Family Registry Research Articles

A case-control genome wide association study of substance use disorder (SUD) identifies novel variants on chromosome 7p14.1 in patients from the United Arab Emirates (UAE).

Genome wide association studies (GWASs) have provided insights into the molecular basis of the disorder in different population. This study presents the first GWAS of substance use disorder (SUD) in patients from the United Arab Emirates (UAE). The aim was to identify genetic association(s) that may provide insights into the molecular basis of the disorder. The GWAS discovery cohort consisted of 512 (250 cases and 262 controls) male participants from the UAE. Controls with no prior history of SUD were available from the Emirates family registry. The replication cohort consisted of 520 (415 cases and 105 controls) Australian male Caucasian participants. The GWAS discovery samples were genotyped for 4.6 million single nucleotide polymorphism (SNP). The replication cohort was genotyped using TaqMan assay. The GWAS association analysis identified three potential SNPs rs118129027 (p-value = 6.24 × 10-8 ), rs74477937 (p-value = 8.56 × 10-8 ) and rs78707086 (p-value = 8.55 × 10-8 ) on ch7p14.1, that did not meet the GWAS significance threshold but were highly suggestive. In the replication cohort, the association of the three top SNPs did not reach statistical significance. In a meta-analysis of the discovery and the replication cohorts, there were no strengthen evidence for association of the three SNPs. The top identified rs118129027 overlaps with a regulatory factor (enhancer) region that targets three neighboring genes LOC105375237, LOC105375240, and YAE1D1. The YAE1D1, which represents a potential locus that is involved in regulating translation initiation pathway. Novel associations that require further confirmation were identified, suggesting a new insight to the genetic basis of SUD.

Gastric adenocarcinoma and proximal polyposis of the stomach: diagnosis and clinical perspectives.

Gastric adenocarcinoma and proximal polyposis of the stomach (GAPPS) is a recently described, rare gastric polyposis syndrome. It is characterized by extensive involvement of the fundus and body of the stomach with fundic gland polyps sparing the antrum and lesser curvature, an autosomal dominant inheritance pattern with incomplete penetrance, and a significant predisposition for the development of gastric adenocarcinoma. Due to the recent discovery of APC promotor IB mutations (c.-191T>C, c.-192A>G, and c.-195A>C), which reduce binding of the transcription factor Yin Yang 1 (YY1) and transcriptional activity of the promotor, as its underlying genetic perturbation, GAPPS has been added to the growing molecular class of APC-associated disorders. Recent reports on family members afflicted by gastric polyposis due to GAPPS have described the development of metastatic cancer or the presence of invasive gastric adenocarcinoma in total gastrectomy specimens after variable periods of endoscopic surveillance emphasizing the need for an improved understanding of the to-date poorly characterized natural history of the syndrome. There are, however, currently no guidelines on screening, timing of prophylactic gastrectomy, or endoscopic surveillance for GAPPS available. In this review, we summarize the clinical, pathological, and genetic aspects of GAPPS as well as management approaches to this rare cancer predisposition syndrome, highlighting the need for early recognition, a multidisciplinary approach, and the creation of prospective family registries and consensus guidelines in the near future.

Mendelian randomization analysis of C-reactive protein on colorectal cancer risk.

Chronic inflammation is a risk factor for colorectal cancer (CRC). Circulating C-reactive protein (CRP) is also moderately associated with CRC risk. However, observational studies are susceptible to unmeasured confounding or reverse causality. Using genetic risk variants as instrumental variables, we investigated the causal relationship between genetically elevated CRP concentration and CRC risk, using a Mendelian randomization approach. Individual-level data from 30 480 CRC cases and 22 844 controls from 33 participating studies in three international consortia were used: the Genetics and Epidemiology of Colorectal Cancer Consortium (GECCO), the Colorectal Transdisciplinary Study (CORECT) and the Colon Cancer Family Registry (CCFR). As instrumental variables, we included 19 single nucleotide polymorphisms (SNPs) previously associated with CRP concentration. The SNP-CRC associations were estimated using a logistic regression model adjusted for age, sex, principal components and genotyping phases. An inverse-variance weighted method was applied to estimate the causal effect of CRP on CRC risk. Among the 19 CRP-associated SNPs, rs1260326 and rs6734238 were significantly associated with CRC risk (P = 7.5 × 10-4, and P = 0.003, respectively). A genetically predicted one-unit increase in the log-transformed CRP concentrations (mg/l) was not associated with increased risk of CRC [odds ratio (OR) = 1.04; 95% confidence interval (CI): 0.97, 1.12; P = 0.256). No evidence of association was observed in subgroup analyses stratified by other risk factors. In spite of adequate statistical power to detect moderate association, we found genetically elevated CRP concentration was not associated with increased risk of CRC among individuals of European ancestry. Our findings suggested that circulating CRP is unlikely to be a causal factor in CRC development.

Genome-wide DNA methylation assessment of ‘BRCA1-like’ early-onset breast cancer: Data from the Australian Breast Cancer Family Registry

Breast cancers arising in women carrying a germline mutation in BRCA1 are typically high-grade, early-onset and have distinct morphological features (BRCA1-like). However, the majority of early-onset breast cancers of this morphological type are not associated with germline BRCA1 mutations or constitutional BRCA1 promoter methylation. We aimed to assess DNA methylation across the genome for associations with the “BRCA1-like” morphology. Genome-wide methylation in blood-derived DNA was measured using the Infinium HumanMethylation450K BeadChip assay for women under the age of 40 years participating in the Australian Breast Cancer Family Study (ABCFS) diagnosed with: i) BRCA1-like breast cancer (n = 30); and ii) breast cancer without BRCA1-like morphological features (non BRCA1-like; n = 30), and age-matched unaffected women (controls; n = 30). Corresponding tumour-derived DNA from 43 of the affected women was also assessed. Methylation of blood-derived DNA was found to be elevated across 17 consecutive marks in the BRCA1 promoter region and decreased at several other genomic regions (including TWIST2 and CTBP1) for 7 women (23%) diagnosed with BRCA1-like breast cancer compared with women in the other groups. Corresponding tumour-derived DNA available from 5 of these 7 women had elevated methylation within the BRCA1 and SPHK2 promoter region and decreased methylation within the ADAP1, IGF2BP3 and SPATA13 promoter region when compared with the other breast tumours. These methylation marks could be biomarkers of risk for BRCA1-like breast cancer, and could be responsible in part for their distinctive morphological features and biology. As such, they may assist with prevention and targeted therapies for this cancer subtype.

Age-specific breast cancer risk by body mass index and familial risk: prospective family study cohort (ProF-SC)

BackgroundThe association between body mass index (BMI) and risk of breast cancer depends on time of life, but it is unknown whether this association depends on a woman’s familial risk.MethodsWe conducted a prospective study of a cohort enriched for familial risk consisting of 16,035 women from 6701 families in the Breast Cancer Family Registry and the Kathleen Cunningham Foundation Consortium for Research into Familial Breast Cancer followed for up to 20 years (mean 10.5 years). There were 896 incident breast cancers (mean age at diagnosis 55.7 years). We used Cox regression to model BMI risk associations as a function of menopausal status, age, and underlying familial risk based on pedigree data using the Breast and Ovarian Analysis of Disease Incidence and Carrier Estimation Algorithm (BOADICEA), all measured at baseline.ResultsThe strength and direction of the BMI risk association depended on baseline menopausal status (P < 0.001); after adjusting for menopausal status, the association did not depend on age at baseline (P = 0.6). In terms of absolute risk, the negative association with BMI for premenopausal women has a much smaller influence than the positive association with BMI for postmenopausal women. Women at higher familial risk have a much larger difference in absolute risk depending on their BMI than women at lower familial risk.ConclusionsThe greater a woman’s familial risk, the greater the influence of BMI on her absolute postmenopausal breast cancer risk. Given that age-adjusted BMI is correlated across adulthood, maintaining a healthy weight throughout adult life is particularly important for women with a family history of breast cancer.

Risks of Colorectal Cancer and Cancer-Related Mortality in Familial Colorectal Cancer Type X and Lynch Syndrome Families.

The risk of cancers is well characterized in Lynch syndrome (LS) families but has been less studied in familial colorectal cancer type X (FCCTX) families. In this article, we compare the risk estimates of first and second colorectal cancers (CRCs) in 168 FCTTX and 780 LS families recruited through the Colon Cancer Family Registry as well as the risk of cancer-related deaths and disease-free survival (DFS) after a first CRC. Our methodology is based on a survival analysis approach, developed specifically to model the occurrence of successive cancers (ie, first and second CRCs) in the presence of competing risk events (ie, death from any causes). We found an excess risk of first and second CRC in individuals with LS compared to FCCTX family members. However, for an average age at first CRC of 60 years in FCCTX families and 50 years in LS families, the DFS rates were comparable in men but lower in women from FCCTX vs LS families, eg , 75.1% (95% confidence interval [CI] = 69.0% to 80.9%) vs 78.9% (95% CI = 76.3% to 81.3%) for the 10-year DFS. The 10-year risk of cancer-related death was higher in FCCTX families vs LS families, eg, 15.4% in men (95% CI = 10.9% to 19.8%) and 19.3% in women (95% CI = 13.6% to 24.7%) vs 8.9% (95% CI = 7.5% to 11.4%) and 8.7% (95% CI = 7.1% to 10.8%), respectively. Individuals with CRCs arising in the context of FCCTX do not experience the same improved DFS and overall survival of those with LS, and that difference may be relevant in management decisions.

What have we learned from Turkish familial hypercholesterolemia registries (A-HIT1 and A-HIT2)?

Background and aimsFamilial hypercholesterolemia (FH) is a common genetic disease of high-level cholesterol leading to premature atherosclerosis. One of the key aspects to overcome FH burden is the generation of large-scale reliable data in terms of registries. This manuscript underlines the important results of nation-wide Turkish FH registries (A-HIT1 and A-HIT2). MethodsA-HIT1 is a survey of homozygous FH patients undergoing low density lipoprotein (LDL) apheresis (LA). A-HIT2 is a registry of adult FH patients (homozygous and heterozygous) admitted to outpatient clinics. Both registries used clinical diagnosis of FH. ResultsA-HIT1 evaluated 88 patients (27 ± 11 years, 41 women) in 19 centers. All patients were receiving regular LA. There was a 7.37 ± 7.1-year delay between diagnosis and initiation of LA. LDL-cholesterol levels reached the target only in 5 cases. Mean frequency of apheresis sessions was 19 ± 13 days. None of the centers had a standardized approach for LA. Mean frequency of apheresis sessions was every 19 ± 13 (7–90) days. Only 2 centers were aware of the target LDL levels.A–HIT2 enrolled 1071 FH patients (53 ± 8 years, 606 women) from 31 outpatients clinics specialized in cardiology (27), internal medicine (1), and endocrinology (3); 96.4% were heterozygous. 459 patients were on statin treatment. LDL targets were attained in 23 patients (2.1% of the whole population, 5% receiving statin) on treatment. However, 66% of statin-receiving patients were on intense doses of statins. Awareness of FH was 9.5% in the whole patient population. ConclusionsThe first nationwide FH registries revealed that FH is still undertreated even in specialized centers in Turkey. Additional effective treatment regiments are urgently needed.

Diagnostics for Pleiotropy in Mendelian Randomization Studies: Global and Individual Tests for Direct Effects.

Diagnosing pleiotropy is critical for assessing the validity of Mendelian randomization (MR) analyses. The popular MR-Egger method evaluates whether there is evidence of bias-generating pleiotropy among a set of candidate genetic instrumental variables. In this article, we propose a statistical method-global and individual tests for direct effects (GLIDE)-for systematically evaluating pleiotropy among the set of genetic variants (e.g., single nucleotide polymorphisms (SNPs)) used for MR. As a global test, simulation experiments suggest that GLIDE is nearly uniformly more powerful than the MR-Egger method. As a sensitivity analysis, GLIDE is capable of detecting outliers in individual variant-level pleiotropy, in order to obtain a refined set of genetic instrumental variables. We used GLIDE to analyze both body mass index and height for associations with colorectal cancer risk in data from the Genetics and Epidemiology of Colorectal Cancer Consortium and the Colon Cancer Family Registry (multiple studies). Among the body mass index-associated SNPs and the height-associated SNPs, several individual variants showed evidence of pleiotropy. Removal of these potentially pleiotropic SNPs resulted in attenuation of respective estimates of the causal effects. In summary, the proposed GLIDE method is useful for sensitivity analyses and improves the validity of MR.

Crowd Sourcing for Organs: A Social Dilemma.

Crowd Sourcing for Organs: A Social Dilemma.

Family history-based colorectal cancer screening in Australia: A modelling study of the costs, benefits, and harms of different participation scenarios.

BackgroundThe Australian National Bowel Cancer Screening Programme (NBCSP) was introduced in 2006. When fully implemented, the programme will invite people aged 50 to 74 to complete an immunochemical faecal occult blood test (iFOBT) every 2 years.Methods and findingsTo investigate colorectal cancer (CRC) screening occurring outside of the NBCSP, we classified participants (n = 2,480) in the Australasian Colorectal Cancer Family Registry (ACCFR) into 3 risk categories (average, moderately increased, and potentially high) based on CRC family history and assessed their screening practices according to national guidelines. We developed a microsimulation to compare hypothetical screening scenarios (70% and 100% uptake) to current participation levels (baseline) and evaluated clinical outcomes and cost for each risk category. The 2 main limitations of this study are as follows: first, the fact that our cost-effectiveness analysis was performed from a third-party payer perspective, which does not include indirect costs and results in overestimated cost-effectiveness ratios, and second, that our natural history model of CRC does not include polyp sojourn time, which determines the rate of cancerous transformation.Screening uptake was low across all family history risk categories (64%–56% reported no screening). For participants at average risk, 18% reported overscreening, while 37% of those in the highest risk categories screened according to guidelines. Higher screening levels would substantially reduce CRC mortality across all risk categories (95 to 305 fewer deaths per 100,000 persons in the 70% scenario versus baseline). For those at average risk, a fully implemented NBCSP represented the most cost-effective approach to prevent CRC deaths (AUS$13,000–16,000 per quality-adjusted life year [QALY]). For those at moderately increased risk, higher adherence to recommended screening was also highly cost-effective (AUS$19,000–24,000 per QALY).ConclusionInvesting in public health strategies to increase adherence to appropriate CRC screening will save lives and deliver high value for money.

Physical activity and the risk of colorectal cancer in Lynch syndrome.

Greater physical activity is associated with a decrease in risk of colorectal cancer for the general population; however, little is known about its relationship with colorectal cancer risk in people with Lynch syndrome, carriers of inherited pathogenic mutations in genes affecting DNA mismatch repair (MMR). We studied a cohort of 2,042 MMR gene mutations carriers (n = 807, diagnosed with colorectal cancer), from the Colon Cancer Family Registry. Self-reported physical activity in three age-periods (20-29, 30-49 and ≥50 years) was summarized as average metabolic equivalent of task hours per week (MET-hr/week) during the age-period of cancer diagnosis or censoring (near-term exposure) and across all age-periods preceding cancer diagnosis or censoring (long-term exposure). Weighted Cox regression was used to estimate the hazard ratio (HR) and 95% confidence intervals (CI) for the association between physical activity and colorectal cancer risk. Near-term physical activity was associated with a small reduction in the risk of colorectal cancer (HR ≥35 vs. <3.5 MET-hr/week, 0.71; 95% CI, 0.53-0.96). The strength and direction of associations were similar for long-term physical activity, although the associations were not nominally significant. Our results suggest that physical activity is inversely associated with the risk of colorectal cancer for people with Lynch syndrome; however, further confirmation is warranted. The potential modifying effect of physical activity on colorectal cancer risk in people with Lynch syndrome could be useful for risk prediction and support counseling advice for lifestyle modification to reduce cancer risk.

Design and rationale of gulf familial hypercholesterolemia registry

Aim: There are a few reports on the molecular charasterstics of FH in the Arabian Gulf region. The objective of this registry is to determine FH prevalence, genetic charasterstics current mangement and outcomes in the Arabian Gulf region.

Laxative type in relation to colorectal cancer risk

PurposeExisting studies on laxatives, used by roughly 40% of the U.S. population experiencing constipation and colorectal cancer (CRC) have yielded inconsistent results, which may be due to a failure to account for differential risks by major laxative types: bulk (fiber-based), and nonbulk (or nonfiber-based). MethodsWe examined the association of nonfiber-based laxative use and fiber-based laxative use with the risk of CRC in a subset of the multisite, International Colon Cancer Family Registry cohort comprising 4930 primary invasive CRC cases and 4025 controls selected from the general population. Epidemiologic risk factor questionnaires were administered to all participants at recruitment, and exposures were ascertained approximately 1 year before diagnosis for cases and at a comparable period for controls. We ascertained known and suspected CRC risk factors, including regular laxative use, which was defined as laxative intake at least twice a week for more than a month. Multivariable logistic regression models were used to estimate the adjusted odds ratios (ORs) and 95% confidence intervals (95% CIs). ResultsIndividuals who reported using nonfiber-based laxatives regularly were at a significantly increased risk for CRC compared with those who reported no laxative use (OR = 2.17, 95% CI = 1.47–3.19). No statistically significant associations were observed between fiber-based laxative use and CRC (OR = 0.99, 95% CI = 0.80–1.22). ConclusionsCompared with nonusers, the risk of CRC increased with nonfiber-based laxative use, whereas CRC risk was not significantly associated with fiber-based laxative use.

Pharmacotherapy Before or After Liver Transplantation in Familial Amyloidotic Polyneuropathy (FAP) and Domino recipients – Early Report from the Familial Amyloidotic World Transplant Registry (FAPWTR) and the Domino Liver Transplant Registry (DLTR)

On behalf of the members of the FAPWTR and the DLTR. Background Liver transplantation (LTx) as treatment for hereditary transthyretin amyloidosis (hATTR) has been performed since 1990, when the first hATTR patient with the TTR Val30Met mutation was done in Sweden with overall good outcome. However, with time publications appeared disclosing not only an unhalted disease progression but also progress of cardiomyopathy in a number of patients with regard to some non-Val30Met mutations and ensuing notably for elderly male hATTR Val30Met patients. With the introduction of medical therapy, LTx as treatment for hATTR patients has been significantly reduced. The use of hATTR livers for domino liver transplantation (DLT) is since many years an established way to expand the liver donor pool. However, the procedure carries the risk of transmitting the novo amyloidosis to the recipient with the grafted liver, and several reports indicate the risk to be very real. Using TTR stabilizers is maybe of value for these patients. As all new treatment modalities must be balanced against previous treatments, the long-term survival after TTR stabilizer treatment is yet to be settled. Furthermore, the variable response to TTR stabilizer treatment poses a problem, because delayed transplantation for a patient in whom an acceptable outcome is to be expected will significantly decrease survival. Methods All patients reported to the FAPWTR and DLTR are included in the analysis. Results By Oct 2017, the FAPWTR had data on 2185 hATTR liver transplant recipients and the DLTR contained data on 1186 transplantations with a FAP liver, reported from 21 countries. The first patient given TTR stabilizers before LTx was registered in 2012, and since then 28 patients (20% of LTx patients reported to the FAPWTR since 2012) were reported to be on stabilizer medication before LTx. Duration of pretranplantation medical therapy was 13±10 month (range 3-44). Overall, the frequency of retransplantation (retx) in the DLT recipients was 6.7%. The main reason for retx was arterial thrombosis (27.8%). 10 (12.7%) of the retx were because of de novo amyloidosis. 16 (1.4%) of the patients had been given TTR stabilizers post-DLT. In these patients, the treatment was started 5-13 years after DLT, mean 10.5 years (median 11.1 years). Conclusion These early Registry data show that some hATTR patients will still need LTX despite being given TTR stabilizer medication. To date, only scarce literature has been published on the use of TTR stabilizers relative to LTx. Medical therapy as adjuvant treatment to LTx has not yet been evaluated long enough to establish its definite role relative to LTx. Adjuvant medical therapy and LTx may be relevant particularly for patients displaying worsening after LTx or in DLT recipients.

Abstract 245: Genetic variation related to innate immunity and colorectal cancer risk

Abstract Introduction: Previous studies have shown that polymorphisms in the Toll-like receptor 4 (TLR4) gene may be associated with obesity, inflammatory bowel disease, and various cancers, including prostate, breast, and gastric cancer. However, the data regarding the associations between various TLR4 single-nucleotide polymorphisms (SNPs) and colorectal cancer (CRC) risk are inconsistent. In addition, the effect of interactions between TLR4 SNPs and obesity on the risk of CRC remains unclear. Methods: We selected candidate SNPs involved in the TLR4 pathway that were previously associated with the risk of CRC or other cancer (N=31). SNPs with low minor allele frequency (MAF &amp;lt; 0.05) were excluded (N=2), leaving 29 SNPs in the main analysis. We examined the associations of these SNPs with CRC risk using logistic regression on 10,998 cases of colorectal cancer and 10,691 controls drawn from 14 studies within the Genetics and Epidemiology of Colorectal Cancer Consortium (GECCO) and the Colon Cancer Family Registry (CCFR). BMI was dichotomized into non-obese (BMI ≤25) and obese (BMI &amp;gt;25) categories. Overall and BMI-stratified analyses were performed across studies, with regression models adjusting for sex, age, study site, and the first three principal components from EIGENSTRAT to account for potential population substructure. A false discovery rate at 0.2 was applied to correct for multiple testing. Results: Before adjustment for multiple comparisons, TLR4 SNPs rs10116253, rs11536891, rs7873784, rs1927911, rs4986791, and rs4986790 were associated with CRC risk. Additionally, for both rs4986791 and rs4986790, this association was more pronounced in those with a BMI ≤25 (rs4986791 - OR: 1.17; 95% CI: 1.02-1.34; rs4986790 - OR: 1.20; 95% CI: 1.04-1.38) compared to those who had a BMI &amp;gt;25 (rs4986791 - OR: 1.03; 95% CI: 0.93-1.15; rs4986790 - OR: 1.03; 95% CI: 0.92-1.15). However, after accounting for multiple comparisons, there were no statistically significant associations between candidate SNPs and CRC nor any statistically significant SNP interactions with BMI. Conclusion: This large study provides evidence that neither these identified TLR4 SNPs nor their interaction with obesity are associated with CRC risk. Citation Format: Jessica Citronberg, Barbara Banbury, Andrew T. Chan, Peter T. Campbell, Graham Casey, Jenny Chang-Claude, Steven J. Gallinger, Tabitha Harrison, Michael Hoffmeister, Mark A. Jenkins, Loic Le Marchand, Hongmei Nan, Hongmei Nan, Li Jiao, Robert E. Schoen, Hermann Brenner, Emily White, Ulrike Peters, Polly A. Newcomb. Genetic variation related to innate immunity and colorectal cancer risk [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 245.

Abstract 235: Type 2 diabetes and glycemic traits in relation to colorectal cancer risk: A Mendelian randomization study

Abstract Background: Although type 2 diabetes (T2D) has been linked to an increased risk of colorectal cancer (CRC), a causal relationship remains to be established. Also, the influence of hyperglycemia and impaired beta-cell function on CRC remains to be determined. Methods: We performed a Mendelian randomization (MR) study using common single nucleotide polymorphisms (SNPs) identified from prior genome-wide association studies for T2D (78 SNPs), fasting glucose (36 SNPs), glycosylated hemoglobin (HbA1c, 11 SNPs), and homeostatic model assessment for beta-cell function (HOMA-B, 13 SNPs) (all SNPs reached genome-wide significance at 5 x10-8). We first assessed the association of each SNP with CRC risk using logistic regression in 26,357 CRC cases and 20,505 control participants in the Colon Cancer Family Registry, Colorectal Transdisciplinary Study and the Genetics and Epidemiology of Colorectal Cancer Consortium. The MR estimates for the association of each risk factor with CRC were calculated using the inverse-variance weighted method that combines summary data on the association of the SNPs with each trait derived from previous genome-wide association studies. Given the potential sex difference in the relationship of metabolic factors with CRC, all analyses were performed in men and women separately. Results: We did not find any statistically significant association between each of the genetically predicted risk factors and CRC incidence for sex-stratified or combined analyses. The odds ratios (ORs) of CRC associated with genetic risk of T2D were 1.02 (95% confidence interval [CI], 0.95-1.08, P=0.62) in women and 0.96 (95% CI, 0.90-1.03, P=0.25) in men. For fasting glucose, the ORs of CRC associated with one mmol/L increment was 0.91 (95% CI, 0.68-1.20, P=0.49) in women and 1.20 (95% CI, 0.90-1.59, P=0.22) in men, respectively. For HbA1c, the ORs of CRC associated with one percent increment was 0.83 (95% CI, 0.57-1.22, P=0.35) in women and 0.99 (95% CI, 0.67-1.45, P=0.95) in men. For HOMA-B, the ORs of CRC associated with a unit increase in log-transformed measurement was 0.92 (95% CI, 0.53-1.60, P=0.76) in women and 0.77 (95% CI, 0.44-1.35, P=0.36) in men. Conclusion: Our findings do not support a causal association of T2D, impaired beta-cell function, and hyperglycemia with CRC risk. However, the null findings may be due to weak instrument bias since these common SNPs account for only a limited proportion of the inter-individual variation in these glycemic traits. Citation Format: Mingyang Song, Yiwen Lu, Marc Gunter, Neil Murphy, Barbara L. Banbury, Wenjie Ma, Jennifer Prescott, Graham Casey, Stephen B. Gruber, Edward L. Giovannucci, Ulrike Peters, Andrew T. Chan. Type 2 diabetes and glycemic traits in relation to colorectal cancer risk: A Mendelian randomization study [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 235.

Abstract 4415: Characterization of tumor-derived exosomes in BRCA-associated breast tumors

Abstract Background: BRCA-mutated tumors are usually with higher grade than sporadic tumors and the biology is poorly understood. Exosomes are small membrane-derived vesicles that function to mediate cell-cell communication via the transfer of tumor-promoting microRNAs (miRNAs), RNAs and proteins. Interestingly, different spectrum of miRNAs is released by cancer cells to promote tumor growth and metastasis in breast cancer. However, the selectivity of miRNA released from tumor-derived exosomes and its relevance in cancer treatment has not been widely studied. Hence, this study is sought to characterize the role of exosomal-miRNA (exo-miR) for the development of BRCA-associated tumors. Methods: Plasma samples from patients with BRCA-positive and non-BRCA carriers were recruited and selected from the Hong Kong Hereditary Breast Cancer Family Registry. By using miRCURY LNA array, the exosomal-miRNA expressions in plasma of patient with BRCA-positive (n=4) and non-carriers (n=4), as well as healthy controls (n=4) were profiled. Selected miRNAs were further validated in pre- and post-operative plasma and paired primary tissues (n=40) using real-time RT-PCR. Functional study of miRNA was also carried out in the cell lines. Results: LNA array data showed that differential expressed BRCA-associated exo-miRNAs were identified. Upregulated miRs (miR-106a, miR-20a, miR-23a, miR-451 and miR-486) were validated in BRCA-positive, BRCA-negative and healthy controls by real-time RT-PCR. In addition, the expression levels of miR-106a, miR-451 and miR-486 were significantly lower in post-operative plasma of BRCA-carriers than non-carriers. Importantly, the expression of miR-451 was reduced after tumor resection in BRCA mutation carriers. In parallel, high expression of exo-miR-106a, miR-20a, miR-23a, miR-451 and miR-486 were also seen in breast cancer cell lines (MB-231 and MB-468) relative to normal breast cells (MCF-10A). We found that cells transfected with miR-451 inhibitor significantly reduce cell proliferation. Conclusions: These preliminary results reveal differential exo-miRNA profiles between BRCA carriers and non-carriers with breast cancer, and identify potential targets of dysregulated miRNAs which is crucial in disease progression of BRCA-associated breast cancers. Citation Format: Vivian Y. Shin, Man-Ting Siu, Isabella Cheuk, Ava Kwong. Characterization of tumor-derived exosomes in BRCA-associated breast tumors [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 4415.

Abstract 2965: Functionally informed genome-wide interaction analysis of nonsteroidal anti-inflammatory drugs on colorectal cancer risk

Abstract Background Regular use of aspirin and other non-steroidal anti-inflammatory drugs (NSAIDs) is associated with lower risk of colorectal cancer (CRC). Genome-wide interaction analysis (GxE) has identified a few variants that may modify the effects of NSAIDs on CRC risk. However, limited statistical power remains a concern. Restricting analyses by using functional genomic information to aggregate variants into biologically relevant sets can reduce the number of tests, thereby increasing statistical power. We tested the interactions between variant models of gene expression and NSAIDs use on CRC risk. Methods Functional weights of each variant were estimated using PrediXcan based on jointly measured transcriptomes and genomes data of transverse colon tissues from the Genotype-Tissue Expression (GTEx) Project for all genes with sufficient heritability (≥1%). A mixed-effects model was used to assess the GxE effects in a gene among 9,917 incident CRC cases and 10,533 controls from 17 (nested) case-control studies from the Colon Cancer Family Registry (CCFR) and Genetics and Epidemiology of Colorectal Cancer Consortium (GECCO). GxE analysis was done by modeling the interaction between predicted gene expression and NSAID use (fixed effects), and residual variant-specific GxE effects that are not accounted for (random effects). Regular user of aspirin and/or non-aspirin NSAIDs was compared to non-regular users. False discovery rate (FDR) was used to account for multiple comparison and FDR≤0.2 was considered genome-wide significant. Secondary analysis was performed on significant genes and duration of use among users. Results Regular use of aspirin was higher among controls (30.3%) compared to cases (24.3%). Among the 4,842 genes tested, SORD significantly modified the effect of regular use of aspirin on CRC risk (p-interaction = 1.45×10-5; FDR=0.07). The SORD gene encodes sorbitol dehydrogenase (SORD), which oxidizes sorbitol to fructose in the polyol pathway. Decreased SORD concentrations were previously observed to dramatically increase in colorectal adenoma cells when compared to normal mucosa cells, suggesting the involvement of dysregulated polyol metabolisms in colorectal tumorigenesis. However, the duration of aspirin use was not statistically significantly associated with SORD gene expression on CRC risk (p=0.149) among 5,560 aspirin users. No significant interactions were observed between genetically determined colon gene expression levels and any NSAID use or non-aspirin NSAID use at FDR&amp;lt;0.2. Conclusions Incorporating functional information, we discovered a novel gene that may interact with aspirin use to confer CRC risk. These findings provide preliminary support for new biological insights that could help understand the chemopreventive mechanisms of aspirin on CRC. We aim to replicate these findings in additional studies. Citation Format: Xiaoliang Wang, Yu-Ru Su, Andrew T. Chan, Stephanie Bien, Sonja I. Bernt, Hermann Brenner, Graham Casey, Jenny Chang-Claude, Steven J. Gallinger, Robert W. Haile, Tabitha A. Harrison, Michael Hoffmeister, Mark A. Jenkins, Amit Joshi, Yi Lin, Noralane M. Lindor, Loic Le Marchand, Hongmei Nan, Polly A. Newcomb, John D. Potter, Martha L. Slattery, Steve N. Thibodeau, Emily White, Li Hsu, Ulrike Peters. Functionally informed genome-wide interaction analysis of nonsteroidal anti-inflammatory drugs on colorectal cancer risk [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 2965.

Abstract 5268: Interactions between genetic predictors of gene expression and dietary factors associated with risk of colorectal cancer

Abstract Genome-wide association studies of colorectal cancer (CRC) have identified over 50 susceptibility loci. These variants represent only a small fraction of total heritability for CRC. Gene-environment (GxE) interaction studies may help identify novel loci and biological interactions that give insight to the pathogenesis of CRC. Previous genome-wide GxE studies with dietary factors have identified interactions between loci and processed meat consumption and alcohol; however, limited statistical power remains a primary concern. Set-based SNP testing has the potential to increase statistical power to detect GxE interactions by aggregating functionally relevant SNPs. In this large pooled analysis using 14 case-control and nested case-control studies, we incorporated functional information from the transcriptome prediction tool, PrediXcan, into a novel set-based approach for testing GxE interactions. We used variant weights from the PrediXcan models of tissue-specific gene expression in the transverse colon as a priori variant information for a set-based GxE approach. We restricted our analysis to variants in the PrediXcan transverse colon gene models (n = 4,842). This discovery phase included 10,360 CRC and advanced adenoma cases, and 11,183 controls of European ancestry from the Genetics and Epidemiology of Colorectal Cancer Consortium (GECCO) and the Colon Cancer Family Registry. All 14 studies were analyzed together in a pooled data set using the Mixed Effects Score Tests for interactions. We tested for gene interactions with sex- and study- specific quartiles of dietary intake of red meat (servings/day), processed meat (servings/day), vegetables (servings/day), fruits (servings/day), and fiber (g/day). We detected two genes with suggestive interactions (false discovery rate (FDR) &amp;lt; 0.2) with intake of red meat and risk of CRC: Superoxide Dismutase 2 (SOD2) and Ubiquitin Conjugating Enzyme E2 H (UBE2H). No interactions at FDR &amp;lt; 0.2 were observed for processed meat, vegetables, fruits, or fiber. The SOD2 gene, which encodes an enzyme important in apoptotic signaling and clearing of reactive oxygen species, may regulate response to colonic exposure to heme iron or increased bile acid from high-fat content in red meat. UBE2H is part of the ubiquitin-proteasome system that has a role in Wnt signaling, which can be mediated by heme iron in red meat and is commonly found dysregulated in cancer. These findings highlight the efficacy of integrating functional information and set-based testing for novel discovery of genes interacting with known dietary risk factors of CRC. We plan to replicate these findings in additional studies. Citation Format: Paneen S. Petersen, Yu-Ru Su, Sonja I. Berndt, Stephanie A. Bien, Hermann Brenner, Graham Casey, Andrew T. Chan, Jenny Chang-Claude, Jane C. Figueiredo, Steven J. Gallinger, Robert W. Haile, Tabitha A. Harrison, Michael Hoffmeister, Mark A. Jenkins, Amit D. Joshi, Sébastien Küry, Loic Le Marchand, Yi Lin, Noralane M. Lindor, Polly A. Newcomb, John D. Potter, Robert Schoen, Martha L. Slattery, Stephen N. Thibodeau, Emily White, Li Hsu, Ulrike Peters, CCFR, GECCO. Interactions between genetic predictors of gene expression and dietary factors associated with risk of colorectal cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 5268.

Abstract 4205: Colorectal cancer molecular markers and subtypes in relation to disease survival

Abstract Colorectal cancer (CRC) is a biologically heterogeneous disease. Such biological heterogeneity reflects diversity in tumor etiology and has implications for survival. Previous studies have demonstrated a strong association between the presence of microsatellite instability (MSI) in CRC and longer disease-specific survival. The influence of other tumor markers, including the CpG island methylator phenotype (CIMP) and BRAF and KRAS mutation status, on survival is less clear. However, these four markers are correlated. Thus, consideration for these markers in combination, with recognition for the distinct etiologies those combinations may reflect, is important to further our understanding of CRC survival. We pooled data from 7 observational studies of CRC: the multisite Colon Cancer Family Registry (CCFR), the Cancer Prevention Study-II (CPS-II), the Diet Activity and Lifestyle Study (DALS), the Health Professionals Follow-Up Study (HPFS), the Nurses' Health Study (NHS), the Melbourne Collaborative Cohort Study (MCCS), and The Cancer Genome Atlas (TCGA). All studies collected data on MSI, CIMP, and somatic mutation status for BRAF and KRAS. Participants with complete tumor marker data were classified into five subtypes based on tumor marker combinations previously proposed to reflect different etiologic pathways: Type 1 (MSI-high, CIMP+, BRAF-mutated, KRAS-wildtype); Type 2 (microsatellite-stable/low-instability (MSS/MSI-low), CIMP+, BRAF-mutated, KRAS-wildtype); Type 3 (MSS/MSI-low, non-CIMP, BRAF-wildtype, KRAS-mutated); Type 4 (MSS/MSI-low, non-CIMP, BRAF-wildtype, KRAS-wildtype); and Type 5 (MSI-high, non-CIMP, BRAF-wildtype, KRAS-wildtype). We used Cox regression to estimate hazard ratios (HR) and 95% confidence intervals (CI) for associations with disease-specific (DSS) and overall survival (OS) for each tumor marker individually (N=4727 to 5105) and for the above tumor marker combinations (N=118 to 2109); analyses were adjusted for age, sex, and study population. When considered individually, MSI-high status was associated with significantly longer (HROS=0.74, HRDSS=0.39, p&amp;lt;0.001) and KRAS-mutated status with significantly shorter survival (HROS=1.11, HRDSS=1.31, p=0.04 and &amp;lt;0.001, respectively); BRAF-mutation and CIMP status were not associated with survival. When markers were combined into the subtypes listed above, relative to those with the predominant Type 4 tumor subtype, participants with Type 2 and 3 CRC had significantly shorter DSS (HRType2=1.73, p=0.002; HRType3=1.28, p=0.002) and those with Type 1 and 5 CRC had longer DSS (HRType1=0.30, p&amp;lt;0.001; HRType5=0.46, p=0.003). Associations were similar for OS. In this large, collaborative study, CRC subtype classified by proposed etiologic pathways were associated with marked differences in survival. These findings highlight the clinical importance of molecular heterogeneity in CRC. Citation Format: Amanda I. Phipps, Peter T. Campbell, Barbara Banbury, Daniel Buchanan, Andrew T. Chan, Dallas English, Alton B. Farris, Graham G. Giles, Tabitha Harrison, Roger Milne, Polly A. Newcomb, Martha L. Slattery, Melissa Southey, Shuji Ogino, Ulrike Peters. Colorectal cancer molecular markers and subtypes in relation to disease survival [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 4205.