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Cadmium and lead have been classified as carcinogens by the International Agency for Research on Cancer. However, their associations with breast cancer risk are unknown despite their persistence in ...

Early pregnancy and multiparity are known to reduce the risk of women to develop breast cancer at menopause. Based on the knowledge that the differentiation of the breast induced by the hormones of pregnancy plays a major role in this protection, this work was performed with the purpose of identifying what differentiation-associated molecular changes persist in the breast until menopause. Core needle biopsies (CNB) obtained from the breast of 42 nulliparous (NP) and 71 parous (P) postmenopausal women were analyzed in morphology, immunocytochemistry and gene expression. Whereas in the NP breast, nuclei of epithelial cells were large and euchromatic, in the P breast they were small and hyperchromatic, showing strong methylation of histone 3 at lysine 9 and 27. Transcriptomic analysis performed using Affymetrix HG_U133 oligonucleotide arrays revealed that in CNB of the P breast, there were 267 upregulated probesets that comprised genes controlling chromatin organization, transcription regulation, splicing machinery, mRNA processing and noncoding elements including XIST. We concluded that the differentiation process induced by pregnancy is centered in chromatin remodeling and in the mRNA processing reactome, both of which emerge as important regulatory pathways. These are indicative of a safeguard step that maintains the fidelity of the transcription process, becoming the ultimate mechanism mediating the protection of the breast conferred by full-term pregnancy.

Altered DNA methylation is often seen in malignant cells, potentially contributing to carcinogenesis by suppressing gene expression. We hypothesized that heritable methylation potential might be a risk factor for breast cancer and evaluated possible association with breast cancer for single nucleotide polymorphisms (SNPs) either involving CpG sequences in extended 5'-regulatory regions of candidate genes (ESR1, ESR2, PGR, and SHBG) or CpG and missense coding SNPs in genes involved in methylation (MBD1, MECP2, DNMT1, MGMT, MTHFR, MTR, MTRR, MTHFD1, MTHFD2, BHMT, DCTD, and SLC19A1). Genome-wide searches for genetic risk factors for breast cancers have in general not investigated these SNPs, because of low minor allele frequency or weak haplotype associations. Genotyping was performed using Mass spectrometry-Maldi-Tof in a screening panel of 538 cases and 1,067 controls. Potential association to breast cancer was identified for 15 SNPs and one of these SNPs (rs7766585 in ESR1) was found to associate strongly with breast cancer, OR 1.30 (95% CI 1.17-1.45; p-value 2.1 × 10(-6)), when tested in a verification panel consisting of 3,211 unique breast cancer cases and 4,223 unique controls from five European biobank cohorts. In conclusion, a candidate gene search strategy focusing on methylation-related SNPs did identify a SNP that associated with breast cancer at high significance.

Isozymes of amino acid naphthylamidase were investigated in 11 patients with chronic myeloid leukaemia (CML) and 1 patient with erythroleukaemia. Two isozymes were found in all cases (isozymes A and C) which also occur in normal granulocytes. An isozyme with intermediate mobility appeared in all the patients in two main forms (isozymes BF and BS), which both differed from the isozyme B found in normal granulocytes. This may therefore support the diagnosis. In 3 patients a shift occurred between isozymes BF and BS, the possible significance of which is discussed.

During the period 1978-1982 in the three northernmost countries of Sweden all 143 patients with a registered diagnosis of chronic lymphocytic leukemia (CLL) were retrospectively analyzed. After re-evaluation, 122 cases remained in the study. The mean age was 71 years and the male/female ratio was 2.2:1. Sixty-one patients were Binet stage A, 29 stage B and 32 stage C. The diagnosis CLL was made after routine check-up for other diseases in most of the patients and they had no symptoms from the CLL. The median survival was 51 months and there were no differences in crude survival according to stage or other prognostic factors such as hemoglobin, lymphocytes or thrombocytes in peripheral blood. Analysis of CLL as a cause of specific mortality showed the stage of CLL to have a slight prognostic significance. This could be due to the fact that many of the patients suffered from other serious diseases, allowing the detection of early stage or advanced CLL with no symptoms.

A Swedish national care programme has provided guidelines for staging, treatment and follow-up of all patients with Hodgkin's disease (HD) since 1985. Between January 1985 and December 1992, 920 patients were reported and followed prospectively. Of a total of 533 patients with stage I and II disease, 484 presented with supradiaphragmatic HD and 49 (9%) with infradiaphragmatic HD. The median follow-up time was 4.3 yr (3.3-10 yr). Significant differences in average age (45 +/- 21 yr and 55 +/- 19 yr), male:female ratio (1.1:1 and 2.8:1) and B-symptoms (25% and 47%) were observed in patients with supra- and infradiaphragmatic HD, respectively. Forty-six patients with infradiaphragmatic HD were treated with a curative intention and 40 (87%) achieved a complete response. Eleven (28%) of the 40 patients have recurred and 8 patients have died of HD. Complete response rates and recurrence frequencies did not differ from those observed in patients with supradiaphragmatic HD. Mortality was, however, significantly higher (p = 0.001) in the infradiaphragmatic group; this was due mainly to poorer effects of salvage treatment in a elderly population. In this population-based study, patients with peripheral disease in stage IA respond well to inverted Y irradiation alone, whereas it appears to be important to give stage II patients chemotherapy or a combined modality treatment in order to avoid unacceptably high recurrence rates.

Peripheral blood from 69 patients with non-Hodgkin's lymphoma was examined with respect to B and T cell markers. Evidence for monoclonal B cell was found in 29 cases, 8 of 'high grade' and 21 of 'low grade' malignancy according to the Kiel classification. 17 out of the 29 patients had a normal lymphocyte count. Using conventional staging methods 4 cases of the 29 were in stages II and III, all others in stage IV. The proportion of S-phase cells in peripheral blood, determined by flow cytometry, was found to be elevated in cases with a monoclonal cell population. It is concluded that surface marker analysis of blood cells may be valuable as a diagnostic tool, as an indicator of prognosis and perhaps for the staging procedure of malignant lymphomas.

Excess weight has been associated with increased risk of cancer. The effect of body mass index (BMI, kg/m(2)) on overall cancer risk and on risk of developing several common cancer types was examined in a population-based cohort study. Height and weight measurements were available for 35,362 women and 33,424 men recruited in the Northern Sweden Health and Disease Cohort between 1985 and 2003. Among cohort members, 2,691 incident cancer cases were identified. The association of BMI with cancer risk was examined using Poisson regression. Women with BMI27.1 (top quartile) had a 29% higher risk of developing any malignancy compared to women with BMI of 18.5-22.2 (lowest quartile), which increased to 47% in analysis limited to nonsmokers. Analyses according to WHO cut-off points showed that obese women (BMIor = 30) had a 36% higher risk of cancer than women with BMI in the normal range (18.5-25). Individual cancer sites most strongly related to obesity were endometrium (risk for top quartile = 3.53, 95% confidence interval 1.86-7.43), ovary (2.09, 1.13-4.13) and colon (2.05, 1.04-4.41). BMI was inversely related to breast cancer occurring before age 49 (0.58, 0.29-1.11, p(trend)0.04). In men, there was no association of BMI with overall cancer risk. Obese men (BMIor = 30), however, were at increased risk of developing kidney cancer (3.63, 1.23-10.7) and, after exclusion of cases diagnosed within 1 year of recruitment, colon cancer (1.77, 1.04-2.95). Our study provides further evidence that BMI is positively associated with cancer risk. In women from northern Sweden, up to 7% of all cancers were attributable to overweight and obesity and could be avoided by keeping BMI within the recommended range.

Screening with mammography has been shown to substantially reduce mortality from breast cancer. The incidence of invasive cancer will increase as screening starts, and it is desirable that it gradually returns to the same level as before screening. Age-specific incidence of invasive breast cancer in 11 Swedish counties, including 463,000 women aged 40-74 years, was analysed before and after the start of service screening with mammography. Incidence, as observed on average during 12.8 years from screening start, was compared to expected incidence based on the incidence during a 15-year period preceding screening start. The height of the incidence peak during the first screening round was increasing with increasing age, compatible with the accumulation in the population of slowly growing tumours by age. All analysed age groups showed an increased ratio between observed stabilised incidence 7-14 years after screening start and expected incidence. When relative risks were adjusted for lead time, the estimates were 1.54 (95% confidence interval [CI] 1.33-1.79) and 1.21 (95% CI 1.04-1.41) for the age groups 50-59 and 60-69 years, respectively. In the age groups 40-49 and 70-74, no change was observed. The findings were further confirmed by the observation of a disappearance in the screened population of the notch in the increasing trend of age-specific breast cancer incidence for the ages after menopause. This notch could indicate hormone-related retardation in tumour growth around menopause. It appears that many of these clinically insignificant, retarded tumours are detected with screening mammography.

We investigated the association between smoking and risk of postmenopausal breast cancer in groups defined by high levels of estrogens, a factor known to enhance tumour progression. Two prospective cohorts of Swedish women provided 260 postmenopausal breast cancer cases and 514 controls. Blood samples were collected at baseline, and anthropometry, life-style factors and reproductive history had been assessed. Subjects were classified into quartiles with regard to the level of estrone, and into three categories with regard to estradiol. All analyses of the relation between smoking and breast cancer were repeated in different categories of these hormones. Logistic regression analysis, adjusted for matching factors, i.e., age at baseline, storage time and sub-cohort, yielded odds ratios (OR) with 95% confidence intervals (CI). Ever-smoking was associated with breast cancer in the top category of estrone, 2.02 (1.17–3.49). The highest risk was seen among ex-smokers, 2.96 (1.53–5.75). The pattern was similar for estradiol. Recent smoking cessation was associated with a high OR in top categories of estrone, 4.38 (1.27–15.2) and estradiol 10.0 (1.14–88.7). Smoking initiation before the age of 20 was associated with breast cancer in the top category of estrone, 2.73 (1.27–5.91). Several potential confounders were introduced into the statistical model, but none remained using backward selection. We conclude that ever-smoking was associated with the risk of breast cancer in women with high levels of estrone, and that ex-smoking was associated with breast cancer in women with high levels of estrone or estradiol. © 2004 Wiley-Liss, Inc.

Experimental and epidemiological evidence supports a role for sex steroid hormones in the pathogenesis of ovarian cancer. We investigated the association between ovarian cancer risk and pre-diagnostic blood concentrations of testosterone, androstenedione, DHEAS, estrone and SHBG. A case-control study nested within 3 cohorts, in New York (USA), Umeå (Sweden) and Milan (Italy), included 132 subjects with primary invasive epithelial ovarian cancer. For each case subject, 2 controls were selected who matched a case on cohort, menopausal status, age and date of recruitment and, if premenopausal, day of the menstrual cycle at blood donation. Only women who did not use exogenous hormones at blood donation were included in the study. Conditional logistic regression was used to relate cancer risk to sex steroid hormone concentrations with adjustment for potential confounders. No clear association was observed between ovarian cancer risk and any of the 5 hormones under study. In the premenopausal group, the risk appeared to increase with increasing blood concentrations of androstenedione (upper vs. lower tertile OR = 2.35; 95% CI = 0.81-6.82.), but the small number of subjects in the sub-group precluded reaching unambiguous conclusions about such association. Our study does not support previous observations relating elevations in blood levels of the major sex steroid hormones to an increased risk of ovarian cancer, but offers some evidence that elevated circulating androstenedione before menopause may be associated with increased ovarian cancer risk.

Insulin-like growth factor (IGF)-I, a mitogenic and anti-apoptotic peptide, has been implicated in the development of several cancers. We hypothesized that high circulating IGF-I concentrations may be associated with an increased risk of ovarian cancer. A case-control study was nested within 3 prospective cohorts in New York (USA), Umea (Sweden) and Milan (Italy). One hundred thirty-two women with primary invasive epithelial ovarian cancer diagnosed at least 1 year after blood donation were case subjects. For each case, 2 control subjects were selected, matching the case subject on cohort, menopausal status, age and date of recruitment (n = 263). Only women who did not use exogenous hormones at blood donation were included in the study. There was no association between IGF-I concentrations and ovarian cancer risk in the study group as a whole. In analyses restricted to subjects who had developed ovarian cancer at a young age (

The genes encoding human leukocyte antigens (HLA) have shown to be associated with cervical neoplasia. To obtain reliable data on HLA associations with cervical tumors, the study should be performed within a strictly defined cohort. To investigate the population attributable risk of cervical cancer associated with the HLA class II haplotypes DR15 and DQ6 (DQA1*0102 and DQB1*0602), we performed a nested case-control study of 85 women who developed invasive cervical cancer and 120 healthy women from a population-based cohort of Swedish women. The relative risks of cervical cancer among DR15 and DQ6-positive women were 3.73 [confidence interval (CI): 1.8–7.4] and 4.33 (CI: 2.1–8.5), corresponding to population attributable proportions of 27.9% and 30.8%, respectively. A susceptibility locus in the HLA class II region is involved in a substantial fraction of the etiology of cervical cancer. © 2002 Wiley-Liss, Inc.

The study of the relationship between dietary intake of fatty acids and the risk of breast cancer has not yielded definite conclusions with respect to causality, possibly because of methodological issues inherent to nutritional epidemiology. To evaluate the hypothesis of possible protection of n-3 polyunsaturated fatty acids (PUFA) against breast cancer in women, we examined the fatty-acid composition of phospholipids in pre-diagnostic sera of 196 women who developed breast cancer, and of 388 controls matched for age at recruitment and duration of follow-up, in a prospective cohort study in Umea, northern Sweden. Individual fatty acids were measured as a percentage of total fatty acids, using capillary gas chromatography. Conditional logistic-regression models showed no significant association between n-3 PUFA and breast-cancer risk. In contrast, women in the highest quartile of stearic acid had a relative risk of 0.49 (95% confidence interval, 0.22–1.08) compared with women in the lowest quartile (trend p = 0.047), suggesting a protective role of stearic acid in breast-cancer risk. Besides stearic acid, women in the highest quartile of the 18:0/18:1 n-9c ratio had a relative risk of 0.50 (95% confidence interval, 0.23–1.10) compared with women in the lowest quartile (trend p = 0.064), suggesting a decrease in breast-cancer risk in women with low activity of the enzyme delta 9-desaturase (stearoyl CoA desaturase), which may reflect an underlying metabolic profile characterized by insulin resistance and chronic hyper-insulinemia. Int. J. Cancer 83:585–590, 1999. © 1999 Wiley-Liss, Inc.

Department of Public Health and Clinical Medicine/Nutritional Research, Umea University, Sweden˚Dear Sir,The gene, deleted in malignant brain tumors 1 (DMBT1,OMIM 601969), locating in chromosome 10q25-26, has beensuggested to be a putative candidate tumor suppressor gene inepithelial cancers. Loss or decreased DMBT1 gene expressionhas been originally reported in brain tumors

To estimate the risk of developing cervical intra-epithelial neoplasia (CIN) among women exposed to human papillomavirus (HPV) type 16, we performed a prospective study in a population-based cohort of more than 15,000 women followed for 34.9 months. Seventy-four women developed CIN during follow-up and were matched for age, time of sampling and area of residence with 148 women who remained CIN-free during follow-up. The blood samples taken at enrollment were tested for serum antibodies to HPV types 16, 18 and 33 capsids. Cervical smears or biopsies were analyzed for the presence of HPV DNA by nested PCR using HPV general primers and by HPV 16- and 18-type-specific PCR. HPV serology and HPV-PCR were in good agreement, particularly when the blood sample and the Pap smear were taken less than 6 months apart. HPV DNA was found in 88% of cases and 4% of controls, whereas HPV 16 DNA was present in 44% of cases and in 1 of 142 controls. HPV-16-seropositive women had a 3-fold increased risk of developing CIN. The risk was highest among women younger than 35 years of age, of whom an estimated 3.4% of HPV-16-seropositive and 0.5% of seronegative women developed CIN. Since the risk associated with HPV-16 seropositivity (a measure of past or present infection) was 35-fold lower than that of HPV DNA (present infection), most infections appear to be eliminated before CIN develops. In conclusion, HPV 16 infection does confer an excess risk of CIN development, and HPV DNA detection has a high predictive value for the presence of high-grade CIN. © 1996 Wiley-Liss, Inc.

Letter to the Editor. Comments to the letters by Per-Henrik Zahl and Jan Maehlen and by Peter C Gotzsche concerning our article: : Increased incidence of invasive breast cancer after the introduction of service screening with mammography in Sweden

The effect of adjuvant combination chemotherapy when given to non-laparotomized patients in remission after radiotherapy in stage I or II non-Hodgkin's lymphoma was studied in a prospective randomized multicenter study. Locally extended field radiotherapy was given to a target absorbed dose of 40 Gy in 20 fractions. Fifty-five patients who were in complete remission 6 weeks after conclusion of radiotherapy were randomized to either no further therapy or to 9 cycles of CVP (cyclophosphamide + vincristine + prednisolone). The relapse-free survival at 30 months was 41% for patients without and 86% for patients with adjuvant chemotherapy (p = 0.02). The survival was the same for both treatment arms, being 90% at 30 months. Fifteen patients have relapsed, 14 of them with extensions and 1 with a recurrence within the radiation target volume. Analysis of subgroups showed that adjuvant chemotherapy in the present series significantly prolonged the relapse-free survival in diffuse histiocytic lymphoma.