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A L Børresen-Dale

Publications and source records attributed to A L Børresen-Dale.

At least 19 recordsLinked to original sources
PubMed2003

Predictive value of tumour cell proliferation in locally advanced breast cancer treated with neoadjuvant chemotherapy.

We previously reported that defects in apoptotic pathways (mutations in the TP53 gene) predicted resistance to doxorubicin monotherapy. The aim of this study was to evaluate whether cell proliferation, as assessed by mitotic frequency and Ki-67 levels, may provide additional predictive information in the same tumours and to assess any potential correlations between these markers and mutations in the TP53 gene and erbB-2 overexpression. Surgical specimens were obtained from ninety locally advanced breast cancers before commencing primary chemotherapy consisting of weekly doxorubicin (14 mg/m2) for 16 weeks. 38% of the patients had a partial response (PR) to therapy, 52% had stable disease (SD) while 10% had progressive disease (PD). Univariate analysis showed a significant association between a high cell proliferation rate (expressed as a high mitotic frequency) and resistance to doxorubicin (P = 0.001). Further analyses revealed this association to be limited to the subgroup of tumour expressing wild-type TP53 (P = 0.016), and TP53 mutation status was the only factor predicting drug resistance in the multivariate analyses. The finding that a high mitotic frequency, as well as a high Ki-67 staining, correlated to TP53 mutations (P = 0.001 for both), suggests TP53 mutations are the key predictor of drug resistance, although cell proliferation may play an additional role in tumours harbouring wild-type TP53. Regarding overall (OS) and relapse-free survival (RFS), multivariate analyses (Cox' proportional hazards regression) revealed a high histological grade and negative oestrogen receptor (ER) status to be the variables that were most strongly related to breast cancer death (P = 0.001 and P = 0.001, respectively). A key reason for this difference with respect to the factors predicting chemotherapy resistance could be due to the adjuvant use of tamoxifen in all patients harbouring ER-positive tumours.

Adult↗
PubMed2002

High frequency of skewed X inactivation in young breast cancer patients.

INTRODUCTION: Patients with invasive ovarian cancer were recently shown to have a higher frequency of skewed X chromosome inactivation in peripheral blood cells compared to patients with borderline cancer and controls. In this study, we analysed the X inactivation pattern in peripheral blood from 216 breast cancer patients. METHODS: X inactivation analysis was performed using HpaII predigestion of DNA followed by PCR of the highly polymorphic CAG repeat of the androgen receptor gene (AR), which amplifies the undigested inactive X chromosome only. The X inactivation pattern was classified as skewed when 90% or more of the cells preferentially used one X chromosome. RESULTS: Young breast cancer patients (27-45 years) had a higher frequency of skewed X inactivation than young controls (13 and 1%, respectively) (p=0.009), whereas no difference was found for middle aged and older patients compared to controls of a similar age. CONCLUSIONS: A germline mutation in an X linked tumour suppressor gene may give a proliferative advantage to cells with this mutation on the active X chromosome, thus causing skewed X inactivation and an increased risk for developing cancer. Another possible explanation could be that females with a constitutionally skewed X inactivation pattern are more susceptible to develop breast cancer because of an X linked low penetrance susceptibility allele that is affected by the inactivation pattern.

Adult↗
PubMed2001

Gene expression patterns of breast carcinomas distinguish tumor subclasses with clinical implications.

The purpose of this study was to classify breast carcinomas based on variations in gene expression patterns derived from cDNA microarrays and to correlate tumor characteristics to clinical outcome. A total of 85 cDNA microarray experiments representing 78 cancers, three fibroadenomas, and four normal breast tissues were analyzed by hierarchical clustering. As reported previously, the cancers could be classified into a basal epithelial-like group, an ERBB2-overexpressing group and a normal breast-like group based on variations in gene expression. A novel finding was that the previously characterized luminal epithelial/estrogen receptor-positive group could be divided into at least two subgroups, each with a distinctive expression profile. These subtypes proved to be reasonably robust by clustering using two different gene sets: first, a set of 456 cDNA clones previously selected to reflect intrinsic properties of the tumors and, second, a gene set that highly correlated with patient outcome. Survival analyses on a subcohort of patients with locally advanced breast cancer uniformly treated in a prospective study showed significantly different outcomes for the patients belonging to the various groups, including a poor prognosis for the basal-like subtype and a significant difference in outcome for the two estrogen receptor-positive groups.

Algorithms↗
PubMed2001

[Microarray technology--potential in cancer research].

BACKGROUND: Researchers have worked for decades to solve the enigma of cancer. We know that essential checkpoints in the life cycle of cells have to be disrupted in order to create a tumour cell, and some of the genes and proteins involved have been identified. Most of the previous work on identifying these genes have been based on "educated guesswork", as the methods and technologies used have been limited to the examination of genes one by one, or a few at a time. MATERIAL AND METHODS: Microarray technology allows tens of thousands of genes to be examined at the same time, without any previous information on the genes. Both expression levels and copy numbers of the genes can be evaluated. Our studies of breast cancer and bone tumours are presented, as well as examples from the literature. RESULTS AND DISCUSSION: Microarray analyses have been used to produce molecular portraits of breast cancer, malignant melanomas and other cancers. These portraits may help in sub-classification of tumours, in prognosis, and in the general understanding of cancer. For example, studies of gene expression patterns of breast carcinomas, similar with respect to classic prognostic markers (such as ER status, grading and morphology), have identified subgroups of patients that show differences in survival.

Bone Neoplasms↗
PubMed2001

Quantitative analysis of chromosomal CGH in human breast tumors associates copy number abnormalities with p53 status and patient survival.

We present a general method for rigorously identifying correlations between variations in large-scale molecular profiles and outcomes and apply it to chromosomal comparative genomic hybridization data from a set of 52 breast tumors. We identify two loci where copy number abnormalities are correlated with poor survival outcome (gain at 8q24 and loss at 9q13). We also identify a relationship between abnormalities at two loci and the mutational status of p53. Gain at 8q24 and loss at 5q15-5q21 are linked with mutant p53. The 9q and 5q losses suggest the possibility of gene products involved in breast cancer progression. The analytical techniques are general and also are applicable to the analysis of array-based expression data.

Breast Neoplasms↗
PubMed2001

[Measurement of gene activity by DNA microarrays].

BACKGROUND: DNA microarray is a tool that can be used to measure in one single analysis simultaneous changes in the activity of tens of thousands of genes. MATERIAL AND METHODS: The method is based upon advanced robotic techniques; High-density arrays of DNA probes are placed on a solid surface; this is followed by hybridisation with a fluorescence labelled sample and analysis of fluorescence signals. RESULTS: The analysis create huge data sets which have to be transformed into formats that can be interpreted and correlated with existing knowledge. This means that bioinformatics is an integrated part of microarray analysis. INTERPRETATION: DNA microarray may be used to examine complex physiological and pathological conditions and will most likely be very important in functional studies addressing the structural knowledge of genes obtained through the Human Genome Project. Dedicated microchips are already being tested in the diagnosis of malignant and premalignant diseases and being used to characterize HIV viruses with respect to choice of therapy.

Computational Biology↗
PubMed2001

Influence of TP53 gene alterations and c-erbB-2 expression on the response to treatment with doxorubicin in locally advanced breast cancer.

TP53 status [mutations, immunostaining, and loss of heterozygosity (LOH)], expression of c-erbB-2, bcl-2, and histological grading were correlated to the response to doxorubicin monotherapy (14 mg/m2) administered weekly to 90 patients with locally advanced breast cancer. Mutations in the TP53 gene, in particular those affecting or disrupting the loop domains L2 or L3 of the p53 protein, were associated with lack of response to chemotherapy (P = 0.063 for all mutations and P = 0.008 for mutations affecting L2/L3, respectively). Similarly, expression of c-erbB-2 (P = 0.041), a high histological grade (P = 0.023), and lack of expression of bcl-2 (P = 0.018) all predicted chemoresistance. No statistically significant association between either p53 immunostaining or TP53 LOH and response to therapy was recorded, despite the finding that both were associated with TP53 mutation status (p53 immunostaining, P < 0.001; LOH, P = 0.021). Lack of immunostaining for p53 despite mutation of the TP53 gene was particularly seen in tumors harboring nonsense mutations or deletions/splices (7 of 10 negative for staining compared with 4 of 16 with missense mutations). TP53 mutations (total/affecting L2/L3 domains) were associated with expression of c-erbB-2 (P < 0.001 for both), high histological grade (P = 0.001 and P = 0.025), and bcl-2 negativity (P = 0.003 and P = 0.002). TP53 mutations, histological grade, and expression of bcl-2 (but not LOH or c-erbB-2 expression) all predicted for relapse-free as well as breast cancer-specific survival in univariate analysis (Ps between <0.0001 and 0.0155), but only tumor grade was found to be predictive in multivariate analysis (P = 0.01 and P = 0.0007, respectively). Our data are consistent with the hypothesis that certain TP53 mutations predict for resistance to doxorubicin in breast cancer patients. However, the observation that the majority of patients with TP53 mutations affecting or disrupting the L2/L3 domains with LOH in addition (n = 12) obtained a partial response (n = 4) or stabilization of disease (n = 5) during chemotherapy suggests redundant mechanisms to compensate for loss of p53 function. Our findings are consistent with the hypothesis that other defects may act in concert with loss of p53 function, causing resistance to doxorubicin in breast cancers.

Adult↗
PubMed2001

Low frequency of E-cadherin alterations in familial breast cancer.

In order to explore the possible role of E-cadherin in familial cancer, 19 familial breast cancer patients, whose tumours demonstrated loss of heterozygosity (LOH) at the E-cadherin locus, were screened for germline mutations. No pathogenic germline alterations were detected in these individuals. However, a somatic mutation was found (49-2A-->C) in one of the tumours. This tumour showed a pattern of both ductal and lobular histology. Another 10 families with cases of breast, gastric and colon cancer were also screened for germline mutations, and no mutations were found. A missense mutation in exon 12 of E-cadherin (1774G-->A; Ala592Thr) was previously found in one family with diffuse gastric cancer, and colon and breast cancer. An allelic association study was performed to determine whether the Ala592Thr alteration predisposes to breast cancer. In total, we studied 484 familial breast cancer patients, 614 sporadic breast cancer patients and 497 control individuals. The frequencies of this alteration were similar in these groups. However, a correlation between the Ala592Thr alteration and ductal comedo-type tumour was seen. These results, together with previously reported studies, indicate that germline mutations and, more commonly, somatic mutations in E-cadherin may have an influence on the behaviour of the tumours, rather than predispose to breast cancer.

Adult↗
PubMed2001

Cancer in patients with ataxia-telangiectasia and in their relatives in the nordic countries.

BACKGROUND: Epidemiologic studies of the families of patients with ataxia-telangiectasia (A-T), a recessive genetic neurologic disorder caused by mutation of the ATM gene, suggest that heterozygous carriers of an ATM mutation are at increased risk of cancer. A population-based study of cancer incidence in A-T families with unbiased selection and tracing of relatives would confirm this hypothesis. METHODS: We conducted a study in the Nordic countries of 1218 blood relatives of 56 A-T patients from 50 families. The relatives were identified from population registries, and the occurrence of cancer was determined from cancer registry files in each country and compared with national incidence rates. All statistical tests were two-sided. RESULTS: Among the 56 patients with A-T, we observed six cases of cancer (four leukemias and two non-Hodgkin's lymphomas) compared with 0.16 expected, yielding a standardized incidence ratio (SIR) of 37 (95% confidence interval [CI] = 13 to 80). Among the 1218 relatives, 150 cancers were recorded, with 126 expected (SIR = 1.19; 95% CI = 1.01 to 1.40). Invasive breast cancer occurred in 21 female relatives of A-T patients (SIR = 1.54; 95% CI = 0.95 to 2.36), including five of the 50 mothers (all of whom are obligate ATM mutation carriers) (SIR = 7.1; 95% CI = 2.3 to 17). Relatives who were less likely to be carriers of a mutant ATM allele had no increase or only a modest, statistically nonsignificant increase in the risk of breast cancer. There was no evidence of increased risk for cancer at any other site. CONCLUSIONS: We confirmed the previously recognized high risk of lymphoma and leukemia in A-T patients. Our data are also consistent with an increased risk of breast cancer among blood relatives of A-T patients. The epidemiologic findings suggest, however, that, even if ATM mutations are responsible for some breast cancer cases, ATM is a relatively weak genetic risk factor for the disease.

Adult↗
PubMed2001

Fibroblast growth factor receptor 3 (FGFR3) - analyses of the S249C mutation and protein expression in primary cervical carcinomas.

Fibroblast growth factor receptor 3 (FGFR3) seems to play an inhibitory role in bone development, as activating mutations in the gene underlie disorders such as achondroplasia and thanatophoric dysplasia. Findings from multiple myeloma (MM) indicate that FGFR3 also can act as an oncogene, and mutation of codon 249 in the fibroblast growth factor receptor 3 (FGFR3) gene was recently detected in 3/12 primary cervical carcinomas. We have analysed 91 cervical carcinomas for this specific S249C mutation using amplification created restriction site methodology (ACRS), and detected no mutations. Immunohistochemistry was performed on 73 of the tumours. Reduced protein staining was seen in 43 (58.8%) samples. Six of the tumours (8.2%) revealed increased protein staining compared with normal cervical tissue. These patients had a better prognosis than those with reduced or normal levels, although not statistically significant. This report weakens the hypothesis of FGFR3 as an oncogene of importance in cervical carcinomas.

Adult↗
PubMed2001

Microarrays in primary breast cancer--lessons from chemotherapy studies.

Current development in molecular techniques has extended the opportunities to explore genetic alterations in malignant tissue. There is a need to improve prognostication and, in particular, to understand the mechanisms of treatment resistance in different tumours. Gene analyses by microarrays allow concomitant analyses of several genes in concert, providing new opportunities for tumour classification and understanding of key biological disturbances. This paper outlines our continuing studies exploring prognostic and, we hope, predictive factors in breast cancer therapy.

Breast Neoplasms↗
PubMed2001

High-throughput methods for detection of genetic variation.

Understanding human genetic variation is currently believed to reveal the cause of individual susceptibility to disease and the large variation observed in response to treatment. In this review, we will focus on different approaches to identify and visualize genetic alterations. The various approaches for allele discrimination are formally systematically divided into (i) enzymatic approaches, in which the properties of different enzymes to discriminate between nucleotides are used (restriction enzymes type II, Cleavase and Resolvase, DNA polymerase, and ligase); (ii) electrophoretic methods, in which the allele discrimination is based on the difference in mobility in polymeric gels or capillaries (single- and double-stranded conformation assays, heteroduplex analysis, and DNA sequencing); (iii) solid-phase determination of allelic variants, including high-density oligonucleotide arrays for hybridization analysis, minisequencing primer extension analysis, and fiberoptic DNA sensor array; (iv) chromatographic methods such as denaturing high-performance liquid chromatography (DHPLC); (v) other physical methods of discrimination of allelic variants such as mass spectrometry (mass and charge) or fluorescence exchange-based techniques; and (vi) in silico methods such as high-throughput analysis of expressed sequence tag data. The most frequently used techniques and instrumental settings applied in different combinations are described, and other methods that are less broadly used but have interesting potentials are discussed.

Alleles↗
PubMed2001

Automated constant denaturant capillary electrophoresis applied for detection of KRAS exon 1 mutations.

In this study, we have applied automated constant denaturant capillary electrophoresis (ACDCE) for the detection of KRAS exon 1 mutations. Samples from 191 sporadic colon carcinomas previously analyzed for KRAS mutations with allele-specific PCR (ASPCR), temporal temperature gradient electrophoresis (TTGE), and constant denaturant capillary electrophoresis (CDCE) were analyzed. In ACDCE, an unmodified ABI Prism 310 genetic analyzer with constant denaturant conditions separated fluorescein-labeled PCR products. Temperature in combination with a chemical denaturant was used for separation. The optimal separation conditions for PCR-amplified KRAS exon 1 fragments were determined by adjusting the temperature before electrophoresis. In the ACDCE analysis, the sequence of a mutant was determined by comparing the electropherogram of the fragment to that of known mutations followed by mixing the sample with control mutations before reanalysis. In a titration experiment mixing mutant and wild-type alleles, the sensitivity for mutation detection was shown to be 0.6% in this automated CDCE technique. The automation of CDCE allowed rapid analysis of a large number of test samples over as short period of time and with a commercially available apparatus.

Autoanalysis↗
PubMed2000

Molecular portraits of human breast tumours.

Human breast tumours are diverse in their natural history and in their responsiveness to treatments. Variation in transcriptional programs accounts for much of the biological diversity of human cells and tumours. In each cell, signal transduction and regulatory systems transduce information from the cell's identity to its environmental status, thereby controlling the level of expression of every gene in the genome. Here we have characterized variation in gene expression patterns in a set of 65 surgical specimens of human breast tumours from 42 different individuals, using complementary DNA microarrays representing 8,102 human genes. These patterns provided a distinctive molecular portrait of each tumour. Twenty of the tumours were sampled twice, before and after a 16-week course of doxorubicin chemotherapy, and two tumours were paired with a lymph node metastasis from the same patient. Gene expression patterns in two tumour samples from the same individual were almost always more similar to each other than either was to any other sample. Sets of co-expressed genes were identified for which variation in messenger RNA levels could be related to specific features of physiological variation. The tumours could be classified into subtypes distinguished by pervasive differences in their gene expression patterns.

Breast Neoplasms↗
PubMed2000

Oncogenic aberrations in the p53 pathway are associated with a high S phase fraction and poor patient survival in B-cell Non-Hodgkin's lymphoma.

The implications of aberrations in the p53 pathway for induction of apoptosis and regulation of S phase entry, and for patient survival, were investigated in 83 B-cell Non-Hodgkin's lymphomas. Eight cases had missense mutations in exons 5, 7, 8 and 9 as revealed by constant denaturant gel electrophoresis and sequencing. Fifteen cases had lost 1 TP53 allele as revealed by fluorescent in situ hybridization and comparative genomic hybridization. Ten cases expressed high levels of p53 as assessed by immunoblotting and immunohistochemistry. S phase fractions were higher, apoptotic fractions were the same and survival times were shorter in all aberration groups compared with the cases with no TP53/p53 aberrations. Since many tumors had more than one TP53/p53 aberration, the tumors were divided into groups with the following characteristics: no TP53/p53 aberrations; loss of one TP53 allele only (9 cases), TP53 point mutation (8 cases), high-level p53 expression and no TP53 mutation (3 cases). Tumors from the 3 latter groups had higher median S phase fractions (5%, 7.6%, and 5%, respectively, p<0.02) than the cases without any aberrations (1.1%), and survival time for these patients was much shorter (relative risks of 5.9, 8.9, and 6.6, respectively, p<0.003). Apoptotic fractions were similar in all these groups (p=0.09). Multivariate analysis showed that the presence of TP53/p53 aberrations is a strong and independent prognostic parameter in B-cell Non-Hodgkin's lymphoma.

Adult↗
PubMed2000

Genetic variants of CYP19 (aromatase) and breast cancer risk.

The effect of a SNP in exon 10 of CYP19 on tumor mRNA levels and splice variants were studied and correlated with clinical parameters and risk of breast cancer. In the vast majority of breast cancers, the estrogen levels modulate the tumor growth and depend on the activity of CYP19. Patients (n=481) and controls (n=236) were genotyped by T-tracks in a single sequencing reaction (SSR). The frequency of TT genotypes was significantly higher in patients versus controls (P=0.007) particularly among those with stage III and IV disease (P=0.004) and with tumors larger than 5 cm (P=0.001). A significant association between presence of the T allele and the level of aromatase mRNA in the tumors was observed (P=0.018), as well as with a switch from adipose promoter to ovary promoter (P=0. 004). Previously, we reported a rare polymorphic allele of CYP19 (repeat (TTTA)12) to be significantly more frequent in breast cancer patients than in controls. Here we describe another polymorphism, a C - T substitution in exon 10 of the CYP19 gene which is in strong linkage disequilibrium with the (TTTA)n polymorphism but with higher frequency of the variant allele. Our data suggest that the T-allele of the CYP19 gene is associated with a 'high activity' phenotype. Oncogene (2000) 19, 1329 - 1333.

3' Untranslated Regions↗
PubMed2000

Re-expression of E-cadherin, alpha-catenin and beta-catenin, but not of gamma-catenin, in metastatic tissue from breast cancer patients [seecomments].

Tumour cell invasion and metastasis are the processes which kill most cancer patients. Tumour cells with the greatest invasive and metastatic capacity may be those with the highest number of genetic aberrations. The present study has analysed the expression of several tumour-related proteins in both primary tumours and metastatic lesions from 34 breast cancer patients. Protein expression of p53, bcl-2, p21, cyclin D1, E-cadherin, alpha-catenin, beta-catenin, and gamma-catenin was investigated by immunohistochemistry (IHC) using monoclonal antibodies. Metastatic tissue showed a different expression profile from the primary tumour in most patients. The most significant finding was the re-expression of E-cadherin, alpha-catenin, and beta-catenin, and increased down-regulation of gamma-catenin, in metastatic lesions. These results demonstrate that tumour cells, when released from the primary site and after regrowth elsewhere, are capable of re-expression of adhesion molecules. gamma-catenin may play a different role in metastatic lesions than in primary tumours, since it is selectively down-regulated in tumour tissue at the metastatic site.

Breast Neoplasms↗