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Background There is increasing evidence that elevated body mass index (BMI) is associated with reduced survival for women with breast cancer. However, the underlying reasons remain unclear. We conducted a Mendelian randomization analysis to investigate a possible causal role of BMI in survival from breast cancer. Methods We used individual-level data from six large breast cancer case-cohorts including a total of 36 210 individuals (2475 events) of European ancestry. We created a BMI genetic risk score (GRS) based on genotypes at 94 known BMI-associated genetic variants. Association between the BMI genetic score and breast cancer survival was analysed by Cox regression for each study separately. Study-specific hazard ratios were pooled using fixed-effect meta-analysis. Results BMI genetic score was found to be associated with reduced breast cancer-specific survival for estrogen receptor (ER)-positive cases [hazard ratio (HR) = 1.11, per one-unit increment of GRS, 95% confidence interval (CI) 1.01–1.22, P = 0.03). We observed no association for ER-negative cases (HR = 1.00, per one-unit increment of GRS, 95% CI 0.89–1.13, P = 0.95). Conclusions Our findings suggest a causal effect of increased BMI on reduced breast cancer survival for ER-positive breast cancer. There is no evidence of a causal effect of higher BMI on survival for ER-negative breast cancer cases.

Previous genome-wide association studies among women of European ancestry identified two independent breast cancer susceptibility loci represented by single nucleotide polymorphisms (SNPs) rs13281615 and rs11780156 at 8q24. We conducted a fine-mapping study across 2.06 Mb (chr8:127,561,724 -129,624,067, hg19) in 55,540 breast cancer cases and 51,168 controls within the Breast Cancer Association Consortium. We found three additional independent association signals in women of European ancestry, represented by rs35961416 (OR = 0.95, 95% CI = 0.93-0.97, conditional P = 5.8 × 10-6), rs7815245 (OR = 0.94, 95% CI = 0.91-0.96, conditional P = 1.1 × 10-6), and rs2033101 (OR = 1.05, 95% CI = 1.02-1.07, conditional P = 1.1 × 10-4). Integrative analysis using functional genomic data from the Roadmap Epigenomics, the Encyclopedia of DNA Elements project, the Cancer Genome Atlas, and other public resources implied that SNPs rs7815245 in Signal 3, and rs1121948 in Signal 5 (in linkage disequilibrium with rs11780156, r2 = 0.77), were putatively functional variants for two of the five independent association signals. Our results highlight multiple 8q24 variants associated with breast cancer susceptibility in women of European ancestry

Background: Survival after a diagnosis of breast cancer varies considerably between patients, and some of this variation may be because of germline genetic variation. We aimed to identify genetic markers associated with breast cancer–specific survival.\ud \ud Methods: We conducted a large meta-analysis of studies in populations of European ancestry, including 37954 patients with 2900 deaths from breast cancer. Each study had been genotyped for between 200000 and 900000 single nucleotide polymorphisms (SNPs) across the genome; genotypes for nine million common variants were imputed using a common reference panel from the 1000 Genomes Project. We also carried out subtype-specific analyses based on 6881 estrogen receptor (ER)–negative patients (920 events) and 23059 ER-positive patients (1333 events). All statistical tests were two-sided.\ud \ud Results: We identified one new locus (rs2059614 at 11q24.2) associated with survival in ER-negative breast cancer cases (hazard ratio [HR] = 1.95, 95% confidence interval [CI] = 1.55 to 2.47, P = 1.91 x 10–8). Genotyping a subset of 2113 case patients, of which 300 were ER negative, provided supporting evidence for the quality of the imputation. The association in this set of case patients was stronger for the observed genotypes than for the imputed genotypes. A second locus (rs148760487 at 2q24.2) was associated at genome-wide statistical significance in initial analyses; the association was similar in ER-positive and ER-negative case patients. Here the results of genotyping suggested that the finding was less robust.\ud \ud Conclusions: This is currently the largest study investigating genetic variation associated with breast cancer survival. Our results have potential clinical implications, as they confirm that germline genotype can provide prognostic information in addition to standard tumor prognostic factors.

Introduction: We have previously shown that a tag single nucleotide polymorphism (rs10235235), which maps to\ud the CYP3A locus (7q22.1), was associated with a reduction in premenopausal urinary estrone glucuronide levels and\ud a modest reduction in risk of breast cancer in women age ≤50 years.\ud Methods: We further investigated the association of rs10235235 with breast cancer risk in a large case control study of\ud 47,346 cases and 47,570 controls from 52 studies participating in the Breast Cancer Association Consortium. Genotyping\ud of rs10235235 was conducted using a custom Illumina Infinium array. Stratified analyses were conducted to determine\ud whether this association was modified by age at diagnosis, ethnicity, age at menarche or tumor characteristics.\ud Results: We confirmed the association of rs10235235 with breast cancer risk for women of European ancestry but found\ud no evidence that this association differed with age at diagnosis. Heterozygote and homozygote odds ratios (ORs) were\ud OR = 0.98 (95% CI 0.94, 1.01; P = 0.2) and OR = 0.80 (95% CI 0.69, 0.93; P = 0.004), respectively (Ptrend = 0.02). There was\ud no evidence of effect modification by tumor characteristics. rs10235235 was, however, associated with age at menarche\ud in controls (Ptrend = 0.005) but not cases (Ptrend = 0.97). Consequently the association between rs10235235 and breast\ud cancer risk differed according to age at menarche (Phet = 0.02); the rare allele of rs10235235 was associated with a\ud reduction in breast cancer risk for women who had their menarche age ≥15 years (ORhet = 0.84, 95% CI 0.75, 0.94;\ud ORhom = 0.81, 95% CI 0.51, 1.30; Ptrend = 0.002) but not for those who had their menarche age ≤11 years (ORhet = 1.06,\ud 95% CI 0.95, 1.19, ORhom = 1.07, 95% CI 0.67, 1.72; Ptrend = 0.29).\ud Conclusions: To our knowledge rs10235235 is the first single nucleotide polymorphism to be associated with both\ud breast cancer risk and age at menarche consistent with the well-documented association between later age at menarche\ud and a reduction in breast cancer risk. These associations are likely mediated via an effect on circulating hormone levels.

A large genotyping project within the Breast Cancer Association Consortium (BCAC) recently identified 41 associations between single nucleotide polymorphisms (SNPs) and overall breast cancer (BC) risk. We investigated whether the effects of these 41 SNPs, as well as six SNPs associated with estrogen receptor (ER) negative BC risk are modified by 13 environmental risk factors for BC. Data from 22 studies participating in BCAC were pooled, comprising up to 26,633 cases and 30,119 controls. Interactions between SNPs and environmental factors were evaluated using an empirical Bayes-type shrinkage estimator. Six SNPs showed interactions with associated p-values (p(int))

BackgroundSomatic mutations in phosphoinositide-3-kinase catalytic subunit alpha (PIK3CA) are frequent in breast tumours and have been associated with oestrogen receptor (ER) expression, human epidermal growth factor receptor-2 overexpression, lymph node metastasis and poor survival. The goal of this study was to evaluate the association between inherited variation in this oncogene and risk of breast cancer.MethodsA single-nucleotide polymorphism from the PIK3CA locus that was associated with breast cancer in a study of Caucasian breast cancer cases and controls from the Mayo Clinic (MCBCS) was genotyped in 5436 cases and 5280 controls from the Cancer Genetic Markers of Susceptibility (CGEMS) study and in 30 949 cases and 29 788 controls from the Breast Cancer Association Consortium (BCAC).ResultsRs1607237 was significantly associated with a decreased risk of breast cancer in MCBCS, CGEMS and all studies of white Europeans combined (odds ratio (OR)=0.97, 95% confidence interval (CI) 0.95-0.99, P=4.6 × 10(-3)), but did not reach significance in the BCAC replication study alone (OR=0.98, 95% CI 0.96-1.01, P=0.139).ConclusionCommon germline variation in PIK3CA does not have a strong influence on the risk of breast cancer.

To evaluate the predictive value of traditional prognostic factors, nuclear morphometry, and flow cytometric data in invasive breast cancer.Open study.One university hospital in Finland.248 women with invasive breast cancer followed up for more than 11 years.Univariate and multivariate analysis of factors thought to indicate prognosis.Diameter of the tumour, lymph node status, S phase fraction. DNA index, the age of the patient, and the SD of nuclear perimeter were significant independent predictors in the whole series in a multivariate analysis. In node negative patients the SED of the nuclear perimeter and diameter of the tumour had independent prognostic value, whereas in node positive patients diameter of the tumour and the S phase fraction were independently related to survival.Diameter of the tumour is an important prognostic factor in breast carcinomas. Histoquantitative methods are superior to conventional histological techniques for the prediction of outcome in women with breast cancer.

The estrogen (ER) and progesterone (PR) receptor status, volume corrected mitotic index (M/V index) and other classical prognostic factors were related to disease outcome in a series of 281 women with breast cancer followed up for over 8 years. The M/V index predicted recurrence only in ER+ or PR+ patients (p = 0.002-0.006). Similarly, the recurrence-free survival was related to M/V index only in ER+ (p = 0.0005) or PR+ (p less than 0.0001) patients. In survival analysis, ER+ (p = 0.0037) and PR+ (p less than 0.0001) patients were accurately divided into different prognostic groups by the M/V index, whereas in ER- and in PR-tumours the M/V index had only suggestive predictive value (p = 0.06-0.5). In N-tumours the M/V index predicted recurrence-free survival only in ER+ (p = 0.0228) and in PR+ (p = 0.0087) tumours. In survival analysis of N-tumours, the M/V index predicted cancer-related survival in ER+ (p = 0.0102) and in PR+ (p = 0.0014) tumours. In ER-/PR-, N-tumours, none of the variables tested had any prognostic value. The present results suggest that adjuvant hormone treatment might be indicated in ER+ or PR+ tumours with a M/V index greater than 10, regardless of the axillary lymph node status. The prognosis of ER+ or PR+ tumours with a M/V index less than 10 is favourable, the risk of recurrence being of the order of 15% only during the 10-year follow-up. Thus, the expensive and distressing adjuvant treatments could be omitted for these women with an inherently favourable disease outcome.

Gene therapy has been suggested as a novel approach against pancreatic cancer, a disease with a grim prognosis with current modes of therapy. Despite recent advances in in vitro and experimental in vivo studies, there is no data available concerning gene transfer efficiency in intrapancreatic tumours in immunocompetent animal models.In in vitro studies rat pancreatic carcinoma cells (DSL-6A/C1) were transduced with replication-deficient adenovirus carrying Escherichia Coli beta-galactosidase (lacZ) gene. Gene transfer efficacy was assessed at different multiplicities of infection (MOIs). Pancreatic tumours were induced by inoculating cultured DSL-6A/C1 cancer cells into Lewis rat pancreases. Established tumours were transduced and three days post-transduction, pancreatic tumours as well as other intra-abdominal organs were harvested and processed for histological analyses, including staining for marker gene expression.In vitro assays showed that DSL-6A/C1 cells were transduced efficiently, even at low MOIs. In vivo gene transfer was successful in all animals, and all pancreatic samples showed reporter gene expression. Positive cells were detected in the peritumoural areas as well as to a lesser extent within the tumours. The transgene activity was not evenly distributed and the gene transfer efficiency varied from a few detectable blue cells to 11% per field. Our studies demonstrated safe in vivo gene transfer into intrapancreatic tumours, suggesting that pancreatic tumours are potential targets for in vivo delivery of therapeutic genes.

The expression of c-myc proteins was analysed immunohistochemically in a series of 206 breast carcinomas with special focus on established prognostic factors and patient survival. Nuclear expression of c-myc proteins was detected in 12% of carcinomas, and it was related to the lack of estrogen receptors (p = 0.05). Cytoplasmic expression of c-myc was present in 95% of the tumours. Expression of cytoplasmic c-myc at the invasive margin was related to tumour grade (p = 0.0013), low mitotic index (p = 0.0002) and low S phase fraction (p = 0.026), and weakly associated with distant metastasis at diagnosis (p = 0.06) and to a high proportion of intraductal growth (p = 0.08). Long recurrence-free survival of the patients was related to strong cytoplasmic expression of c-myc at the invasive margin in the entire series (p = 0.0049) and in axillary lymph node-negative (ANN) (p = 0.0028) tumours. Cytoplasmic c-myc expression in the central areas of the tumour predicted metastasis at diagnosis (p = 0.002), non-ductal type of growth (p = 0.018) and low mitotic index (p = 0.005). Expression of c-myc in the stroma was related to the lack of estrogen receptors (p = 0.02) and to high S phase fraction (p = 0.01). The results show that overexpression of c-myc is involved in a highly complex manner with the early stages of breast cancer development, but it shows hardly any independent prognostic value over standard prognostic factors in clinical disease.

GASC1 (gene amplified in squamous cell carcinoma 1) encodes a nuclear protein that epigenetically catalyses the lysine demethylation of histones. We investigated the expression of GASC1 in different histological subtypes of lung cancer (n=289). Percentage value of GASC1 immunohistochemical expression was evaluated separately in the nuclei and cytoplasms of epithelial cancer cells. The results were compared with clinicopathologic factors and the smoking history of the patients. In lung tumor cells, 38% of nuclei and 54% of the cytoplasms stained positive for GASC1. Adenocarcinomas expressed more GASC1 nuclear (p=0.00011) and cytoplasmic (p=0.00074) positivity than squamous cell carcinoma. Smokers displayed less nuclear and cytoplasmic GASC1 expression than non-smokers (p=0.028 and p=0.036, respectively). Similarly, patients with more cytoplasmic positive staining had fewer pack years (p=0.043). Nuclear GASC1 expression had an impairing effect on survival when all histological lung cancer types were analysed together (p=0.039) and separately in squamous cell lung carcinoma (p=0.016). The results reveal that GASC1 expression is higher in adenocarcinoma than squamous cell carcinoma. Smoking decreases GASC1 expression in tumor cells, indicating that tobacco smoke may influence the methylation of histone 3 lysine residues in lung cancer. Nonetheless, nuclear GASC1 predicts a poor prognosis, especially in squamous cell carcinoma.

Clinical features, 8 histological features, 7 nuclear morphometric variables and 2 mitotic indices were entered in a univariate and in a multivariate survival analysis to assess their independent predictive value in 56 breast cancer patients under the age of 40 years who were followed up for over 10 years. The most important predictor of recurrence-free survival (RFS) in univariate analysis was the SD of nuclear perimetry (p = 0.003) followed by SD of nuclear area (p = 0.006), M/V index (p = 0.036), pN status (p = 0.046), nuclear area of 10 largest nuclei (p = 0.07), nuclear perimetry (p = 0.09) and nuclear area (p = 0.09) in that order. In pN(-) patients, SDPE (p = 0.04), SDNA (p = 0.07) and NA10 (p = 0.07) predicted RFS. In pN+ patients the most important predictor of RFS was the SDNA (p = 0.001) followed by NA 10 (p = 0.003), SDPE (p = 0.009), PE (p = 0.01), NA (p = 0.01) and Dmin (shortest diameter) (p = 0.04). In multivariate analysis the pN-status independently predicted RFS. Tumour size (p = 0.001), pN status (p = 0.002) and M/V-index (p = 0.079) were related to BS (breast cancer survival). In pN-patients, NA 10 (p = 0.097) predicted BS, whereas in pN+ tumours tumour size (p = 0.06) was the most important predictor of BS. In a multivariate analysis, tumour size (p = 0.02) and pN-status (p = 0.016) were independent predictors of BS.

Expression of an acidic lysosomal protease, cathepsin-D (CD), was analysed immunohistochemically in a series of 151 breast carcinomas with special reference to its prognostic significance, Strong expression of CD was detected in 22% of cases. This intense expression was significantly associated with a number of established prognostic factors, including the non-ductal type of carcinoma (p = 0.0243) and metastases at the time of diagnosis (p = 0.0068). On the other hand, high expression of CD was not related to the lymph-node status, tumour size, ER/PR content or histological grade. Patients with CD overexpression has a significantly lower survival probability (p = 0.0478) than did the patients with low expression of this protease. The relationship between the high expression of CD and short disease-free survival was almost significant (p = 0.0519). Intense immunostaining of CD was associated with a significantly impaired disease outlook in patients with confirmed lymph node metastasis (N+) (p = 0.0137) but not in those with negative lymph nodes (N-) (p = 0.0620). In Cox's multivariate analysis, expression of CD had no independent prognostic value over the conventional prognostic factors. The results suggest that expression of CD is of borderline significance in evaluating the intrinsic malignancy of female breast cancer in general. The potential of CD as a prognostic factor in specific subgroups of breast cancers will be the subject of further studies.

To assess the independent power of certain clinical, histological, and morphometric variables to predict survival after first recurrence of breast cancer.Long term follow up study.Departments of surgery and pathology, University Hospital.212 patients (from a consecutive series of 517) who developed recurrence after primary treatment of breast cancer between 1968 and 1990.Re-examination of histology of primary tumours, follow up of patients, and calculation of predictive score by Cox's regression analysis.The nodal status at the time of diagnosis (p less than 0.001), the SD of the nuclear area (p = 0.01), the degree of tubule formation (p = 0.003), and the age of patient, were all independent predictors. The most important predictor of survival was the prognostic score derived from the coefficients of the Cox's model (p less than 0.0001).Survival after first recurrence can be accurately predicted by advanced histological analysis of the primary tumour tissue. Combination of independent predictors permits even more accurate estimation of survival time.

Polybenzimidazole (PBI)-based membranes are one of the systems of choice for polymer electrolyte fuel cells. Monomer sulphonation is one of the strategies suggested to improve proton transport in these membranes. We report a NMR and dynamic mechanical study aiming to investigate the effect of the sulphonation on the proton dynamics and the mechanical properties of the membranes. The analyses of 1H self-diffusion coefficients and 1H and 31P spectra versus temperature show that sulphonation causes the formation of interchain cross-links, which involve phosphoric acid molecules and the sulfonic groups. This, in turn, reduces the proton mobility and, consequently, the ionic conductivity. The increase of the membrane stiffness with sulphonation is confirmed by dynamic mechanical analysis through the behavior of the storage modulus.