Intratumor Heterogeneity of the Estrogen Receptor and the Long-term Risk of Fatal Breast Cancer.

Background:Breast cancer patients with estrogen receptor (ER)-positive disease have a continuous long-term risk for fatal breast cancer, but the biological factors influencing this risk are unknown. We aimed to determine whether high intratumor heterogeneity of ER predicts an increased long-term risk (25 years) of fatal breast cancer. Methods:The STO-3 trial enrolled 1780 postmenopausal lymph node-negative breast cancer patients randomly assigned to receive adjuvant tamoxifen vs not. The fraction of cancer cells for each ER intensity level was scored by breast cancer pathologists, and intratumor heterogeneity of ER was calculated using Rao's quadratic entropy and categorized into high and low heterogeneity using a predefined cutoff at the second tertile (67%). Long-term breast cancer-specific survival analyses by intra-tumor heterogeneity of ER were performed using Kaplan-Meier and multivariable Cox proportional hazard modeling adjusting for patient and tumor characteristics. Results:A statistically significant difference in long-term survival by high vs low intratumor heterogeneity of ER was seen for all ER-positive patients (P < .001) and for patients with luminal A subtype tumors (P = .01). In multivariable analyses, patients with high intratumor heterogeneity of ER had a twofold increased long-term risk as compared with patients with low intratumor heterogeneity (ER-positive: hazard ratio [HR] = 1.98, 95% confidence interval [CI] = 1.31 to 3.00; luminal A subtype tumors: HR = 2.43, 95% CI = 1.18 to 4.99). Conclusions:Patients with high intratumor heterogeneity of ER had an increased long-term risk of fatal breast cancer. Interestingly, a similar long-term risk increase was seen in patients with luminal A subtype tumors. Our findings suggest that intratumor heterogeneity of ER is an independent long-term prognosticator with potential to change clinical management, especially for patients with luminal A tumors

Is Genetic Background Important in Lung Cancer Survival?

BACKGROUND:In lung cancer, a patient's survival is poor with a wide variation in survival within the stage of disease. The aim of this study was to investigate the familial concordance in lung cancer survival by means of analyses of pairs with different degrees of familial relationships. METHODS:Our population-based Swedish family database included three million families and over 58,100 lung cancer patients. We modelled the proband (parent, sibling, spouse) survival utilizing a multivariate proportional hazard (Cox) model adjusting for possible confounders of survival. Subsequently, the survival in proband's relative (child, sibling, spouse) was analysed with a Cox model. FINDINGS:By use of Cox modelling with 5 years follow-up, we noted a decreased hazard ratio for death in children with good parental survival (Hazard Ratio [HR] = 0.71, 95% CI = 0.51 to 0.99), compared to those with poor parental survival. Also for siblings, a very strong protective effect was seen (HR = 0.14, 95% CI = 0.030 to 0.65). Finally, in spouses no correlation in survival was found. INTERPRETATION:Our findings suggest that genetic factors are important in lung cancer survival. In a clinical setting, information on prognosis in a relative may be vital in foreseeing the survival in an individual newly diagnosed with lung cancer. Future molecular studies enhancing the understanding of the underlying mechanisms and pathways are needed

Is breast cancer prognosis inherited?

Introduction: A genetic component is well established in the etiology of breast cancer. It is not well known, however, whether genetic traits also influence prognostic features of the malignant phenotype. Methods: We carried out a population-based cohort study in Sweden based on the nationwide Multi-Generation Register. Among all women with breast cancer diagnosed from 1961 to 2001, 2,787 mother-daughter pairs and 831 sister pairs with breast cancer were identified; we achieved complete follow-up and classified 5-year breast cancer-specific prognosis among proband (mother or oldest sister) into tertiles as poor, intermediary, or good. We used Kaplan-Meier estimates of survival proportions and Cox models to calculate relative risks of dying from breast cancer within 5 years depending on the proband's outcome. Results: The 5-year survival proportion among daughters whose mothers died within 5 years was 87% compared to 91% if the mother was alive (p = 0.03). Among sisters, the corresponding proportions were 70% and 88%, respectively (p = 0.001). After adjustment for potential confounders, daughters and sisters of a proband with poor prognosis had a 60% higher 5-year breast cancer mortality compared to those of a proband with good prognosis (hazard ratio [HR], 1.6; 95% confidence interval [CI], 1.2 to 2.2; p for trend 0.002). This association was slightly stronger among sisters (HR, 1.8; 95% CI, 1.0 to 3.4) than among daughters (HR, 1.6; 95% CI, 1.1 to 2.3). Conclusion: Breast cancer prognosis of a woman predicts the survival in her first-degree relatives with breast cancer. Our novel findings suggest that breast cancer prognosis might be inherited

A genome-wide linkage study of mammographic density, a risk factor for breast cancer

Abstract Introduction Mammographic breast density is a highly heritable (h2 > 0.6) and strong risk factor for breast cancer. We conducted a genome-wide linkage study to identify loci influencing mammographic breast density (MD). Methods Epidemiological data were assembled on 1,415 families from the Australia, Northern California and Ontario sites of the Breast Cancer Family Registry, and additional families recruited in Australia and Ontario. Families consisted of sister pairs with age-matched mammograms and data on factors known to influence MD. Single nucleotide polymorphism (SNP) genotyping was performed on 3,952 individuals using the Illumina Infinium 6K linkage panel. Results Using a variance components method, genome-wide linkage analysis was performed using quantitative traits obtained by adjusting MD measurements for known covariates. Our primary trait was formed by fitting a linear model to the square root of the percentage of the breast area that was dense (PMD), adjusting for age at mammogram, number of live births, menopausal status, weight, height, weight squared, and menopausal hormone therapy. The maximum logarithm of odds (LOD) score from the genome-wide scan was on chromosome 7p14.1-p13 (LOD = 2.69; 63.5 cM) for covariate-adjusted PMD, with a 1-LOD interval spanning 8.6 cM. A similar signal was seen for the covariate adjusted area of the breast that was dense (DA) phenotype. Simulations showed that the complete sample had adequate power to detect LOD scores of 3 or 3.5 for a locus accounting for 20% of phenotypic variance. A modest peak initially seen on chromosome 7q32.3-q34 increased in strength when only the 513 families with at least two sisters below 50 years of age were included in the analysis (LOD 3.2; 140.7 cM, 1-LOD interval spanning 9.6 cM). In a subgroup analysis, we also found a LOD score of 3.3 for DA phenotype on chromosome 12.11.22-q13.11 (60.8 cM, 1-LOD interval spanning 9.3 cM), overlapping a region identified in a previous study. Conclusions The suggestive peaks and the larger linkage signal seen in the subset of pedigrees with younger participants highlight regions of interest for further study to identify genes that determine MD, with the goal of understanding mammographic density and its involvement in susceptibility to breast cancer

Efficacy of a church-based lifestyle intervention programme to control high normal blood pressure and/or high normal blood glucose in church members: a randomized controlled trial in Pretoria, South Africa

BACKGROUND: In persons 15 years and above in South Africa the prevalence of pre-diabetes and diabetes has been estimated at 9.1% and 9.6%, respectively, and the prevalence of systolic prehypertension and hypertension, 38.2% and 24.6%, respectively. Elevated blood glucose and elevated blood pressure are prototype of preventable chronic cardiovascular disease risk factors. Lifestyle interventions have been shown to control high normal blood pressure and/or high normal blood glucose. METHODS/DESIGN: This study proposes to evaluate the efficacy of a community (church)-based lifestyle intervention programme to control high normal blood pressure and/or high normal blood glucose in church members in a randomized controlled trial in Gauteng, South Africa. The objectives are to: (1) measure non-communicable diseases profile, including hypertension and diabetes, health behaviours, weight management and psychological distress of church members; (2) measure the reduction of blood glucose and blood pressure levels after the intervention; (3) prevent the development of impaired glucose tolerance; (4) compare health behaviours, weight management and psychological distress, blood glucose and blood pressure levels between intervention and control groups, and within group during 6, 12, 24 and 36 months during and post intervention. The study will use a group-randomized design, recruiting 300 church members from 12 churches. Churches will be randomly assigned to experimental and control conditions. DISCUSSION: Lifestyle interventions may prevent from the development of high blood pressure and/or diabetes. The findings will impact public health and will enable the health ministry to formulate policy related to lifestyle interventions to control blood pressure and glucose. TRIAL REGISTRATION NUMBER: PACTR20110500029715

2q36.3 is associated with prognosis for oestrogen receptor-negative breast cancer patients treated with chemotherapy

Large population-based registry studies have shown that breast cancer prognosis is inherited. Here we analyse single-nucleotide polymorphisms (SNPs) of genes implicated in human immunology and inflammation as candidates for prognostic markers of breast cancer survival involving 1,804 oestrogen receptor (ER)-negative patients treated with chemotherapy (279 events) from 14 European studies in a prior large-scale genotyping experiment, which is part of the Collaborative Oncological Gene-environment Study (COGS) initiative. We carry out replication using Asian COGS samples (n=522, 53 events) and the Prospective Study of Outcomes in Sporadic versus Hereditary breast cancer (POSH) study (n=315, 108 events). Rs4458204-A near CCL20 (2q36.3) is found to be associated with breast cancer-specific death at a genome-wide significant level (n=2,641, 440 events, combined allelic hazard ratio (HR)=1.81 (1.49-2.19); P for trend=1.90 × 10 â ̂'9). Such survival-associated variants can represent ideal targets for tailored therapeutics, and may also enhance our current prognostic prediction capabilities

2q36.3 is associated with prognosis for oestrogen receptor-negative breast cancer patients treated with chemotherapy.

Large population-based registry studies have shown that breast cancer prognosis is inherited. Here we analyse single-nucleotide polymorphisms (SNPs) of genes implicated in human immunology and inflammation as candidates for prognostic markers of breast cancer survival involving 1,804 oestrogen receptor (ER)-negative patients treated with chemotherapy (279 events) from 14 European studies in a prior large-scale genotyping experiment, which is part of the Collaborative Oncological Gene-environment Study (COGS) initiative. We carry out replication using Asian COGS samples (n=522, 53 events) and the Prospective Study of Outcomes in Sporadic versus Hereditary breast cancer (POSH) study (n=315, 108 events). Rs4458204_A near CCL20 (2q36.3) is found to be associated with breast cancer-specific death at a genome-wide significant level (n=2,641, 440 events, combined allelic hazard ratio (HR)=1.81 (1.49-2.19); P for trend=1.90 × 10(-9)). Such survival-associated variants can represent ideal targets for tailored therapeutics, and may also enhance our current prognostic prediction capabilities

Rare and low-frequency coding variants alter human adult height

Height is a highly heritable, classic polygenic trait with ~700 common associated variants identified so far through genome - wide association studies . Here , we report 83 height - associated coding variants with lower minor allele frequenc ies ( range of 0.1 - 4.8% ) and effects of up to 2 16 cm /allele ( e.g. in IHH , STC2 , AR and CRISPLD2 ) , >10 times the average effect of common variants . In functional follow - up studies, rare height - increasing alleles of STC2 (+1 - 2 cm/allele) compromise d proteolytic inhibition of PAPP - A and increased cleavage of IGFBP - 4 in vitro , resulting in higher bioavailability of insulin - like growth factors . The se 83 height - associated variants overlap genes mutated in monogenic growth disorders and highlight new biological candidates ( e.g. ADAMTS3, IL11RA, NOX4 ) and pathways ( e.g . proteoglycan/ glycosaminoglycan synthesis ) involved in growth . Our results demonstrate that sufficiently large sample sizes can uncover rare and low - frequency variants of moderate to large effect associated with polygenic human phenotypes , and that these variants implicate relevant genes and pathways