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Biomedical subjects

Håkan Olsson

Publications and source records attributed to Håkan Olsson.

At least 19 recordsLinked to original sources
PubMed2006

Occupational factors and risk of adult bone sarcomas: a multicentric case-control study in Europe.

We investigated the association between occupational factors and risk of bone sarcoma, a rare tumor with a largely unknown aetiology. A multicentric case-control study was conducted in 7 European countries in 1995-97. Ninety-six cases aged 35-69 years with a centrally reviewed diagnosis of bone sarcoma (68 chondrosarcomas and 28 osteosarcomas) were compared to 2,632 population (68%) or colon cancer (32%) controls. Subjects were interviewed to obtain information on occupational, medical and reproductive history, smoking and alcohol consumption and selected exposures including use of pesticides. Response proportions were 90% among cases and 66% among controls. Odds ratios (OR) and 95% confidence intervals (CI) were estimated for selected categories of job titles and branches of industry and for use of pesticides. We found an increased OR for bone sarcoma among blacksmiths, toolmakers, machine-tool operators (OR = 2.14, 95% CI 1.08-4.26), woodworkers (OR = 2.68, 95% CI 1.36-5.29) and construction workers (OR = 1.62, 95% CI 0.92-2.87). Ever users of pesticide had an OR of 2.33 (95% CI 1.31-4.13), with similar risks for exposure to insecticides and exposure to herbicides. Neither duration of employment in any of the analyzed occupational categories nor duration of use of pesticides showed an increasing trend in the risk of bone sarcoma. ORs of bone sarcoma were 1.03 (95% CI 0.23-4.57), 3.13 (95% CI 1.26-7.76) and 1.44 (95% CI 0.43-4.85) for the first, second and third tertile of days of use of pesticides. Our study suggests that novel and previously reported (woodworking) occupational factors play a role in the aetiology of bone sarcomas.

Adult↗
PubMed2005

Mapping of a novel ocular and cutaneous malignant melanoma susceptibility locus to chromosome 9q21.32.

An estimated 10% of all cutaneous malignant melanoma (CMM) cases are inherited, but the genetics of familial CMM are largely unknown. Ocular malignant melanoma (OMM), which is rare, may be associated with familial CMM. We performed a genome-wide scan of two Danish pedigrees with multiple cases of OMM (N = 10) and CMM (N = 3) and other malignancies (with no germline mutations in CDKN2A, CDK4, BRCA1, and BRCA2) to identify melanoma susceptibility genes. Results of parametric linkage analysis are presented as logarithm of the odds (LOD) scores, and all P values are two-sided. Peak two-point parametric LOD score of 2.2 (P = .0007) at D9S167 on chromosome 9q21 was observed. Targeted analysis of a third Danish family with OMM and CMM patients confirmed 9q21 linkage, providing a combined four-point parametric LOD score of 3.02 (nominal P = .00003 and genome-wide P = .086). Two families shared a common haplotype comprising three adjacent and highly polymorphic markers, limiting the region to less than 5 cM and 3 Mbp at 9q21.32. Expression of RASEF, a known gene in this region, was examined in tumor tissue from 10 sporadic CMM lesions and was found to be decreased in 70% of these tumors compared with RASEF expression in a human reference RNA pool from 10 different cell types and in 10 breast tumors.

Chromosome Mapping↗
PubMed2005

Distinct genomic profiles in hereditary breast tumors identified by array-based comparative genomic hybridization.

Mutations in BRCA1 and BRCA2 account for a significant proportion of hereditary breast cancers. Earlier studies have shown that inherited and sporadic tumors progress along different somatic genetic pathways and that global gene expression profiles distinguish between these groups. To determine whether genomic profiles similarly discriminate among BRCA1, BRCA2, and sporadic tumors, we established DNA copy number profiles using comparative genomic hybridization to BAC-clone microarrays providing <1 Mb resolution. Tumor DNA was obtained from BRCA1 (n = 14) and BRCA2 (n = 12) mutation carriers, as well as sporadic cases (n = 26). Overall, BRCA1 tumors had a higher frequency of copy number alterations than sporadic breast cancers (P = 0.00078). In particular, frequent losses on 4p, 4q, and 5q in BRCA1 tumors and frequent gains on 7p and 17q24 in BRCA2 tumors distinguish these from sporadic tumors. Distinct amplicons at 3q27.1-q27.3 were identified in BRCA1 tumors and at 17q23.3-q24.2 in BRCA2 tumors. A homozygous deletion on 5q12.1 was found in a BRCA1 tumor. Using a set of 169 BAC clones that detect significantly (P < 0.001) different frequencies of copy number changes in inherited and sporadic tumors, these could be discriminated into separate groups using hierarchical clustering. By comparing DNA copy number and RNA expression for genes in these regions, several candidate genes affected by up- or down-regulation were identified. Moreover, using support vector machines, we correctly classified BRCA1 and BRCA2 tumors (P < 0.0000004 and 0.00005, respectively). Further validation may prove this tumor classifier to be useful for selecting familial breast cancer cases for further mutation screening, particularly, as these data can be obtained using archival tissue.

Breast Neoplasms↗
PubMed2005

Impact of teenage oral contraceptive use in a population-based series of early-onset breast cancer cases who have undergone BRCA mutation testing.

Oral contraceptive (OC) use in young women has been associated with an increased risk of breast cancer. This matched case-control study aims to elucidate the combined effects of OC use and genetic factors in a population-based series of BRCA1/2 mutation-tested early-onset breast cancers. A first invasive breast cancer was diagnosed in 259 women aged 40 years between 1990 and 1995 in the South Swedish Health Care Region. A total of 245 women were included in this study. Information on family history of cancer, reproductive factors, smoking and OC use was obtained from questionnaires or patient charts. Three age-matched controls per case were chosen from a prospective South Swedish cohort. Ever OC use and current OC use were not associated with breast cancer. Cases were more likely to have used OCs before age 20 years (adjusted odds ratio (OR) 2.10 (95% CI 1.32-3.33)) and before their first child (adjusted OR 1.63 (95% CI 1.02-2.62)). When stratified by age, the effect of early OC use was limited to women diagnosed prior to age 36 years (OR 1.53 (1.17-1.99) per year of OC use prior to age 20 years). The risks were similar for low-dose and high-dose OCs. The probability of being a BRCA1/2 mutation carrier was three times higher among cases who started OC use prior to age 20 years compared with cases who started at age 20 years or older or who had never used OCs. However, the duration of OC use was similar among cases with and without BRCA1/2 mutations. No association was seen with a first-degree family history of breast cancer. Each year of OC use prior to age 20 years conferred a significantly increased risk for early-onset breast cancer, while there was no risk associated with use after age 20 years.

Adolescent↗
PubMed2005

High follicular phase luteinizing hormone levels in young healthy BRCA1 mutation carriers: implications for breast and ovarian cancer risk.

BRCA1 mutation carriers have up to 80% life-time risk of developing breast cancer and 20-40% risk of developing ovarian cancer. High LH levels have been linked to increased risks of both breast and ovarian cancers in some studies and it is unknown whether gonadotropin levels are associated with BRCA1 mutation status. The aim of the study was to explore whether gonadotropin levels were associated with BRCA1 mutation status among healthy 40-year-old-women from hereditary breast cancer families. All women completed a questionnaire including information on reproductive factors and OC use. We measured height, weight, breast volumes, and plasma levels of LH, FSH, and estradiol (E2) once during menstrual cycle days 5-10 and once again during cycle days 18-23 in 43 non-carriers from BRCA1 families, 20 BRCA1 mutation carriers, and 101 women from non-BRCA1/2 families. The strongest predictors of high LH levels among BRCA1 mutation carriers and non-carriers during cycle days 5-10 were being a BRCA1 mutation carrier (p=0.002), lack of current OC use (p=0.003), and being nulliparous (p=0.01), adjusted for age and menstrual cycle day when the samples were obtained. This association was seen both in non-OC users and current OC users but was only significant in the former group (p=0.005). Because of multiple analyses it is possible that our finding is a result of a Type 1 statistical error. After a permutation test the new adjusted p value in non-OC users was 0.05. FSH and E2 were similar in non-carriers, BRCA1 mutation carriers and women from non-BRCA1/2 families. We found significantly elevated LH levels in the follicular phase among young healthy BRCA1 mutation carriers compared with non-carriers from BRCA1 families. This is a small study and confirmatory studies are warranted to establish whether elevated LH levels are part of the BRCA1 phenotype and may be manipulated in order to reduce cancer risks in BRCA1 mutation carriers.

Breast Neoplasms↗
PubMed2005

Fat from different foods show diverging relations with breast cancer risk in postmenopausal women.

The aim was to explore previous findings within the Malmö Diet and Cancer cohort (Sweden) that omega6-fatty acid intakes are positively associated with breast cancer risk among women 50 yr of age and older and specifically examine relations between breast cancer risk and fat from different food groups. Incident breast cancer cases (n = 237) were matched to controls (n = 673) on age and screening date. A modified diet history method, a structured questionnaire, and anthropometric measurements provided data. Fat-food variables from 24 food groups were computed. Conditional logistic regression examined breast cancer risk associated with energy-adjusted exposure categories of fat-food variables. Fat from fermented milk products was negatively associated with breast cancer risk (trend, P = 0.003). The highest quartiles of vegetable oil-based dietary fats (odds ratio, OR = 1.74; confidence interval, CI = 1.12-2.72) and dried soup powders (OR = 1.59; CI = 1.04-2.43) showed positive associations. Dietary fiber did not influence associations.

Anthropometry↗
PubMed2004

High fat and alcohol intakes are risk factors of postmenopausal breast cancer: a prospective study from the Malmö diet and cancer cohort.

Associations between intakes of relative fat, total alcohol and alcoholic beverages and risk of breast cancer were examined in a subsample of 11726 postmenopausal women from the MDC cohort. The MDC conducted baseline examinations from 1991 to 1996; the end of follow-up was 31 December 2001. Data were obtained by an interview-based diet history method, a structured questionnaire, anthropometric measurements and national and regional cancer registries. During 89602 person-years of follow-up, 342 incident cases were documented. Cox regression analysis examined breast cancer risks adjusted for potential confounders. Two energy-adjustment approaches (i.e., adjusting for total energy vs. adjusting for nonalcohol energy) were used. High total alcohol intake was associated with a nonsignificantly elevated risk. High wine intake was associated with a significantly elevated breast cancer risk (relative risk = 2.12, 95% CI 1.24-3.60). There were significant trends of increased breast cancer risk across quintiles of relative fat intake. Mutual adjustment did not affect risk estimates for total alcohol or relative fat intakes. The specific energy-adjustment approach did not influence associations differentially.

Alcohol Drinking↗
PubMed2004

Alcohol drinking may increase risk of breast cancer in men: a European population-based case-control study.

OBJECTIVE: It has been estimated that alcohol drinking increases the risk of breast cancer in women by approximately 7% for each increment of 10 g alcohol per day. However, the few studies conducted on breast cancer among men have failed to detect an association with quantitative measures of alcohol drinking, even if the alcohol intake is generally higher in men than in women. On the other hand, increased risks of male breast cancer were inconsistently reported in alcoholics or patients with liver cirrhosis. We have investigated the role of alcohol drinking in male breast cancer using data collected in a population-based case-control study on seven rare cancers, conducted in Denmark, France, Germany, Italy, and Sweden. METHODS: The cases were 74 histologically verified male breast cancer patients aged 35-70 years. The controls (n = 1432) were selected from population registers, and frequency-matched to the cases by age group and geographic area. To check for consistency, a separate analysis was conducted using as controls the patients with a rare cancer other than male breast recruited simultaneously in the European study (n = 519 men). RESULTS: Based on population controls, the risk of developing breast cancer in men increased by 16% (95% CI: 7-26%) per 10 g alcohol /day (p < 0.001). An odds ratio of 5.89 (95% CI: 2.21-15.69) was observed for alcohol intake greater than 90 g per day, as compared with light consumers (< 15 g per day). Similar associations were observed when other rare cancers patients were used as controls. CONCLUSION: We found that the relative risk of breast cancer in men is comparable to that in women for alcohol intakes below 60 g per day. It continues to increase at high consumption levels not usually studied in women.

Adult↗
PubMed2004

The need for oncogenetic counselling. Ten years' experience of a regional oncogenetic clinic.

A monogenic inheritance, mainly seen as a dominant pattern, accounts for 5-10% of all cancer cases. The increased knowledge and identification of high-risk genes have led to a need for specialized cancer family clinic was the expression used by Eeles and Murday. The Oncogenetic Clinic at the University Hospital in Lund was started in 1993 and the authors' 10-year experience is summarized in this paper. The clinic offers service to the South Swedish Health Care Region comprising a total of 1.6 million inhabitants. During these first 10 years a total of 1059 individuals from 789 families have been individually counselled. The most common reason for referral was a family history of breast cancer, followed by a family history of colorectal cancer. According to the commonly used criteria, 437 (55%) of the families were considered as autosomal dominantly inherited; 147 families (19%) did not fulfil these criteria but had a strong clustering of breast/ovarian or colorectal/endometrial cancer. The remaining 205 families (26%) were not recognized as any previously described hereditary cancer syndrome with early onset. However, most of these families had a family history of cancer. Mutation analysis was performed in 386/789 (49%) of the families. In families with breast and ovarian cancer a genetic aberration was identified in 45/76 (59%) and in breast-only families in 27/129 (21%). In MSI-positive colon cancer families 16/34 (47%) of the families had a germline mutation. Thus, the majority of the families referred to the clinic were in obvious need of genetic counselling concerning cancer and heredity and in a substantial number of the families a germline mutation could be identified.

Ambulatory Care Facilities↗
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

Differential prognostic impact of the cyclins E and B in premenopausal and postmenopausal women with lymph node-negative breast cancer.

Searching for new prognostic factors, we investigated the influence of cyclin expression on breast cancer prognosis. A total of 273 archival tumor specimens from patients with pT1/pT2 N0 breast cancers treated by surgery and local irradiation were immunostained for cyclins E, A and B. Outcome was evaluated as metastasis-free (MFS) and disease-specific survival (DSS) over a median observation period of 99 months. In postmenopausal women, DSS was significantly predicted by cyclin E, and in premenopausal patients by cyclin B. No statistical significance was found for cyclin A. When the prognostic impact of cyclins was compared to that of standard prognostic indicators in a multivariate analysis, both cyclin E and cyclin B were selected as independent predictors of survival in postmenopausal and premenopausal patients, respectively. After inclusion of Ki-67 in the model, cyclin E lost its significance, whereas cyclin B remained the only independent prognostic factor with a hazard ratio of 4.5 (p = 0.026) for tumor-related death. Assessment of cyclin expression may, therefore, refine current prognostic models if considered in relation to menopausal status. The prognostic relevance of cyclins is likely attributable to an influence on proliferation, cell survival and genetic instability. Awareness of the molecular mechanisms leading to deregulated cyclin expression may guide decisions for risk-adapted therapy regimens.

Adult↗
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

In vivo tumor growth inhibition and biodistribution studies of locked nucleic acid (LNA) antisense oligonucleotides.

Locked nucleic acids (LNA) are novel high-affinity DNA analogs that can be used as genotype-specific drugs. The LNA oligonucleotides (LNA PO ODNs) are very stable in vitro and in vivo without the need for a phosphorothiolated backbone. In this study we tested the biological fate and the efficacy in tumor growth inhibition of antisense oligonucleotides directed against the gene of the large subunit of RNA polymerase II (POLR2A) that are completely synthesized as LNA containing diester backbones. These full LNA oligonucleotides strongly reduce POLR2A protein levels. Full LNA PO ODNs appeared to be very stable compounds when injected into the circulation of mice. Full LNA PO ODNs were continuously administered for 14 days to tumor-bearing nude mice. Tumor growth was inhibited sequence specifically at dosages from 1 mg/kg/day. LNA PO ODNs appeared to be non-toxic at dosages <5 mg/kg/day. Biodistribution studies showed the kidneys to have the highest uptake of LNA PO ODNs and urinary secretion as the major route of clearance. This report shows that LNA PO ODNs are potent genotype-specific drugs that can inhibit tumor growth in vivo.

Animals↗
PubMed2003

A prospective study of adiposity and postmenopausal breast cancer risk: the Malmö Diet and Cancer Study.

High BMI is a well-known risk factor for postmenopausal breast cancer. There have been some reports of excess risk in association with weight gain and WHR, but little is known about the influence of body fatness per se. Using data from the Malmö Diet and Cancer Study, a prospective cohort study, 12,159 postmenopausal women (59.9 +/- 7.7 years) were categorized by quintiles of baseline anthropometric and impedance measures and reported weight change since age 20. RRs from multivariate Cox regression models were calculated. All analyses were adjusted for age, height, smoking, alcohol consumption, occupation, marital status, parity, age at first pregnancy, age at menarche and current hormone use. During the 5.7 years of follow-up, there were 246 incident breast cancer cases. Weight, height, BMI and %BF were positively associated with risk of breast cancer (p(trend) 21 kg (top quintile) had an RR of 1.75 (95% CI 1.11-2.77) compared to women with low weight gain. Breast cancer risk in postmenopausal women is predicted by increased body fat and weight gain. %BF is a more discriminating risk factor for breast cancer incidence than the commonly used BMI.

Adipose Tissue↗
PubMed2003

Expression of cyclins E, A, and B, and prognosis in lymph node-negative breast cancer.

Unexpected outcomes in breast cancer demand a refinement of prognostic criteria. This study therefore investigated the prognostic relevance of cyclin expression in a cohort of 332 T1-T2 N0 infiltrating ductal carcinomas with long-term follow-up (median 99 months). By univariate analysis, tumour size, histopathological grade, hormone receptor content, cyclin E, cyclin B, and the Ki-S5 (Ki-67) index significantly predicted disease-specific and metastasis-free survival. Cyclin A did not achieve statistical significance. In a multivariate analysis, both cyclin E [relative risk (RR) 2.01, p = 0.021] and cyclin B (RR 1.85, p = 0.033) were selected as independent prognosticators of metastasis-free survival when the Ki-67 index was omitted, but only cyclin E expression was associated with disease-specific survival (RR 2.56, p = 0.006). When Ki-67 was included as a covariate, cyclin E lost its significance with respect to disease-specific survival but remained significant for metastasis-free survival. In an analogous analysis including Ki-67, the number of concurrently overexpressed cyclins did not attain statistical significance regarding disease-specific survival but was selected as the leading predictor of metastatic disease. It is concluded that combined overexpression of cyclins may imply genetic instability enhancing metastatic potential, but that survival ultimately depends on the proliferative activity of tumour cells.

Adult↗
PubMed2003

Comparative cytogenetic and DNA flow cytometric analysis of 242 primary breast carcinomas.

The cytogenetic and DNA flow cytometric findings in 242 breast carcinomas were compared. The combined use of both techniques improved the detection of abnormal cell populations from 65% by cytogenetic analysis alone and 59% by DNA flow cytometric analysis alone to 84%. Informative and comparable cytogenetic and flow cytometric data were obtained for 155 tumors. Among these 155 tumors, there was good concordance (64%) between the estimates of genomic changes by the two methods. Most discrepancies were among the DNA-diploid cases, where cytogenetic analysis detected small genomic changes. There were, however, also some exceptions in which large genomic changes detected by one method were missed by the other. Of the specific breast cancer-associated cytogenetic aberrations subjected to separate correlation analysis, polysomy for chromosome 20 was significantly associated with a high S-phase fraction, whereas loss of the long arm of chromosome 16 and/or the presence of a der(1;16) were significantly associated with a low S-phase fraction. Our data show that cytogenetic and DNA flow cytometric analyses of breast carcinomas give largely comparable results, and that combining data from both methods significantly improves the information obtained by either technique used alone on the genetic abnormalities in these tumors.

Breast Neoplasms↗