Identification of potential mediators of the relationship between body mass index and colorectal cancer: a Mendelian randomization analysis.

BACKGROUND: Colorectal cancer (CRC) is the third-most-common cancer worldwide and its rates are increasing. Elevated body mass index (BMI) is an established risk factor for CRC, although the molecular mechanisms behind this association remain unclear. Using the Mendelian randomization (MR) framework, we aimed to investigate the mediating effects of putative biomarkers and other CRC risk factors in the association between BMI and CRC. METHODS: We selected as mediators biomarkers of established cancer-related mechanisms and other CRC risk factors for which a plausible association with obesity exists, such as inflammatory biomarkers, glucose homeostasis traits, lipids, adipokines, insulin-like growth factor 1 (IGF1), sex hormones, 25-hydroxy-vitamin D, smoking, physical activity (PA) and alcohol consumption. We used inverse-variance weighted MR in the main univariable analyses and performed sensitivity analyses (weighted-median, MR-Egger, Contamination Mixture). We used multivariable MR for the mediation analyses. RESULTS: Genetically predicted BMI was positively associated with CRC risk [odds ratio per SD (5 kg/m2) = 1.17, 95% CI: 1.08-1.24, P-value = 1.4 × 10-5] and robustly associated with nearly all potential mediators. Genetically predicted IGF1, fasting insulin, low-density lipoprotein cholesterol, smoking, PA and alcohol were associated with CRC risk. Evidence for attenuation was found for IGF1 [explained 7% (95% CI: 2-13%) of the association], smoking (31%, 4-57%) and PA (7%, 2-11%). There was little evidence for pleiotropy, although smoking was bidirectionally associated with BMI and instruments were weak for PA. CONCLUSIONS: The effect of BMI on CRC risk is possibly partly mediated through plasma IGF1, whereas the attenuation of the BMI-CRC association by smoking and PA may reflect confounding and shared underlying mechanisms rather than mediation.

Ready, Set, Go: Setting Off on the Mission to Target KRAS in Colorectal Cancer.

Understanding the landscape of KRAS mutations in #CRC is crucial with over 2.8M annual diagnoses worldwide. Explore promising therapies and ongoing challenges in this comprehensive review. #CancerResearch #KRAS #ColorectalCancer.

Genome-wide interaction study of dietary intake of fibre, fruits, and vegetables with risk of colorectal cancer.

BACKGROUND: Consumption of fibre, fruits and vegetables have been linked with lower colorectal cancer (CRC) risk. A genome-wide gene-environment (G × E) analysis was performed to test whether genetic variants modify these associations. METHODS: A pooled sample of 45 studies including up to 69,734 participants (cases: 29,896; controls: 39,838) of European ancestry were included. To identify G × E interactions, we used the traditional 1--degree-of-freedom (DF) G × E test and to improve power a 2-step procedure and a 3DF joint test that investigates the association between a genetic variant and dietary exposure, CRC risk and G × E interaction simultaneously. FINDINGS: The 3-DF joint test revealed two significant loci with p-value <5 × 10-8. Rs4730274 close to the SLC26A3 gene showed an association with fibre (p-value: 2.4 × 10-3) and G × fibre interaction with CRC (OR per quartile of fibre increase = 0.87, 0.80, and 0.75 for CC, TC, and TT genotype, respectively; G × E p-value: 1.8 × 10-7). Rs1620977 in the NEGR1 gene showed an association with fruit intake (p-value: 1.0 × 10-8) and G × fruit interaction with CRC (OR per quartile of fruit increase = 0.75, 0.65, and 0.56 for AA, AG, and GG genotype, respectively; G × E -p-value: 0.029). INTERPRETATION: We identified 2 loci associated with fibre and fruit intake that also modify the association of these dietary factors with CRC risk. Potential mechanisms include chronic inflammatory intestinal disorders, and gut function. However, further studies are needed for mechanistic validation and replication of findings. FUNDING: National Institutes of Health, National Cancer Institute. Full funding details for the individual consortia are provided in acknowledgments.

Efficacy and Safety of Atezolizumab and Bevacizumab in Appendiceal Adenocarcinoma.

PURPOSE: Appendiceal adenocarcinoma (AA) remains an orphan disease with limited treatment options for patients unable to undergo surgical resection. Evidence supporting the efficacy of combined VEGF and PD-1 inhibition in other tumor types provided a compelling rationale for investigating this combination in AA, where immune checkpoint inhibitors have not been explored previously. EXPERIMENTAL DESIGN: We conducted a prospective, single-arm phase II study evaluating efficacy and safety of atezolizumab in conjunction with bevacizumab (Atezo+Bev) in advanced, unresectable AA. RESULTS: Patients treated with the Atezo+Bev combination had 100% disease control rate (1 partial response, 15 stable disease) with progression-free survival (PFS) of 18.3 months and overall survival not-yet-reached with median duration of follow-up of 40 months. These survival intervals were significantly longer relative to a clinically and molecularly matched synthetic control cohort treated with cytotoxic chemotherapy designed for colorectal cancer (PFS of 4.4 months, P = 0.041). CONCLUSIONS: In light of recent data demonstrating a lack of efficacy of 5-fluorouracil-based chemotherapy, Atezo+Bev is a promising treatment option for patients with low-grade unresectable AA; further study is warranted. SIGNIFICANCE: AA remains an orphan disease with limited systemic therapy options for patients who are not candidates for surgical resection. These data suggest activity from combined VEGF and PD-L1 inhibition that warrants further study.

Body size and risk of colorectal cancer molecular defined subtypes and pathways: Mendelian randomization analyses.

BACKGROUND: Obesity has been positively associated with most molecular subtypes of colorectal cancer (CRC); however, the magnitude and the causality of these associations is uncertain. METHODS: We used Mendelian randomization (MR) to examine potential causal relationships between body size traits (body mass index [BMI], waist circumference, and body fat percentage) with risks of Jass classification types and individual subtypes of CRC (microsatellite instability [MSI] status, CpG island methylator phenotype [CIMP] status, BRAF and KRAS mutations). Summary data on tumour markers were obtained from two genetic consortia (CCFR, GECCO). FINDINGS: A 1-standard deviation (SD:5.1 kg/m2) increment in BMI levels was found to increase risks of Jass type 1MSI-high,CIMP-high,BRAF-mutated,KRAS-wildtype (odds ratio [OR]: 2.14, 95% confidence interval [CI]: 1.46, 3.13; p-value = 9 × 10-5) and Jass type 2non-MSI-high,CIMP-high,BRAF-mutated,KRAS-wildtype CRC (OR: 2.20, 95% CI: 1.26, 3.86; p-value = 0.005). The magnitude of these associations was stronger compared with Jass type 4non-MSI-high,CIMP-low/negative,BRAF-wildtype,KRAS-wildtype CRC (p-differences: 0.03 and 0.04, respectively). A 1-SD (SD:13.4 cm) increment in waist circumference increased risk of Jass type 3non-MSI-high,CIMP-low/negative,BRAF-wildtype,KRAS-mutated (OR 1.73, 95% CI: 1.34, 2.25; p-value = 9 × 10-5) that was stronger compared with Jass type 4 CRC (p-difference: 0.03). A higher body fat percentage (SD:8.5%) increased risk of Jass type 1 CRC (OR: 2.59, 95% CI: 1.49, 4.48; p-value = 0.001), which was greater than Jass type 4 CRC (p-difference: 0.03). INTERPRETATION: Body size was more strongly linked to the serrated (Jass types 1 and 2) and alternate (Jass type 3) pathways of colorectal carcinogenesis in comparison to the traditional pathway (Jass type 4). FUNDING: Cancer Research UK, National Institute for Health Research, Medical Research Council, National Institutes of Health, National Cancer Institute, American Institute for Cancer Research, Brigham and Women's Hospital, Prevent Cancer Foundation, Victorian Cancer Agency, Swedish Research Council, Swedish Cancer Society, Region Västerbotten, Knut and Alice Wallenberg Foundation, Lion's Cancer Research Foundation, Insamlingsstiftelsen, Umeå University. Full funding details are provided in acknowledgements.

Targeting All BRAF Alterations: The (Re)-Search Continues.

VivekSubbiah & colleagues delve into the @ASCO #TAPURStudy, shedding light on the importance of targeting ALL #BRAFAlterations, beyond V600E. (Re)-search continues, urging us to push the boundaries and unlock new possibilities in #PrecisionMedicine. #CancerResearch #JCOPO.

Allometric versus traditional body-shape indices and risk of colorectal cancer: a Mendelian randomization analysis.

BACKGROUND: Traditional body-shape indices such as Waist Circumference (WC), Hip Circumference (HC), and Waist-to-Hip Ratio (WHR) are associated with colorectal cancer (CRC) risk, but are correlated with Body Mass Index (BMI), and adjustment for BMI introduces a strong correlation with height. Thus, new allometric indices have been developed, namely A Body Shape Index (ABSI), Hip Index (HI), and Waist-to-Hip Index (WHI), which are uncorrelated with weight and height; these have also been associated with CRC risk in observational studies, but information from Mendelian randomization (MR) studies is missing. METHODS: We used two-sample MR to examine potential causal cancer site- and sex-specific associations of the genetically-predicted allometric body-shape indices with CRC risk, and compared them with BMI-adjusted traditional body-shape indices, and BMI. Data were obtained from UK Biobank and the GIANT consortium, and from GECCO, CORECT and CCFR consortia. RESULTS: WHI was positively associated with CRC in men (OR per SD: 1.20, 95% CI: 1.03-1.39) and in women (1.15, 1.06-1.24), and similarly for colon and rectal cancer. ABSI was positively associated with colon and rectal cancer in men (1.27, 1.03-1.57; and 1.40, 1.10-1.77, respectively), and with colon cancer in women (1.20, 1.07-1.35). There was little evidence for association between HI and colon or rectal cancer. The BMI-adjusted WHR and HC showed similar associations to WHI and HI, whereas WC showed similar associations to ABSI only in women. CONCLUSIONS: This large MR study provides strong evidence for a potential causal positive association of the allometric indices ABSI and WHI with CRC in both sexes, thus establishing the association between abdominal fat and CRC without the limitations of the traditional waist size indices and independently of BMI. Among the BMI-adjusted traditional indices, WHR and HC provided equivalent associations with WHI and HI, while differences were observed between WC and ABSI.

Causal relationships between risk of venous thromboembolism and 18 cancers: a bidirectional Mendelian randomization analysis.

BACKGROUND: People with cancer experience high rates of venous thromboembolism (VTE). Risk of subsequent cancer is also increased in people experiencing their first VTE. The causal mechanisms underlying this association are not completely understood, and it is unknown whether VTE is itself a risk factor for cancer. METHODS: We used data from large genome-wide association study meta-analyses to perform bidirectional Mendelian randomization analyses to estimate causal associations between genetic liability to VTE and risk of 18 different cancers. RESULTS: We found no conclusive evidence that genetic liability to VTE was causally associated with an increased incidence of cancer, or vice versa. We observed an association between liability to VTE and pancreatic cancer risk [odds ratio for pancreatic cancer: 1.23 (95% confidence interval: 1.08-1.40) per log-odds increase in VTE risk, P = 0.002]. However, sensitivity analyses revealed this association was predominantly driven by a variant proxying non-O blood group, with inadequate evidence to suggest a causal relationship. CONCLUSIONS: These findings do not support the hypothesis that genetic liability to VTE is a cause of cancer. Existing observational epidemiological associations between VTE and cancer are therefore more likely to be driven by pathophysiological changes which occur in the setting of active cancer and anti-cancer treatments. Further work is required to explore and synthesize evidence for these mechanisms.

Causal relationships between risk of venous thromboembolism and 18 cancers: a bidirectional Mendelian randomisation analysis.

Background: People with cancer experience high rates of venous thromboembolism (VTE). Additionally, risk of subsequent cancer is increased in people experiencing their first VTE. The causal mechanisms underlying this association are not completely understood, and it is unknown whether VTE is itself a risk factor for cancer. Methods: We used data from large genome-wide association study meta-analyses to perform bi-directional Mendelian randomisation analyses to estimate causal associations between genetically-proxied lifetime risk of VTE and risk of 18 different cancers. Results: We found no conclusive evidence that genetically-proxied lifetime risk of VTE was causally associated with an increased incidence of cancer, or vice-versa. We observed an association between VTE and pancreatic cancer risk (odds ratio for pancreatic cancer 1.23 (95% confidence interval 1.08 - 1.40) per log-odds increase in risk of VTE, P = 0.002). However, sensitivity analyses revealed this association was predominantly driven by a variant proxying non-O blood group, with inadequate evidence from Mendelian randomisation to suggest a causal relationship. Conclusions: These findings do not support the hypothesis that genetically-proxied lifetime risk of VTE is a cause of cancer. Existing observational epidemiological associations between VTE and cancer are therefore more likely to be driven by pathophysiological changes which occur in the setting of active cancer and anti-cancer treatments. Further work is required to explore and synthesise evidence for these mechanisms.

Genetically proxied glucose-lowering drug target perturbation and risk of cancer: a Mendelian randomisation analysis.

AIMS/HYPOTHESIS: Epidemiological studies have generated conflicting findings on the relationship between glucose-lowering medication use and cancer risk. Naturally occurring variation in genes encoding glucose-lowering drug targets can be used to investigate the effect of their pharmacological perturbation on cancer risk. METHODS: We developed genetic instruments for three glucose-lowering drug targets (peroxisome proliferator activated receptor γ [PPARG]; sulfonylurea receptor 1 [ATP binding cassette subfamily C member 8 (ABCC8)]; glucagon-like peptide 1 receptor [GLP1R]) using summary genetic association data from a genome-wide association study of type 2 diabetes in 148,726 cases and 965,732 controls in the Million Veteran Program. Genetic instruments were constructed using cis-acting genome-wide significant (p<5×10-8) SNPs permitted to be in weak linkage disequilibrium (r2<0.20). Summary genetic association estimates for these SNPs were obtained from genome-wide association study (GWAS) consortia for the following cancers: breast (122,977 cases, 105,974 controls); colorectal (58,221 cases, 67,694 controls); prostate (79,148 cases, 61,106 controls); and overall (i.e. site-combined) cancer (27,483 cases, 372,016 controls). Inverse-variance weighted random-effects models adjusting for linkage disequilibrium were employed to estimate causal associations between genetically proxied drug target perturbation and cancer risk. Co-localisation analysis was employed to examine robustness of findings to violations of Mendelian randomisation (MR) assumptions. A Bonferroni correction was employed as a heuristic to define associations from MR analyses as 'strong' and 'weak' evidence. RESULTS: In MR analysis, genetically proxied PPARG perturbation was weakly associated with higher risk of prostate cancer (for PPARG perturbation equivalent to a 1 unit decrease in inverse rank normal transformed HbA1c: OR 1.75 [95% CI 1.07, 2.85], p=0.02). In histological subtype-stratified analyses, genetically proxied PPARG perturbation was weakly associated with lower risk of oestrogen receptor-positive breast cancer (OR 0.57 [95% CI 0.38, 0.85], p=6.45×10-3). In co-localisation analysis, however, there was little evidence of shared causal variants for type 2 diabetes liability and cancer endpoints in the PPARG locus, although these analyses were likely underpowered. There was little evidence to support associations between genetically proxied PPARG perturbation and colorectal or overall cancer risk or between genetically proxied ABCC8 or GLP1R perturbation with risk across cancer endpoints. CONCLUSIONS/INTERPRETATION: Our drug target MR analyses did not find consistent evidence to support an association of genetically proxied PPARG, ABCC8 or GLP1R perturbation with breast, colorectal, prostate or overall cancer risk. Further evaluation of these drug targets using alternative molecular epidemiological approaches may help to further corroborate the findings presented in this analysis. DATA AVAILABILITY: Summary genetic association data for select cancer endpoints were obtained from the public domain: breast cancer ( https://bcac.ccge.medschl.cam.ac.uk/bcacdata/ ); and overall prostate cancer ( http://practical.icr.ac.uk/blog/ ). Summary genetic association data for colorectal cancer can be accessed by contacting GECCO (kafdem at fredhutch.org). Summary genetic association data on advanced prostate cancer can be accessed by contacting PRACTICAL (practical at icr.ac.uk). Summary genetic association data on type 2 diabetes from Vujkovic et al (Nat Genet, 2020) can be accessed through dbGAP under accession number phs001672.v3.p1 (pha004945.1 refers to the European-specific summary statistics). UK Biobank data can be accessed by registering with UK Biobank and completing the registration form in the Access Management System (AMS) ( https://www.ukbiobank.ac.uk/enable-your-research/apply-for-access ).

Body mass index is negatively associated with telomere length: a collaborative cross-sectional meta-analysis of 87 observational studies.

Background: Even before the onset of age-related diseases, obesity might be a contributing factor to the cumulative burden of oxidative stress and chronic inflammation throughout the life course. Obesity may therefore contribute to accelerated shortening of telomeres. Consequently, obese persons are more likely to have shorter telomeres, but the association between body mass index (BMI) and leukocyte telomere length (TL) might differ across the life span and between ethnicities and sexes. Objective: A collaborative cross-sectional meta-analysis of observational studies was conducted to investigate the associations between BMI and TL across the life span. Design: Eighty-seven distinct study samples were included in the meta-analysis capturing data from 146,114 individuals. Study-specific age- and sex-adjusted regression coefficients were combined by using a random-effects model in which absolute [base pairs (bp)] and relative telomere to single-copy gene ratio (T/S ratio) TLs were regressed against BMI. Stratified analysis was performed by 3 age categories ("young": 18-60 y; "middle": 61-75 y; and "old": >75 y), sex, and ethnicity. Results: Each unit increase in BMI corresponded to a -3.99 bp (95% CI: -5.17, -2.81 bp) difference in TL in the total pooled sample; among young adults, each unit increase in BMI corresponded to a -7.67 bp (95% CI: -10.03, -5.31 bp) difference. Each unit increase in BMI corresponded to a -1.58 × 10(-3) unit T/S ratio (0.16% decrease; 95% CI: -2.14 × 10(-3), -1.01 × 10(-3)) difference in age- and sex-adjusted relative TL in the total pooled sample; among young adults, each unit increase in BMI corresponded to a -2.58 × 10(-3) unit T/S ratio (0.26% decrease; 95% CI: -3.92 × 10(-3), -1.25 × 10(-3)). The associations were predominantly for the white pooled population. No sex differences were observed. Conclusions: A higher BMI is associated with shorter telomeres, especially in younger individuals. The presently observed difference is not negligible. Meta-analyses of longitudinal studies evaluating change in body weight alongside change in TL are warranted.

The TGFß-signaling pathway and colorectal cancer: associations between dysregulated genes and miRNAs.

BACKGROUND: The TGFß-signaling pathway plays an important role in the pathogenesis of colorectal cancer (CRC). Loss of function of several genes within this pathway, such as bone morphogenetic proteins (BMPs) have been seen as key events in CRC progression. METHODS: In this study we comprehensively evaluate differential gene expression (RNASeq) of 81 genes in the TGFß-signaling pathway and evaluate how dysregulated genes are associated with miRNA expression (Agilent Human miRNA Microarray V19.0). We utilize paired carcinoma and normal tissue from 217 CRC cases. We evaluate the associations between differentially expressed genes and miRNAs and sex, age, disease stage, and survival months. RESULTS: Thirteen genes were significantly downregulated and 14 were significantly upregulated after considering fold change (FC) of > 1.50 or < 0.67 and multiple comparison adjustment. Bone morphogenetic protein genes BMP5, BMP6, and BMP2 and growth differentiation factor GDF7 were downregulated. BMP4, BMP7, INHBA (Inhibin beta A), TGFBR1, TGFB2, TGIF1, TGIF2, and TFDP1 were upregulated. In general, genes with the greatest dysregulation, such as BMP5 (FC 0.17, BMP6 (FC 0.25), BMP2 (FC 0.32), CDKN2B (FC 0.32), MYC (FC 3.70), BMP7 (FC 4.17), and INHBA (FC 9.34) showed dysregulation in the majority of the population (84.3, 77.4, 81.1, 80.2, 82.0, 51.2, and 75.1% respectively). Four genes, TGFBR2, ID4, ID1, and PITX2, were un-associated or slightly upregulated in microsatellite-stable (MSS) tumors while downregulated in microsatellite-unstable (MSI) tumors. Eight dysregulated genes were associated with miRNA differential expression. E2F5 and THBS1 were associated with one or two miRNAs; RBL1, TGFBR1, TGIF2, and INHBA were associated with seven or more miRNAs with multiple seed-region matches. Evaluation of the joint effects of mRNA:miRNA identified interactions that were stronger in more advanced disease stages and varied by survival months. CONCLUSION: These data support an interaction between miRNAs and genes in the TGFß-signaling pathway in association with CRC risk. These interactions are associated with unique clinical characteristics that may provide targets for further investigations.

Infrequently expressed miRNAs in colorectal cancer tissue and tumor molecular phenotype.

This corrects the article DOI: 10.1038/modpathol.2017.38.

Infrequently expressed miRNAs influence survival after diagnosis with colorectal cancer.

Half of miRNAs expressed in colorectal tissue are expressed < 50% of the population. Many infrequently expressed miRNAs have low levels of expression. We hypothesize that less frequently expressed miRNAs, when expressed at higher levels, influence both disease stage and survival after diagnosis with colorectal cancer (CRC); low levels of expression may be background noise. We examine 304 infrequently expressed miRNAs in 1893 population-based cases of CRC with paired carcinoma and normal mucosa miRNA profiles. We evaluate miRNAs with disease stage and survival after adjusting for age, study center, sex, MSI status, and AJCC stage. These miRNAs were further evaluated with RNA-Seq data to identify miRNA::mRNA associations that may provide insight into the functionality of miRNAs. Eleven miRNAs were associated with advanced disease stage among colon cancer patients (Q value = 0.10). Eight infrequently expressed miRNAs influenced survival if highly expressed in overall CRC. Of these, five increased likelihood of dying if they were highly expressed, i.e. miR-124-3p, miR-143-5p, miR-145-3p, miR31-5p, and miR-99b-5p, while three were associated with better survival if highly expressed, i.e. miR-362-5p, miR-374a-5p, and miR-590-5p. Thirteen miRNAs infrequently expressed in colon-specific carcinoma tissue were associated with CRC survival if highly expressed. Evaluation of miRNAs::mRNA associations showed that mRNA expression influenced by infrequently expressed miRNA contributed to networks and pathways shown to influence disease progression and prognosis. Our large study enabled us to examine the implications of infrequently expressed miRNAs after removal of background noise. These results require replication in other studies. Confirmation of our findings in other studies could lead to important markers for prognosis.

Infrequently expressed miRNAs in colorectal cancer tissue and tumor molecular phenotype.

We have previously shown that commonly expressed miRNAs influenced tumor molecular phenotype in colorectal cancer. We hypothesize that infrequently expressed miRNAs, when showing higher levels of expression, help to define tumor molecular phenotype. In this study, we examine 304 miRNAs expressed in at least 30 individuals, but in <50% of the population and with a mean level of expression above 1.0 relative florescent unit. We examine associations in 1893 individuals who have the tumor molecular phenotype data as well as miRNA expression levels for both carcinoma and normal colorectal tissue. We compare miRNAs uniquely associated with tumor molecular phenotype to the RNAseq data to identify genes associated with these miRNAs. This information is used to further identify unique pathways associated with tumor molecular phenotypes of TP53-mutated, KRAS-mutated, CpG island methylator phenotype and microsatellite instability tumors. Thirty-seven miRNAs were uniquely associated with TP53-mutated tumors; 30 of these miRNAs had higher level of expression in TP53-mutated tumors, while seven had lower levels of expression. Of the 34 miRNAs associated with CpG island methylator phenotype-high tumors, 16 were more likely to have a CpG island methylator phenotype-high tumor and 19 were less likely to be CpG island methylator phenotype-high. For microsatellite instability, 13 of the 22 infrequently expressed miRNAs were significantly less likely to be expressed in microsatellite unstable tumors. KRAS-mutated tumors were not associated with any miRNAs after adjustment for multiple comparisons. Of the dysregulated miRNAs, 17 were more likely to be TP53-mutated tumors while simultaneously being less likely to be CpG island methylator phenotype-high and/or microsatellite instability tumors. Genes regulated by these miRNAs were involved in numerous functions and pathways that influence cancer risk and progression. In summary, some infrequently expressed miRNAs, when expressed at higher levels, appear to have significant biological meaning in terms of tumor molecular phenotype and gene expression profiles.

Genetic variants in the TGFß-signaling pathway influence expression of miRNAs in colon and rectal normal mucosa and tumor tissue.

The TGF-ß signaling pathway is involved in regulation of cell growth, angiogenesis, and metastasis. We test the hypothesis that genetic variation in the TGF-ß signaling pathway alters miRNA expression.We use data from 1188 colorectal cancer cases to evaluate associations between 80 SNPs in 21 genes.Seven variants eIF4E rs12498533, NFκB1 rs230510, TGFB1 rs4803455, TGFBR1 rs1571590 and rs6478974, SMAD3 rs3743343, and RUNX1 rs8134179 were associated with expression level of miRNAs in normal colorectal mucosa. RUNX2 rs12333172 and BMPR1B rs13134042 were associated with miRNAs in normal colon mucosa; eIF4EBP3 rs250425, SMAD3 rs12904944, SMAD7 rs3736242, and PTEN rs532678 were associated with miRNA expression in normal rectal mucosa. Evaluation of the differential expression between carcinoma and normal mucosa showed that SMAD3 rs12708491 and rs2414937, NFκB1 rs230510 and rs3821958, and RUNX3 rs6672420 were associated with several miRNAs for colorectal carcinoma. Evaluation of site-specific differential miRNA expression showed that BMPR1B rs2120834, BMPR2 rs2228545, and eIF4EBP3 rs250425 were associated with differential miRNA expression in colon tissue and SMAD3 rs12901071, rs1498506, and rs2414937, BMPR2 rs2228545, and RUNX2 rs2819854, altered differential miRNA expression in rectal tissue.These data support the importance of the TGF-ß signaling pathway to the carcinogenic process, possibly through their influence on miRNA expression levels.

Telomere Length, TERT, and miRNA Expression.

It has been proposed that miRNAs are involved in the control of telomeres. We test that hypothesis by examining the association between miRNAs and telomere length (TL). Additionally, we evaluate if genetic variation in telomerase reverse transcriptase (TERT) is associated with miRNA expression levels. We use data from a population-based study of colorectal cancer (CRC), where we have previously shown associations between TL and TERT and CRC, to test associations between TL and miRNA expression and TERT and miRNA expression. To gain insight into functions of miRNAs associated with TERT we tested linear associations between miRNAs and their targeted gene mRNAs. An Agilent platform that contained information on over 2000 miRNAs was used. TL was measured using a multiplexed quantitative PCR (qPCR). RNAseq was used to assess gene expression. Our sample consisted of 1152 individuals with SNP data and miRNA expression data; 363 individuals with both TL and miRNA; and 148 individuals with miRNA and mRNA data. Thirty-three miRNAs were directly associated with TL after adjusting for age and sex (false discovery rate (FDR) of 0.05). TERT rs2736118 was associated with differences in miRNA expression between carcinoma and normal colonic mucosa for 75 miRNAs (FDR <0.05). Genes regulated by these miRNAs, as indicated by mRNA/miRNA associations, were associated with major signaling pathways beyond their TL-related functions, including PTEN, and PI3K/AKT signaling. Our data support a direct association between miRNAs and TL; differences in miRNA expression levels by TERT genotype were observed. Based on miRNA and targeted mRNA associations our data suggest that TERT is involved in non-TL-related functions by acting through altered miRNA expression.

Dietary intake alters gene expression in colon tissue: possible underlying mechanism for the influence of diet on disease.

BACKGROUND: Although the association between diet and disease is well documented, the biologic mechanisms involved have not been entirely elucidated. In this study, we evaluate how dietary intake influences gene expression to better understand the underlying mechanisms through which diet operates. METHODS: We used data from 144 individuals who had comprehensive dietary intake and gene expression data from RNAseq using normal colonic mucosa. Using the DESeq2 statistical package, we identified genes that showed statistically significant differences in expression between individuals in high-intake and low-intake categories for several dietary variables of interest adjusting for age and sex. We examined total calories, total fats, vegetable protein, animal protein, carbohydrates, trans-fatty acids, mutagen index, red meat, processed meat, whole grains, vegetables, fruits, fiber, folate, dairy products, calcium, and prudent and western dietary patterns. RESULTS: Using a false discovery rate of less than 0.1, meat-related foods were statistically associated with 68 dysregulated genes, calcium with three dysregulated genes, folate with four dysregulated genes, and nonmeat-related foods with 65 dysregulated genes. With a more stringent false discovery rate of less than 0.05, there were nine meat-related dysregulated genes and 23 nonmeat-related genes. Ingenuity pathway analysis identified three major networks among genes identified as dysregulated with respect to meat-related dietary variables and three networks among genes identified as dysregulated with respect to nonmeat-related variables. The top networks (Ingenuity Pathway Analysis network score >30) associated with meat-related genes were (i) cancer, organismal injury, and abnormalities, tumor morphology, and (ii) cellular function and maintenance, cellular movement, cell death, and survival. Among genes related to nonmeat consumption variables, the top networks were (i) hematological system development and function, nervous system development and function, tissue morphology and (ii) connective tissue disorders, organismal injury, and abnormalities. CONCLUSION: Several dietary factors were associated with gene expression in our data. These findings provide insight into the possible mechanisms by which diet may influence disease processes.

Energy homeostasis genes and survival after breast cancer diagnosis: the Breast Cancer Health Disparities Study.

PURPOSE: The leptin-signaling pathway and other genes involved in energy homeostasis (EH) have been examined in relation to breast cancer risk as well as to obesity. We test the hypothesis that genetic variation in EH genes influences survival after diagnosis with breast cancer and that body mass index (BMI) will modify that risk. METHODS: We evaluated associations between 10 EH genes and survival among 1,186 non-Hispanic white and 1,155 Hispanic/Native American women diagnosed with breast cancer. Percent Native American (NA) ancestry was determined from 104 ancestry-informative markers. Adaptive rank truncation product (ARTP) was used to determine gene and pathway significance. RESULTS: The overall EH pathway was marginally significant for all-cause mortality among women with low NA ancestry (P(ARTP) = 0.057). Within the pathway, ghrelin(GHRL) and leptin receptor (LEPR) were significantly associated with all-cause mortality (P(ARTP) = 0.035 and 0.007, respectively). The EH pathway was significantly associated with breast cancer-specific mortality among women with low NA ancestry (P(ARTP) = 0.038). Three genes cholecystokinin (CCK), GHRL, and LEPR were significantly associated with breast cancer-specific mortality among women with low NA ancestry (P(ARTP) = 0.046,0.015, and 0.046, respectively), while neuropeptide Y (NPY) was significantly associated with breast cancer-specific mortality among women with higher NA ancestry(P(ARTP) = 0.038). BMI did not modify these associations. CONCLUSIONS: Our data support our hypothesis that certain EH genes influence survival after diagnosis with breast cancer; associations appear to be most important among women with low NA ancestry.

SEPP1 influences breast cancer risk among women with greater native american ancestry: the breast cancer health disparities study.

Selenoproteins are a class of proteins containing a selenocysteine residue, many of which have been shown to have redox functions, acting as antioxidants to decrease oxidative stress. Selenoproteins have previously been associated with risk of various cancers and redox-related diseases. In this study we evaluated possible associations between breast cancer risk and survival and single nucleotide polymorphisms (SNPs) in the selenoprotein genes GPX1, GPX2, GPX3, GPX4, SELS, SEP15, SEPN1, SEPP1, SEPW1, TXNRD1, and TXNRD2 among Hispanic/Native American (2111 cases, 2597 controls) and non-Hispanic white (NHW) (1481 cases, 1586 controls) women in the Breast Cancer Health Disparities Study. Adaptive Rank Truncated Product (ARTP) analysis was used to determine both gene and pathway significance with these genes. The overall selenoprotein pathway PARTP was not significantly associated with breast cancer risk (PARTP = 0.69), and only one gene, GPX3, was of borderline significance for the overall population (PARTP =0.09) and marginally significant among women with 0-28% Native American (NA) ancestry (PARTP=0.06). The SEPP1 gene was statistically significantly associated with breast cancer risk among women with higher NA ancestry (PARTP=0.002) and contributed to a significant pathway among those women (PARTP=0.04). GPX1, GPX3, and SELS were associated with Estrogen Receptor-/Progesterone Receptor+ status (PARTP = 0.002, 0.05, and 0.01, respectively). Four SNPs (GPX3 rs2070593, rsGPX4 rs2074451, SELS rs9874, and TXNRD1 rs17202060) significantly interacted with dietary oxidative balance score after adjustment for multiple comparisons to alter breast cancer risk. GPX4 was significantly associated with breast cancer survival among those with the highest NA ancestry (PARTP = 0.05) only. Our data suggest that SEPP1 alters breast cancer risk among women with higher levels of NA ancestry.