Genetically Predicted Body Mass Index and Breast Cancer Risk: Mendelian Randomization Analyses of Data from 145,000 Women of European Descent.

Background: Observational epidemiological studies have shown that high body mass index (BMI) is associated with a reduced risk of breast cancer in premenopausal women but an increased risk in postmenopausal women. It is unclear whether this association is mediated through shared genetic or environmental factors.

Methods: We applied Mendelian randomization to evaluate the association between BMI and risk of breast cancer occurrence using data from two large breast cancer consortia.

Assessment of variation in immunosuppressive pathway genes reveals TGFBR2 to be associated with risk of clear cell ovarian cancer.

Background: Regulatory T (Treg) cells, a subset of CD4+ T lymphocytes, are mediators of immunosuppression in cancer, and, thus, variants in genes encoding Treg cell immune molecules could be associated with ovarian cancer.

Methods: In a population of 15,596 epithelial ovarian cancer (EOC) cases and 23,236 controls, we measured genetic associations of 1,351 SNPs in Treg cell pathway genes with odds of ovarian cancer and tested pathway and gene-level associations, overall and by histotype, for the 25 genes, using the admixture likelihood (AML) method. The most significant single SNP associations were tested for correlation with expression levels in 44 ovarian cancer patients.

Association of genetic susceptibility variants for type 2 diabetes with breast cancer risk in women of European ancestry.

Purpose: Type 2 diabetes (T2D) has been reported to be associated with an elevated risk of breast cancer. It is unclear, however, whether this association is due to shared genetic factors.

Methods: We constructed a genetic risk score (GRS) using risk variants from 33 known independent T2D susceptibility loci and evaluated its relation to breast cancer risk using the data from two consortia, including 62,328 breast cancer patients and 83,817 controls of European ancestry.

Breast cancer risk variants at 6q25 display different phenotype associations and regulate ESR1, RMND1 and CCDC170.

We analyzed 3,872 common genetic variants across the ESR1 locus (encoding estrogen receptor α) in 118,816 subjects from three international consortia. We found evidence for at least five independent causal variants, each associated with different phenotype sets, including estrogen receptor (ER(+) or ER(-)) and human ERBB2 (HER2(+) or HER2(-)) tumor subtypes, mammographic density and tumor grade. The best candidate causal variants for ER(-) tumors lie in four separate enhancer elements, and their risk alleles reduce expression of ESR1, RMND1 and CCDC170, whereas the risk alleles of the strongest candidates for the remaining independent causal variant disrupt a silencer element and putatively increase ESR1 and RMND1 expression.

Height and Breast Cancer Risk: Evidence From Prospective Studies and Mendelian Randomization.

Background: Epidemiological studies have linked adult height with breast cancer risk in women. However, the magnitude of the association, particularly by subtypes of breast cancer, has not been established. Furthermore, the mechanisms of the association remain unclear.

The SNP rs6500843 in 16p13.3 is associated with survival specifically among chemotherapy-treated breast cancer patients.

We have utilized a two-stage study design to search for SNPs associated with the survival of breast cancer patients treated with adjuvant chemotherapy. Our initial GWS data set consisted of 805 Finnish breast cancer cases (360 treated with adjuvant chemotherapy). The top 39 SNPs from this stage were analyzed in three independent data sets: iCOGS (n=6720 chemotherapy-treated cases), SUCCESS-A (n=3596), and POSH (n=518).

Genome-wide association analysis of more than 120,000 individuals identifies 15 new susceptibility loci for breast cancer.

Genome-wide association studies (GWAS) and large-scale replication studies have identified common variants in 79 loci associated with breast cancer, explaining ∼14% of the familial risk of the disease. To identify new susceptibility loci, we performed a meta-analysis of 11 GWAS, comprising 15,748 breast cancer cases and 18,084 controls together with 46,785 cases and 42,892 controls from 41 studies genotyped on a 211,155-marker custom array (iCOGS). Analyses were restricted to women of European ancestry.

Fine-mapping identifies two additional breast cancer susceptibility loci at 9q31.2.

We recently identified a novel susceptibility variant, rs865686, for estrogen-receptor positive breast cancer at 9q31.2. Here, we report a fine-mapping analysis of the 9q31.

Inherited variants in the inner centromere protein (INCENP) gene of the chromosomal passenger complex contribute to the susceptibility of ER-negative breast cancer.

The chromosomal passenger complex (CPC) plays a pivotal role in the regulation of cell division. Therefore, inherited CPC variability could influence tumor development. The present candidate gene approach investigates the relationship between single nucleotide polymorphisms (SNPs) in genes encoding key CPC components and breast cancer risk.

Identification and characterization of novel associations in the CASP8/ALS2CR12 region on chromosome 2 with breast cancer risk.

Previous studies have suggested that polymorphisms in CASP8 on chromosome 2 are associated with breast cancer risk. To clarify the role of CASP8 in breast cancer susceptibility, we carried out dense genotyping of this region in the Breast Cancer Association Consortium (BCAC). Single-nucleotide polymorphisms (SNPs) spanning a 1 Mb region around CASP8 were genotyped in 46 450 breast cancer cases and 42 600 controls of European origin from 41 studies participating in the BCAC as part of a custom genotyping array experiment (iCOGS).

ESR1/SYNE1 polymorphism and invasive epithelial ovarian cancer risk: an Ovarian Cancer Association Consortium study.

We genotyped 13 single nucleotide polymorphisms (SNPs) in the estrogen receptor alpha gene (ESR1) region in three population-based case-control studies of epithelial ovarian cancer conducted in the United States, comprising a total of 1,128 and 1,866 non-Hispanic white invasive cases and controls, respectively. A SNP 19 kb downstream of ESR1 (rs2295190, G-to-T change) was associated with invasive ovarian cancer risk, with a per-T-allele odds ratio (OR) of 1.24 [95% confidence interval (CI), 1.

Designing HIGH-COST medicine: hospital surveys, health planning, and the paradox of progressive reform.

Inspired by social medicine, some progressive US health reforms have paradoxically reinforced a business model of high-cost medical delivery that does not match social needs. In analyzing the financial status of their areas' hospitals, for example, city-wide hospital surveys of the 1910s through 1930s sought to direct capital investments and, in so doing, control competition and markets. The 2 national health planning programs that ran from the mid-1960s to the mid-1980s continued similar strategies of economic organization and management, as did the so-called market reforms that followed.

Common germline variation in mismatch repair genes and survival after a diagnosis of colorectal cancer.

The mismatch repair (MMR) genes are involved in the maintenance of genomic integrity. Recently, we showed that common variants in these genes are unlikely to contribute significantly to colorectal cancer risk. The aim of this study was to investigate the role of common variants in the mismatch repair pathway as prognostic markers in colorectal cancer patients.

Genetic variants in epigenetic genes and breast cancer risk.

Epigenetic events, resulting changes in gene expression capacity, are important in tumour progression, and variation in genes involved in epigenetic mechanisms might therefore be important in cancer susceptibility. To evaluate this hypothesis, we examined common variants in 12 genes coding for DNA methyltransferases (DNMT), histone acetyltransferases, histone deacetyltransferases, histone methyltrasferases and methyl-CpG binding domain proteins, for association with breast cancer in a large case-control study (N cases = 4474 and N controls = 4580). We identified 63 single nucleotide polymorphisms (SNPs) that efficiently tag all the known common variants in these genes, and are also expected to tag any unknown SNP in each gene.

IGF1 and IGFBP3 tagging polymorphisms are associated with circulating levels of IGF1, IGFBP3 and risk of breast cancer.

Experimental and observational studies in humans and animals suggest that insulin-like growth factor 1 (IGF1) and its principal binding protein, IGFBP3, may influence breast cancer susceptibility. We have examined the association of nine and four single nucleotide polymorphisms (SNPs) in the IGF1 gene and in the IGFBP3 genes, respectively, with circulating levels of their gene products in a population-based study of 600 middle-aged men and women, and in a breast cancer case-control study, comprised 4647 cases and 4564 controls. All study participants are from the East Anglian region of UK.