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Ake Borg

Publications and source records attributed to Ake Borg.

At least 37 records · Page 2Linked to original sources
PubMed2005

Cytokeratin 5/14-positive breast cancer: true basal phenotype confined to BRCA1 tumors.

Breast ducts contain two types of epithelial cells, inner luminal cells and outer basal/myoepithelial cells. These cells can be distinguished by their immunophenotype. Cytokeratins (CKs) 8 and 18 are expressed in the luminal layer, whereas CK5/14 and the transcription factor p63 characterize the basal epithelial layer. We studied a population-based cohort of 288 sporadic ductal invasive cancers and found 9% positive for CK5/14 and 4% positive for p63. Using a highly sensitive polymer-based immunohistochemical staining, all sporadic tumors were positive for the luminal CK8/18, including those positive for CK5/14. Pairs of primary tumors and metastases (n = 38) were always concordant for CK5/14 expression. The majority of the CK5/14-positive cases were of histologic grade III (P = 0.0007) and steroid hormone receptor negative (P < 0.0001). CK5/14 expression was inversely associated with HER-2 oncogene amplification, but only in the subgroup of estrogen receptor-negative tumors (P = 0.007). In a separate set of 42 hereditary breast cancers, the majority (78%) of the BRCA1-associated tumors, but only one of 15 BRCA2-associated tumors was positive for CK5/14. In contrast to sporadic CK5/14-positive tumors, BRCA1-associated tumors displayed less intense CK8/18 staining, including some truly CK5/14-positive CK8/18-negative cases. These results suggest that CK5/14-positive sporadic breast cancers arise from glandularly committed progenitor cells rather than true CK8/18-negative basal cells.

BRCA1 Protein↗
PubMed2005

[Analysis of prognostic value of TP53 gene mutations in non-small cell lung cancer].

The aim of this study was to assess the frequency and prognostic value of TP53 gene somatic mutations in non-small cell lung cancer. The study group included 240 NSCLC patients who underwent pulmonary resection at the Department of Thoracic Surgery, Medical University of Gdańsk. Tumour samples were evaluated for the presence of TP53 gene mutations in exons 5-8. In 157 cases SSCP method was used as a screening followed by sequencing of positive samples. In the remaining 83 patients mutations were analysed by direct sequencing. A total of 76 mutations (32%) were found, of those a missense type was dominant (67%), followed by silent and null type mutations (14% and 10%, respectively). There was no correlation between mutations and clinical characteristics, including age, sex, histological subtype, differentiation, tumour size, lymph node metastases, pTNM stage and smoking status. A multivariate Cox analysis demonstrated that tumour differentiation and pTNM stage were independent prognostic factors, whereas TP53 gene mutations were not. The results of this study indicate that TP53 gene mutations in NSCLC patients are not correlated with clinical characteristics and have no impact on survival.

Adult↗
PubMed2004

Staf50 is a novel p53 target gene conferring reduced clonogenic growth of leukemic U-937 cells.

The tumor suppressor gene p53 is a transcription factor that mediates both cell cycle arrest and apoptosis. Interestingly, p53 also induces differentiation of a number of tissues, including leukemic cells. However, although p53-mediated differentiation of leukemic U-937 cells depends on the transcriptional activity of p53, a p53 target gene mediating differentiation has hitherto not been identified. To screen for novel p53 target genes in leukemic cells, a cDNA microarray analysis was performed with U-937-4/ptsp53 cells, expressing a temperature-sensitive p53 mutant. We report that transcription of the Staf50 (stimulated transacting factor of 50 kDa) gene is upregulated in response to wild-type p53 in U-937-4, K562 and MCF-7 cells. Staf50 was directly activated by p53, as determined by the independence of de novo protein synthesis. Moreover, while the proximal promoter of Staf50 was found not to be p53 responsive, a functional enhancer-like p53-response element in intron 1 of the Staf50 gene was identified that was also transactivated by the p53-family member p73. Direct binding of p53 to the response element was shown by electrophoretic mobility shift analysis. Ectopic expression of Staf50 in U-937 cells resulted in reduced clonogenic growth. Moreover, levels of endogenous Staf50 mRNA correlated to all-trans retinoic acid-induced differentiation of promyelocytic NB-4 and HL60 cells, suggesting that Staf50 could be involved in proliferation and/or differentiation of leukemic cells.

Amino Acid Motifs↗
PubMed2004

Human neuroblastoma cells exposed to hypoxia: induction of genes associated with growth, survival, and aggressive behavior.

We have recently found that cells derived from human neuroblastoma, a sympathetic nervous system (SNS) tumor, dedifferentiate and acquire a neural crest-like phenotype when exposed to hypoxia. In the present study, global analysis of gene expression and quantitative PCR of relevant genes showed that hypoxia provokes a general adaptive response in neuroblastoma cells and confirm loss of the neuronal phenotype and gain of stem-cell characteristics. Of the approximately 17,000 genes and ESTs analyzed, 199 were consistently upregulated and 36 were downregulated more than 2-fold by hypoxia. As anticipated, several genes involved in glucose and iron metabolism and neovascularization were upregulated, the latter group we here show to include the gene encoding chromogranin C and its cleavage product, secretoneurin, a vascular smooth muscle cell mitogen. We also observed upregulation of genes implicated in cell survival and growth, such as vascular endothelial growth factor (VEGF), neuropilin 1, adrenomedullin, and IGF-2. Several metallothioneins, which are linked to tumor drug resistance, were upregulated, whereas the expression of MDR1 decreased. In hypoxic neuroblastoma cells, proneuronal lineage specifying transcription factors, and their dimerization partner E2-2, were downregulated, whereas their inhibitors Id2 and HES-1 were induced, providing a molecular mechanism for the hypoxia-provoked dedifferentiation of neuroblastoma cells.

ATP Binding Cassette Transporter, Subfamily B, Mem↗
PubMed2004

Predicting continuous values of prognostic markers in breast cancer from microarray gene expression profiles.

The prognostic and treatment-predictive markers currently in use for breast cancer are commonly based on the protein levels of individual genes (e.g., steroid receptors) or aspects of the tumor phenotype, such as histological grade and percentage of cells in the DNA synthesis phase of the cell cycle. Microarrays have previously been used to classify binary classes in breast cancer such as estrogen receptor (ER)-alpha status. To test whether the properties and specific values of conventional prognostic markers are encoded within tumor gene expression profiles, we have analyzed 48 well-characterized primary tumors from lymph node-negative breast cancer patients using 6728-element cDNA microarrays. In the present study, we used artificial neural networks trained with tumor gene expression data to predict the ER protein values on a continuous scale. Furthermore, we determined a gene expression profile-directed threshold for ER protein level to redefine the cutoff between ER-positive and ER-negative classes that may be more biologically relevant. With a similar approach, we studied the prediction of other prognostic parameters such as percentage cells in the S phase of the cell cycle (SPF), histological grade, DNA ploidy status, and progesterone receptor status. Interestingly, there was a consistent reciprocal relationship in expression levels of the genes important for both ER and SPF prediction. This and similar studies may be used to increase our understanding of the biology underlying these markers as well as to improve the currently available prognostic markers for breast cancer.

Biomarkers↗
PubMed2003

Patterns of chromosomal imbalances defines subgroups of breast cancer with distinct clinical features and prognosis. A study of 305 tumors by comparative genomic hybridization.

Chromosomal copy number aberrations (CNAs) are common in breast cancer and involve genomic regions in a frequency and combination, suggesting distinct routes of tumor development. We studied chromosomal gains (+) and losses (-) by comparative genomic hybridization from a series of 305 unselected primary invasive breast cancers. CNAs were observed in >90% of the tumors and involved all chromosomal arms in various frequencies, the most common being +1q (55%), +8q (41%), +16p (40%), +17q (28%), -13q (27%), -16q (22%), +20q (19%), -8p (18%), and +11q (16%). Eighteen pairs of CNAs were revealed as significantly associated using Fisher's exact test with Bonferroni correction, the most common pairs being -8p/+8q, +17q/+20q, and -4q/-13q. To study more complex relationships between individual CNAs, principal component analysis and distance-based tree modeling were performed independently. Three distinct patterns of CNAs were observed. Group A was defined by +1q, +16p, and -16q, group B by +11q, +20q, +17q, and -13q, and group C by -8p and +8q. Group A was correlated to positive estrogen receptor and progesterone receptor (PgR) status (P < 0.001 and P < 0.05, respectively). Groups B and C were correlated to DNA nondiploidy (P < 0.001 and P < 0.05), high histological grade and lymph node positivity (P < 0.05), and group B also to high proliferation rate, large primary tumor size (P < 0.001), and negative PgR status (P < 0.05). Patients with aberrations in group A only had a significantly higher breast cancer survival rate than all other patients. The worst survival was seen for patients with aberrations in group C only along with the patients displaying aberrations from all CNA pattern groups (ABC). The 5-year survival rates vary from 96% in group A to 56% in group C. These correlations were independent of node status, tumor size, and PgR status in a multivariate analysis. We conclude that patterns of copy number gains and losses define breast tumors with distinct clinicopathological features and patient prognosis.

Adult↗
PubMed2003

Cancer incidence in relatives of a population-based set of cases of early-onset breast cancer with a known BRCA1 and BRCA2 mutation status.

BACKGROUND: Relatives of breast cancer cases have an increased risk of the disease. The risk increases with increasing numbers and decreasing age of onset of affected relatives. In families with a BRCA1 or a BRCA2 mutation, individual carrier status predicts the risk of breast cancer. In relatives of cases where both BRCA1 and BRCA2 mutations are excluded, the risk remains undetermined. METHODS: Standardized incidence ratios (SIRs) and cumulative cancer incidences were calculated for relatives of a population-based set of early-onset breast cancer index cases (younger than age 41 years) with a defined BRCA mutation status (n = 203). RESULTS: In first-degree relatives (FDRs) of mutation-negative cases, breast cancer incidences (SIR = 2.3), prostate cancer incidences (SIR = 1.7), cervix cancer incidences (SIR = 3.3) and nonmelanoma skin cancer incidences (SIR = 2.8) were increased. The risks of breast cancer, prostate cancer and nonmelanoma skin cancer were further increased in FDRs of breast cancer cases younger than 36 years of age. In high-risk individuals with at least one relative with breast cancer apart from the index case, but no BRCA mutation in the family, breast cancer incidence was increased (SIR = 5.3); again the prostate cancer incidence was elevated (SIR = 2.5). The cumulative incidence of breast cancer at ages 50 and 70 years for FDRs of index cases without a BRCA mutation was 3.6% and 12.8%, respectively. Similarly, the cumulative incidence of breast cancer for high-risk women was 6.3% and 21.1% at ages 50 and 70 years, and that for FDRs of BRCA mutation carriers was 17.2% and 27.7% at the same ages. CONCLUSION: The incidence of breast cancer is increased for FDRs of women with early-onset breast cancer irrespective of the BRCA status in the family. Risk increases with decreasing age and with increasing number of affected relatives. The incidences of prostate cancer, cervix cancer and nonmelanoma skin cancer are elevated for FDRs of early-onset breast cancer cases without a BRCA mutation, indicating a possible association between these cancers and early-onset breast cancer.

Adult↗
PubMed2003

Lack of HIN-1 methylation in BRCA1-linked and "BRCA1-like" breast tumors.

We recently identified a candidate tumor suppressor gene, HIN-1, that is silenced due to methylation in the majority of sporadic breast carcinomas and is localized to 5q33-qter, an area frequently lost in BRCA1 tumors and thought to harbor a BRCA1 modifier gene. To establish whether germ-line mutations in HIN-1 may influence breast cancer risk, we sequenced the HIN-1 coding region in 10 familial breast cancer patients with positive logarithm of the odds scores of at least one of the markers flanking HIN-1. We also sequenced the HIN-1 coding region in 15 BRCA1 and 35 sporadic breast tumors to determine whether HIN-1 is the target of the frequent 5q loss in BRCA1 tumors. No sequence alterations were found in any of the cases analyzed. However, analysis of HIN-1 promoter methylation status revealed that in striking contrast to sporadic cases, there is a nearly complete lack of HIN-1 methylation in BRCA1 tumors (P < 0.0001). Sporadic breast tumors with a "BRCA1-like" histopathological phenotype also demonstrated significantly lower frequency of HIN-1 promoter methylation (P = 0.01) compared with other cancer types, and there was also a difference among tumors based on their estrogen receptor and HER2 status (P = 0.006), suggesting that HIN-1 methylation patterns are associated with specific breast cancer subtypes.

Breast Neoplasms↗
PubMed2003

Molecular classification of familial non-BRCA1/BRCA2 breast cancer.

In the decade since their discovery, the two major breast cancer susceptibility genes BRCA1 and BRCA2, have been shown conclusively to be involved in a significant fraction of families segregating breast and ovarian cancer. However, it has become equally clear that a large proportion of families segregating breast cancer alone are not caused by mutations in BRCA1 or BRCA2. Unfortunately, despite intensive effort, the identification of additional breast cancer predisposition genes has so far been unsuccessful, presumably because of genetic heterogeneity, low penetrance, or recessive/polygenic mechanisms. These non-BRCA1/2 breast cancer families (termed BRCAx families) comprise a histopathologically heterogeneous group, further supporting their origin from multiple genetic events. Accordingly, the identification of a method to successfully subdivide BRCAx families into recognizable groups could be of considerable value to further genetic analysis. We have previously shown that global gene expression analysis can identify unique and distinct expression profiles in breast tumors from BRCA1 and BRCA2 mutation carriers. Here we show that gene expression profiling can discover novel classes among BRCAx tumors, and differentiate them from BRCA1 and BRCA2 tumors. Moreover, microarray-based comparative genomic hybridization (CGH) to cDNA arrays revealed specific somatic genetic alterations within the BRCAx subgroups. These findings illustrate that, when gene expression-based classifications are used, BRCAx families can be grouped into homogeneous subsets, thereby potentially increasing the power of conventional genetic analysis.

Adult↗
PubMed2003

BRCA1 and BRCA2 mutation analysis in breast-ovarian cancer families from northeastern Poland.

Sixty high-risk breast and/or ovarian cancer families from North-Eastern Poland were screened for germline mutations in BRCA1 (MIM# 113705) and BRCA2 (MIM# 600185), using a combination of protein truncation test, denaturing high-performance liquid chromatography and direct sequencing. Sixteen (27%) of the families were found to carry nine different BRCA mutations, including 14 families with BRCA1 mutation and two families with BRCA2 mutation. The results suggest the presence of two strong BRCA1 founder mutations in the Polish population - 5382insC (6 families) and 300T>G (Cys61Gly; 3 families). The remaining seven mutations were found in single families and included three previously reported BRCA1 mutations (185delAG, 2682C>T [Gln855Ter] and 3819del5), a novel BRCA1 mutation (IVS14+1G>A), as well as two BRCA2 mutations (4088delA and 7985G>A [Trp2586Ter]) not previously observed in Polish families. We confirm the strong influence of two Central-Eastern European BRCA1 founder mutations in familial breast and/or ovarian cancer in Poland. We also conclude that the Polish population has a more dispersed BRCA mutation spectrum than had been earlier thought. This warrants further careful BRCA mutation screening in order to optimise genetic counselling and disease prevention in affected families.

Adult↗
PubMed2003

Characterization of a novel breast carcinoma xenograft and cell line derived from a BRCA1 germ-line mutation carrier.

A human tumor xenograft (L56Br-X1) was established from a breast cancer axillary lymph node metastasis of a 53-year-old woman with a BRCA1 germ-line nonsense mutation (1806C>T; Q563X), and a cell line (L56Br-C1) was subsequently derived from the xenograft. The xenograft carries only the mutant BRCA1 allele and expresses mutant BRCA1 mRNA but no BRCA1 protein as determined by immunoprecipitation or Western blotting. The primary tumor, lymph node metastasis, and xenograft were hypodiploid by DNA flow cytometry, whereas the cell line displayed an aneuploidy apparently developed via polyploidization. Cytogenetic analysis, spectral karyotyping, and comparative genomic hybridization of the cell line revealed a highly complex karyotype with numerous unbalanced translocations. The xenograft and cell line had retained a somatic TP53 missense mutation (S215I) originating from the primary tumors, as well as a lack of immunohistochemically detectable expression of steroid hormone receptors, epidermal growth factor receptor, human epidermal growth factor receptor 2 (HER-2), and keratin 8. Global gene expression analysis by cDNA microarrays supported a correlation between the expression profiles of the primary tumor, lymph node metastasis, xenograft, and cell line. We conclude that L56Br-X1 and L56Br-C1 are useful model systems for studies of the pathogenesis and new therapeutic modalities of BRCA1-induced human breast cancer.

Aneuploidy↗
PubMed2002

Survival in prospectively ascertained familial breast cancer: analysis of a series stratified by tumour characteristics, BRCA mutations and oophorectomy.

Dedicated clinics have been established for the early diagnosis and treatment of women at risk for inherited breast cancer, but the effects of such interventions are currently unproven. This second report on prospectively diagnosed inherited breast cancer from the European collaborating centres supports the previous conclusions and adds information on genetic heterogeneity and the effect of oophorectomy. Of 249 patients, 20% had carcinoma in situ (CIS), 54% had infiltrating cancer without spread (CaN0) and 26% had cancer with spread (CaN+). Five-year survival was 100% for CIS, 94% for CaN0 and 72% for CaN+ (p = 0.007). Thirty-six patients had BRCA1 mutations, and 8 had BRCA2 mutations. Presence of BRCA1 mutation was associated with infiltrating cancer, high grade and lack of oestrogen receptor (p < 0.05 for all 3 characteristics). For BRCA1 mutation carriers, 5-year survival was 63% vs. 91% for noncarriers (p = 0.04). For CaN0 patients, mutation carriers had 75% 5-year disease-free survival vs. 96% for noncarriers (p = 0.01). Twenty-one of the mutation carriers had undergone prophylactic oophorectomy, prior to or within 6 months of diagnosis in 13 cases. All but 1 relapse occurred in the 15 who had kept their ovaries, (p < 0.01); no relapse occurred in those who had removed the ovaries within 6 months (p = 0.04) Contralateral cancer was more frequently observed in mutation noncarriers, but this finding did not reach statistical significance. Our findings support the concept that BRCA1 cancer is biologically different from other inherited breast cancers. While current screening protocols appear satisfactory for the majority of women at risk of familial breast cancer, this may not be the case for BRCA1 mutation carriers. The observed effect of oophorectomy was striking.

Adult↗
PubMed2002

Expression profiling to predict outcome in breast cancer: the influence of sample selection.

Gene expression profiling of tumors using DNA microarrays is a promising method for predicting prognosis and treatment response in cancer patients. It was recently reported that expression profiles of sporadic breast cancers could be used to predict disease recurrence better than currently available clinical and histopathological prognostic factors. Having observed an overlap in those data between the genes that predict outcome and those that predict estrogen receptor-alpha status, we examined their predictive power in an independent data set. We conclude that it may be important to define prognostic expression profiles separately for estrogen receptor-alpha-positive and estrogen receptor-alpha-negative tumors.

Breast Neoplasms↗
PubMed2002

Increased CpG methylation of the estrogen receptor gene in BRCA1-linked estrogen receptor-negative breast cancers.

A distinctive feature of BRCA1-linked breast cancers is that they typically do not express estrogen receptor-alpha (ER(alpha)). Previous investigation suggests that methylation of CpGs within the ER(alpha) promoter mediates repression of gene expression in some ER(alpha)-negative breast cancers. To determine if methylation of CpGs within the ER(alpha) promoter is associated with BRCA1-linked breast cancers, we evaluated methylation in exon 1 of the ER(alpha) gene in 40 ER(alpha)-negative breast cancers, 20 of which were non BRCA1-linked and 20 BRCA1-linked. CpG methylation was evaluated by either methylation-sensitive restriction digest (HpaII), methylation-sensitive PCR (MSP), or direct sequencing of bisulfite-treated genomic DNA. Results from HpaII digests and MSP documented a high degree of methylation, the MSP data showing slightly higher methylation in the BRCA1-linked group. CpGs analysed by direct sequencing showed an overall average methylation of 25% among non BRCA1-linked cancers and 40% among BRCA1-linked cancers (P=0.0031). The most notable difference was found at five particular CpGs, each of which exhibited a greater than twofold increase in methylation in the BRCA1-linked group compared to the non BRCA1-linked group (P<0.03 for each CpG). Methylation of certain critical CpGs may represent an important factor in transcriptional repression of the ER(alpha) gene in BRCA1-linked breast cancers.

Adult↗
PubMed2002

BioArray Software Environment (BASE): a platform for comprehensive management and analysis of microarray data.

The microarray technique requires the organization and analysis of vast amounts of data. These data include information about the samples hybridized, the hybridization images and their extracted data matrices, and information about the physical array, the features and reporter molecules. We present a web-based customizable bioinformatics solution called BioArray Software Environment (BASE) for the management and analysis of all areas of microarray experimentation. All software necessary to run a local server is freely available.

Database Management Systems↗
PubMed2002

Distinct sets of gene alterations in endometrial carcinoma implicate alternate modes of tumorigenesis.

BACKGROUND: Endometrial carcinomas seem to carry a different prognosis depending on the presence or absence of concomitant complex atypical hyperplasia (hyperplasia). The molecular genetic profile of these two pathogenetic types, based on the genes reportedly mutated in these cancers, remains to be defined. Although microsatellite inability is reported in approximately 25% of endometrial carcinomas, its relation with the 2 pathogenetic types is not investigated. METHODS: To elucidate their underlying genetic changes, we analyzed 53 sporadic endometrial tumors, including 19 with and 34 without hyperplasia, for microsatellite instability (MSI), DNA ploidy (by flow cytometry), and for mutations in different genes. RESULTS: Microsatellite instability was present in 21%, DNA nondiploidy in 15%, and mutations in the PTEN, KRAS, CTNNB1/beta-catenin, TP53, and CDKN2A genes were detected in 32, 11, 13, 17, and 0% of the tumors, respectively. Microsatellite instability and mutations in these genes were present in tumors both with and without complex atypical hyperplasia. All cases with complex atypical hyperplasia were early stage (I-II) endometrioid tumors and associated with long progression free disease (P = 0.0004). Furthermore, most tumors with hyperplasia had low World Health Organization or International Federation of Gynecology and Obstetrics grade, had less myometrial invasion, and showed expression of estrogen receptors. All MSI tumors were diploid and had a significantly higher rate of PTEN mutations, but similar rates of KRAS, beta-catenin, and TP53 mutations compared with microsatellite stable tumors. TP53 mutations more often were found in nondiploid tumors but never in tumors with PTEN, KRAS, or beta-catenin mutations, and all PTEN mutations occurred in diploid tumors. CONCLUSIONS: Thus, PTEN, KRAS, beta-catenin, and TP53 mutations occurred in tumors both with and without hyperplasia, but PTEN and TP53 mutations were more common in tumors without hyperplasia. However, none of these genes seems to clearly distinguish tumors with and without hyperplasia, suggesting that other factors may be involved. Conversely, alterations in the PTEN and TP53 genes seem to define distinct subgroups of endometrial carcinoma, the former associated with diploidy and MSI, the latter with macroscopic chromosomal instability.

Aged↗