16
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Tidskriftsartikel (refereegranskat)abstract
- Germline mutations in the CDKN2A tumor suppressor gene located on 9p21 have been linked to development of melanomas in some families. A germline 3-bp insertion in exon 2 of CDKN2A, leading to an extra arginine at codon 113 (113insR), has been identified in 17 Swedish melanoma families. Analysis of 10 microsatellite markers, spanning approximately 1 Mbp in the 9p21 region, showed that all families share a common allele for at least one of the markers closest to the CDKN2A gene, suggesting that the 113insR mutation is an ancestral founder mutation. Differences in the segregating haplotypes, due to meiotic recombinations and/or mutations in the short-tandem-repeat markers, were analyzed further to estimate the age of the mutation. Statistical analysis using a maximum likelihood approach indicated that the mutation arose 98 generations (90% confidence interval: 52-167 generations), or approximately 2,000 years, ago. Thus, 113insR would be expected to have a more widespread geographic distribution in European and North American regions with ancestral connections to Sweden. Alternatively, CDKN2A may lie in a recombination hot spot region, as suggested by the many meiotic recombinations in this narrow approximately 1-cM region on 9p21.
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| 10. |
- Hedenfalk, I, et al.
(författare)
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Gene-expression profiles in hereditary breast cancer
- 2001
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Ingår i: New England Journal of Medicine. - 0028-4793. ; 344:8, s. 48-539
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Tidskriftsartikel (refereegranskat)abstract
- BACKGROUND: Many cases of hereditary breast cancer are due to mutations in either the BRCA1 or the BRCA2 gene. The histopathological changes in these cancers are often characteristic of the mutant gene. We hypothesized that the genes expressed by these two types of tumors are also distinctive, perhaps allowing us to identify cases of hereditary breast cancer on the basis of gene-expression profiles.METHODS: RNA from samples of primary tumor from seven carriers of the BRCA1 mutation, seven carriers of the BRCA2 mutation, and seven patients with sporadic cases of breast cancer was compared with a microarray of 6512 complementary DNA clones of 5361 genes. Statistical analyses were used to identify a set of genes that could distinguish the BRCA1 genotype from the BRCA2 genotype.RESULTS: Permutation analysis of multivariate classification functions established that the gene-expression profiles of tumors with BRCA1 mutations, tumors with BRCA2 mutations, and sporadic tumors differed significantly from each other. An analysis of variance between the levels of gene expression and the genotype of the samples identified 176 genes that were differentially expressed in tumors with BRCA1 mutations and tumors with BRCA2 mutations. Given the known properties of some of the genes in this panel, our findings indicate that there are functional differences between breast tumors with BRCA1 mutations and those with BRCA2 mutations.CONCLUSIONS: Significantly different groups of genes are expressed by breast cancers with BRCA1 mutations and breast cancers with BRCA2 mutations. Our results suggest that a heritable mutation influences the gene-expression profile of the cancer.
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