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BackgroundEwing sarcoma (EwS) is a rare, aggressive solid tumor of childhood, adolescence and young adulthood associated with pathognomonic EWSR1-ETS fusion oncoproteins altering transcriptional regulation. Genome-wide association studies (GWAS) have identified 6 common germline susceptibility loci but have not investigated low-frequency inherited variants with minor allele frequencies below 5% due to limited genotyped cases of this rare tumor.MethodsWe investigated the contribution of rare and low-frequency variation to EwS susceptibility in the largest EwS genome-wide association study to date (733 EwS cases and 1,346 unaffected controls of European ancestry).ResultsWe identified two low-frequency variants, rs112837127 and rs2296730, on chromosome 20 that were associated with EwS risk (OR = 0.186 and 2.038, respectively; P-value < 5×10-8) and located near previously reported common susceptibility loci. After adjusting for the most associated common variant at the locus, only rs112837127 remained a statistically significant independent signal (OR = 0.200, P-value = 5.84×10-8).ConclusionsThese findings suggest rare variation residing on common haplotypes are important contributors to EwS risk.ImpactMotivate future targeted sequencing studies for a comprehensive evaluation of low-frequency and rare variation around common EwS susceptibility loci.

Approximately 15-30% of all breast cancer tumors are estrogen receptor negative (ER-). Compared with ER-positive (ER+) disease they have an earlier age at onset and worse prognosis. Despite the vast number of risk variants identified for numerous cancer types, only seven loci have been unambiguously identified for ER-negative breast cancer. With the aim of identifying new susceptibility SNPs for this disease we performed a pleiotropic genome-wide association study (GWAS). We selected 3079 SNPs associated with a human complex trait or disease at genome-wide significance level (P

The immune system is likely to play a key role in the etiology of gliomas. Genetic polymorphisms in the mannose-binding lectin gene, a key activator in the lectin complement pathway, have been associated with risk of several cancers.To examine the role of the lectin complement pathway, we combined data from prospectively collected cohorts with available DNA specimens. Using a nested case-control design, we genotyped 85 single nucleotide polymorphisms (SNPs) in 9 genes in the lectin complement pathway and 3 additional SNPs in MBL2 were tested post hoc). Initial SNPs were selected using tagging SNPs for haplotypes; the second group of SNPs for MBL2 was selected based on functional SNPs related to phenotype. Associations were examined using logistic regression analysis. All statistical tests were two-sided. Nominal p-values are presented and are not corrected for multiple comparisons.A total of 143 glioma cases and 419 controls were available for this analysis. Statistically significant associations were observed for two SNPs in the mannose-binding lectin 2 (ML2) gene and risk of glioma (rs1982266 and rs1800450, test for trend p = 0.003 and p = 0.04, respectively, using the additive model). One of these SNPs, rs1800450, was associated with a 58% increase in glioma risk among those carrying one or two mutated alleles (odds ratio = 1.58, 95% confidence interval = 0.99-2.54), compared to those homozygous for the wild type allele.Overall, our findings suggest that MBL may play a role in the etiology of glioma. Future studies are needed to confirm these findings which may be due to chance, and if reproduced, to determine mechanisms that link glioma pathogenesis with the MBL complement pathway.

Genome-wide association studies (GWAS) have successfully identified common genetic variants that contribute to breast cancer risk. Discovering additional variants has become difficult, as power to detect variants of weaker effect with present sample sizes is limited. An alternative approach is to look for variants associated with quantitative traits that in turn affect disease risk. As exposure to high circulating estradiol and testosterone, and low sex hormone-binding globulin (SHBG) levels is implicated in breast cancer etiology, we conducted GWAS analyses of plasma estradiol, testosterone, and SHBG to identify new susceptibility alleles. Cancer Genetic Markers of Susceptibility (CGEMS) data from the Nurses' Health Study (NHS), and Sisters in Breast Cancer Screening data were used to carry out primary meta-analyses among ~1600 postmenopausal women who were not taking postmenopausal hormones at blood draw. We observed a genome-wide significant association between SHBG levels and rs727428 (joint β = -0.126; joint P = 2.09 × 10(-16)), downstream of the SHBG gene. No genome-wide significant associations were observed with estradiol or testosterone levels. Among variants that were suggestively associated with estradiol (P

The mTOR (mammalian target of rapamycin) signal transduction pathway integrates various signals, regulating ribosome biogenesis and protein synthesis as a function of available energy and amino acids, and assuring an appropriate coupling of cellular proliferation with increases in cell size. In addition, recent evidence has pointed to an interplay between the mTOR and p53 pathways. We investigated the genetic variability of 67 key genes in the mTOR pathway and in genes of the p53 pathway which interact with mTOR. We tested the association of 1,084 tagging SNPs with prostate cancer risk in a study of 815 prostate cancer cases and 1,266 controls nested within the European Prospective Investigation into Cancer and Nutrition (EPIC). We chose the SNPs (n = 11) with the strongest association with risk (p

Polymorphisms in the mitochondrial genome are hypothesized to be associated with risk of various diseases, including cancer. However, there has been conflicting evidence for associations between a common polymorphism in the mitochondrial genome (A10398G, G10398A in some prior reports) and breast cancer risk. Reactive oxygen species, a by-product of mitochondrial energy production, can lead to oxidative stress and DNA damage in both the mitochondria and their cells. Alcohol consumption, which may also lead to oxidative stress, is associated with breast cancer risk. Therefore, we hypothesized that polymorphisms in the mitochondrial genome interact with alcohol consumption to alter breast cancer risk. We genotyped the A10398G polymorphism in a case-control study nested within the Nurses' Health Study (NHS, 1,561 cases, 2,209 controls). We observed an interaction between alcohol consumption (yes/no) and A10398G on breast cancer risk (p-int = 0.03). The risk associated with alcohol consumption was limited to carriers of the 10398G allele (Odds Ratio 1.52, 95% Confidence Interval 1.10-2.08 comparing drinkers to non-drinkers). However, we were unable to replicate these findings in the Women's Health Study (WHS, 678 cases, 669 controls), although the power to detect this interaction in the WHS was low (power = 0.57). Further examination of this interaction, such as sufficiently powered epidemiological studies of cancer risk or associations with biomarkers of oxidative stress, may provide further evidence for GxE interactions between the A10398G mitochondrial polymorphism and alcohol consumption on breast cancer risk.

IGF-1 has been shown to promote proliferation of normal epithelial breast cells, and the IGF pathway has also been linked to mammary carcinogenesis in animal models. We comprehensively examined the association between common genetic variation in the IGF1, IGFBP1, and IGFBP3 genes in relation to circulating IGF-I and IGFBP-3 levels and breast cancer risk within the NCI Breast and Prostate Cancer Cohort Consortium (BPC3). This analysis included 6,912 breast cancer cases and 8,891 matched controls (n = 6,410 for circulating IGF-I and 6,275 for circulating IGFBP-3 analyses) comprised primarily of Caucasian women drawn from six large cohorts. Linkage disequilibrium and haplotype patterns were characterized in the regions surrounding IGF1 and the genes coding for two of its binding proteins, IGFBP1 and IGFBP3. In total, thirty haplotype-tagging single nucleotide polymorphisms (htSNP) were selected to provide high coverage of common haplotypes; the haplotype structure was defined across four haplotype blocks for IGF1 and three for IGFBP1 and IGFBP3. Specific IGF1 SNPs individually accounted for up to 5% change in circulating IGF-I levels and individual IGFBP3 SNPs were associated up to 12% change in circulating IGFBP-3 levels, but no associations were observed between these polymorphisms and breast cancer risk. Logistic regression analyses found no associations between breast cancer and any htSNPs or haplotypes in IGF1, IGFBP1, or IGFBP3. No effect modification was observed in analyses stratified by menopausal status, family history of breast cancer, body mass index, or postmenopausal hormone therapy, or for analyses stratified by stage at diagnosis or hormone receptor status. In summary, the impact of genetic variation in IGF1 and IGFBP3 on circulating IGF levels does not appear to substantially influence breast cancer risk substantially among primarily Caucasian postmenopausal women.