Insulin Resistance and Cancer-Specific and All-Cause Mortality in Postmenopausal Women: The Women\u27s Health Initiative

© The Author(s) 2019. Published by Oxford University Press. All rights reserved. For permissions, please email: [email protected]. BACKGROUND: Insulin resistance has been proposed as a mediator of the increased cancer incidence and mortality associated with obesity. However, prior studies included limited cancer deaths and had inconsistent findings. Therefore, we evaluated insulin resistance and cancer-specific and all-cause mortality in postmenopausal women participating in the Women\u27s Health Initiative (WHI). METHODS: Eligible were a subsample of 22 837 WHI participants aged 50-79 years enrolled at 40 US clinical centers from 1993 to 1998 who had baseline fasting glucose and insulin levels. Baseline insulin resistance was measured by the homeostasis model assessment of insulin resistance (HOMA-IR). Cancers were verified by central medical record review and deaths verified by medical record and death certificate review enhanced by National Death Index queries. Cox proportional hazards regression models were used to calculate adjusted hazard ratios (HRs) and 95% confidence intervals (CIs) for cancer-specific and all-cause mortality. All statistical tests were two-sided. RESULTS: During a median of 18.9 years of follow-up, 1820 cancer deaths and 7415 total deaths occurred. Higher HOMA-IR quartile was associated with higher cancer-specific mortality (Q4 vs Q1, HR = 1.26, 95% CI = 1.09 to 1.47; Ptrend = .003) and all-cause mortality (Q4 vs Q1, HR = 1.63, 95% CI = 1.51 to 1.76; Ptrend \u3c .001). A sensitivity analysis for diabetes status did not change findings. Among women with body mass index less than 25 kg/m2, higher HOMA-IR quartile was associated with higher cancer mortality (Fine and Gray, P = .004). CONCLUSIONS: High insulin resistance, as measured by HOMA-IR, identifies postmenopausal women at higher risk for cancer-specific and all-cause mortality who could potentially benefit from early intervention

A miRNA signature predicts benefit from addition of hypoxia-modifying therapy to radiation treatment in invasive bladder cancer

From Springer Nature via Jisc Publications RouterHistory: received 2020-09-03, rev-recd 2021-02-11, accepted 2021-02-19, registration 2021-02-19, pub-electronic 2021-04-12, online 2021-04-12, pub-print 2021-07-06Publication status: PublishedFunder: U.S. Department of Defense (United States Department of Defense); doi: https://doi.org/10.13039/100000005; Grant(s): W81XWH-17-1-0543Abstract: Background: miRNAs are promising biomarkers in oncology as their small size makes them less susceptible to degradation than mRNA in FFPE tissue. We aimed to derive a hypoxia-associated miRNA signature for bladder cancer. Methods: Taqman miRNA array cards identified miRNA seed genes induced under hypoxia in bladder cancer cell lines. A signature was derived using feature selection methods in a TCGA BLCA training data set. miRNA expression data were generated for 190 tumours from the BCON Phase 3 trial and used for independent validation. Results: A 14-miRNA hypoxia signature was derived, which was prognostic for poorer overall survival in the TCGA BLCA cohort (n = 403, p = 0.001). Univariable analysis showed that the miRNA signature predicted an overall survival benefit from having carbogen–nicotinamide with radiotherapy (HR = 0.30, 95% CI 0.094–0.95, p = 0.030) and performed similarly to a 24-gene mRNA signature (HR = 0.47, 95% CI 0.24–0.92, p = 0.025). Combining the signatures improved performance (HR = 0.26, 95% CI 0.08–0.82, p = 0.014) with borderline significance for an interaction test (p = 0.065). The interaction test was significant for local relapse-free survival LRFS (p = 0.033). Conclusion: A 14-miRNA hypoxia signature can be used with an mRNA hypoxia signature to identify bladder cancer patients benefitting most from having carbogen and nicotinamide with radiotherapy

Statin use and all-cancer survival: prospective results from the Women's Health Initiative

Background: This study aims to investigate the association between statin use and all-cancer survival in a prospective cohort of postmenopausal women, using data from the Women's Health Initiative Observational Study (WHI-OS) and Clinical Trial (WHI-CT). Methods: The WHI study enrolled women aged 50–79 years from 1993 to 1998 at 40 US clinical centres. Among 146 326 participants with median 14.6 follow-up years, 23 067 incident cancers and 3152 cancer deaths were observed. Multivariable-adjusted Cox proportional hazards models were used to investigate the relationship between statin use and cancer survival. Results: Compared with never-users, current statin use was associated with significantly lower risk of cancer death (hazard ratio (HR), 0.78; 95% confidence interval (CI), 0.71–0.86, P<0.001) and all-cause mortality (HR, 0.80; 95% CI, 0.74–0.88). Use of other lipid-lowering medications was also associated with increased cancer survival (P-interaction (int)=0.57). The lower risk of cancer death was not dependent on statin potency (P-int=0.22), lipophilicity/hydrophilicity (P-int=0.43), type (P-int=0.34) or duration (P-int=0.33). However, past statin users were not at lower risk of cancer death compared with never-users (HR, 1.06; 95% CI, 0.85–1.33); in addition, statin use was not associated with a reduction of overall cancer incidence despite its effect on survival (HR, 0.96; 95% CI, 0.92–1.001). Conclusions: In a cohort of postmenopausal women, regular use of statins or other lipid-lowering medications was associated with decreased cancer death, regardless of the type, duration, or potency of statin medications used

Dietary vitamin D and calcium intake and mammographic density in postmenopausal women

Dietary intake of vitamin D and calcium may be related to risk of breast cancer, possibly by affecting mammographic density. However, the few studies that have evaluated the association between these nutrients and mammographic density in postmenopausal women have had inconsistent results

Genetic Sharing with Cardiovascular Disease Risk Factors and Diabetes Reveals Novel Bone Mineral Density Loci.

Bone Mineral Density (BMD) is a highly heritable trait, but genome-wide association studies have identified few genetic risk factors. Epidemiological studies suggest associations between BMD and several traits and diseases, but the nature of the suggestive comorbidity is still unknown. We used a novel genetic pleiotropy-informed conditional False Discovery Rate (FDR) method to identify single nucleotide polymorphisms (SNPs) associated with BMD by leveraging cardiovascular disease (CVD) associated disorders and metabolic traits. By conditioning on SNPs associated with the CVD-related phenotypes, type 1 diabetes, type 2 diabetes, systolic blood pressure, diastolic blood pressure, high density lipoprotein, low density lipoprotein, triglycerides and waist hip ratio, we identified 65 novel independent BMD loci (26 with femoral neck BMD and 47 with lumbar spine BMD) at conditional FDR < 0.01. Many of the loci were confirmed in genetic expression studies. Genes validated at the mRNA levels were characteristic for the osteoblast/osteocyte lineage, Wnt signaling pathway and bone metabolism. The results provide new insight into genetic mechanisms of variability in BMD, and a better understanding of the genetic underpinnings of clinical comorbidity

Novel Common Genetic Susceptibility Loci for Colorectal Cancer

BACKGROUND: Previous genome-wide association studies (GWAS) have identified 42 loci (P < 5 × 10-8) associated with risk of colorectal cancer (CRC). Expanded consortium efforts facilitating the discovery of additional susceptibility loci may capture unexplained familial risk. METHODS: We conducted a GWAS in European descent CRC cases and control subjects using a discovery-replication design, followed by examination of novel findings in a multiethnic sample (cumulative n = 163 315). In the discovery stage (36 948 case subjects/30 864 control subjects), we identified genetic variants with a minor allele frequency of 1% or greater associated with risk of CRC using logistic regression followed by a fixed-effects inverse variance weighted meta-analysis. All novel independent variants reaching genome-wide statistical significance (two-sided P < 5 × 10-8) were tested for replication in separate European ancestry samples (12 952 case subjects/48 383 control subjects). Next, we examined the generalizability of discovered variants in East Asians, African Americans, and Hispanics (12 085 case subjects/22 083 control subjects). Finally, we examined the contributions of novel risk variants to familial relative risk and examined the prediction capabilities of a polygenic risk score. All statistical tests were two-sided. RESULTS: The discovery GWAS identified 11 variants associated with CRC at P < 5 × 10-8, of which nine (at 4q22.2/5p15.33/5p13.1/6p21.31/6p12.1/10q11.23/12q24.21/16q24.1/20q13.13) independently replicated at a P value of less than .05. Multiethnic follow-up supported the generalizability of discovery findings. These results demonstrated a 14.7% increase in familial relative risk explained by common risk alleles from 10.3% (95% confidence interval [CI] = 7.9% to 13.7%; known variants) to 11.9% (95% CI = 9.2% to 15.5%; known and novel variants). A polygenic risk score identified 4.3% of the population at an odds ratio for developing CRC of at least 2.0. CONCLUSIONS: This study provides insight into the architecture of common genetic variation contributing to CRC etiology and improves risk prediction for individualized screenin

New genetic loci link adipose and insulin biology to body fat distribution.

Body fat distribution is a heritable trait and a well-established predictor of adverse metabolic outcomes, independent of overall adiposity. To increase our understanding of the genetic basis of body fat distribution and its molecular links to cardiometabolic traits, here we conduct genome-wide association meta-analyses of traits related to waist and hip circumferences in up to 224,459 individuals. We identify 49 loci (33 new) associated with waist-to-hip ratio adjusted for body mass index (BMI), and an additional 19 loci newly associated with related waist and hip circumference measures (P < 5 × 10(-8)). In total, 20 of the 49 waist-to-hip ratio adjusted for BMI loci show significant sexual dimorphism, 19 of which display a stronger effect in women. The identified loci were enriched for genes expressed in adipose tissue and for putative regulatory elements in adipocytes. Pathway analyses implicated adipogenesis, angiogenesis, transcriptional regulation and insulin resistance as processes affecting fat distribution, providing insight into potential pathophysiological mechanisms