Martin, Lynn

Abstract Blood lipids have been associated with the development of a range of cancers, including breast, lung and colorectal cancer. For endometrial cancer, observational studies have reported inconsistent associations between blood lipids and cancer risk. To reduce biases from unmeasured confounding, we performed a bidirectional, two‐sample Mendelian randomization analysis to investigate the relationship between levels of three blood lipids (low‐density lipoprotein [LDL] and high‐density lipoprotein [HDL] cholesterol, and triglycerides) and endometrial cancer risk. Genetic variants associated with each of these blood lipid levels ( P < 5 × 10 −8 ) were identified as instrumental variables, and assessed using genome‐wide association study data from the Endometrial Cancer Association Consortium (12 906 cases and 108 979 controls) and the Global Lipids Genetic Consortium (n = 188 578). Mendelian randomization analyses found genetically raised LDL cholesterol levels to be associated with lower risks of endometrial cancer of all histologies combined, and of endometrioid and non‐endometrioid subtypes. Conversely, higher genetically predicted HDL cholesterol levels were associated with increased risk of non‐endometrioid endometrial cancer. After accounting for the potential confounding role of obesity (as measured by genetic variants associated with body mass index), the association between genetically predicted increased LDL cholesterol levels and lower endometrial cancer risk remained significant, especially for non‐endometrioid endometrial cancer. There was no evidence to support a role for triglycerides in endometrial cancer development. Our study supports a role for LDL and HDL cholesterol in the development of non‐endometrioid endometrial cancer. Further studies are required to understand the mechanisms underlying these findings.

Abstract Pathogenic sequence variants (PSV) in BRCA1 or BRCA2 (BRCA1/2) are associated with increased risk and severity of prostate cancer. We evaluated whether PSVs in BRCA1/2 were associated with risk of overall prostate cancer or high grade (Gleason 8+) prostate cancer using an international sample of 65 BRCA1 and 171 BRCA2 male PSV carriers with prostate cancer, and 3,388 BRCA1 and 2,880 BRCA2 male PSV carriers without prostate cancer. PSVs in the 3′ region of BRCA2 (c.7914+) were significantly associated with elevated risk of prostate cancer compared with reference bin c.1001-c.7913 [HR = 1.78; 95% confidence interval (CI), 1.25–2.52; P = 0.001], as well as elevated risk of Gleason 8+ prostate cancer (HR = 3.11; 95% CI, 1.63–5.95; P = 0.001). c.756-c.1000 was also associated with elevated prostate cancer risk (HR = 2.83; 95% CI, 1.71–4.68; P = 0.00004) and elevated risk of Gleason 8+ prostate cancer (HR = 4.95; 95% CI, 2.12–11.54; P = 0.0002). No genotype–phenotype associations were detected for PSVs in BRCA1. These results demonstrate that specific BRCA2 PSVs may be associated with elevated risk of developing aggressive prostate cancer. Significance: Aggressive prostate cancer risk in BRCA2 mutation carriers may vary according to the specific BRCA2 mutation inherited by the at-risk individual.

AbstractEpidemiological, biological, and molecular data suggest links between endometriosis and endometrial cancer, with recent epidemiological studies providing evidence for an association between a previous diagnosis of endometriosis and risk of endometrial cancer. We used genetic data as an alternative approach to investigate shared biological etiology of these two diseases. Genetic correlation analysis of summary level statistics from genomewide association studies (GWAS) using LD Score regression revealed moderate but significant genetic correlation (rg = 0.23, P = 9.3 × 10−3), and SNP effect concordance analysis provided evidence for significant SNP pleiotropy (P = 6.0 × 10−3) and concordance in effect direction (P = 2.0 × 10−3) between the two diseases. Cross‐disease GWAS meta‐analysis highlighted 13 distinct loci associated at P ≤ 10−5 with both endometriosis and endometrial cancer, with one locus (SNP rs2475335) located within PTPRD associated at a genomewide significant level (P = 4.9 × 10−8, OR = 1.11, 95% CI = 1.07–1.15). PTPRD acts in the STAT3 pathway, which has been implicated in both endometriosis and endometrial cancer. This study demonstrates the value of cross‐disease genetic analysis to support epidemiological observations and to identify biological pathways of relevance to multiple diseases.

While elevated blood cholesterol has been associated with an increased risk of colorectal cancer (CRC) in observational studies, causality is uncertain. Here we apply a Mendelian randomisation (MR) analysis to examine the potential causal relationship between lipid traits and CRC risk. We used single nucleotide polymorphisms (SNPs) associated with blood levels of total cholesterol (TC), triglyceride (TG), low‐density lipoprotein (LDL), and high‐density lipoprotein (HDL) as instrumental variables (IV). We calculated MR estimates for each risk factor with CRC using SNP‐CRC associations from 9,254 cases and 18,386 controls. Genetically predicted higher TC was associated with an elevated risk of CRC (odds ratios (OR) per unit SD increase = 1.46, 95% confidence interval [CI]: 1.20–1.79, p = 1.68 × 10−4). The pooled ORs for LDL, HDL, and TG were 1.05 (95% CI: 0.92–1.18, p = 0.49), 0.94 (95% CI: 0.84–1.05, p = 0.27), and 0.98 (95% CI: 0.85–1.12, p = 0.75) respectively. A genetic risk score for 3‐hydoxy‐3‐methylglutaryl‐coenzyme A reductase (HMGCR) to mimic the effects of statin therapy was associated with a reduced CRC risk (OR = 0.69, 95% CI: 0.49–0.99, p = 0.046). This study supports a causal relationship between higher levels of TC with CRC risk, and a further rationale for implementing public health strategies to reduce the prevalence of hyperlipidaemia.

Abstract Background: The strongest known risk factor for endometrial cancer is obesity. To determine whether SNPs associated with increased body mass index (BMI) or waist–hip ratio (WHR) are associated with endometrial cancer risk, independent of measured BMI, we investigated relationships between 77 BMI and 47 WHR SNPs and endometrial cancer in 6,609 cases and 37,926 country-matched controls. Methods: Logistic regression analysis and fixed effects meta-analysis were used to test for associations between endometrial cancer risk and (i) individual BMI or WHR SNPs, (ii) a combined weighted genetic risk score (wGRS) for BMI or WHR. Causality of BMI for endometrial cancer was assessed using Mendelian randomization, with BMIwGRS as instrumental variable. Results: The BMIwGRS was significantly associated with endometrial cancer risk (P = 3.4 × 10−17). Scaling the effect of the BMIwGRS on endometrial cancer risk by its effect on BMI, the endometrial cancer OR per 5 kg/m2 of genetically predicted BMI was 2.06 [95% confidence interval (CI), 1.89–2.21], larger than the observed effect of BMI on endometrial cancer risk (OR = 1.55; 95% CI, 1.44–1.68, per 5 kg/m2). The association attenuated but remained significant after adjusting for BMI (OR = 1.22; 95% CI, 1.10–1.39; P = 5.3 × 10−4). There was evidence of directional pleiotropy (P = 1.5 × 10−4). BMI SNP rs2075650 was associated with endometrial cancer at study-wide significance (P &lt; 4.0 × 10−4), independent of BMI. Endometrial cancer was not significantly associated with individual WHR SNPs or the WHRwGRS. Conclusions: BMI, but not WHR, is causally associated with endometrial cancer risk, with evidence that some BMI-associated SNPs alter endometrial cancer risk via mechanisms other than measurable BMI. Impact: The causal association between BMI SNPs and endometrial cancer has possible implications for endometrial cancer risk modeling. Cancer Epidemiol Biomarkers Prev; 25(11); 1503–10. ©2016 AACR.