Stephanie L. Schmit

The OncoArray Consortium: a Network for Understanding the Genetic Architecture of Common Cancers.

Background: Common cancers develop through a multistep process often including inherited susceptibility. Collaboration among multiple institutions, and funding from multiple sources, has allowed the development of an inexpensive genotyping microarray, the OncoArray. The array includes a genome-wide backbone, comprising 230,000 SNPs tagging most common genetic variants, together with dense mapping of known susceptibility regions, rare variants from sequencing experiments, pharmacogenetic markers, and cancer-related traits. Methods: The OncoArray can be genotyped using a novel technology developed by Illumina to facilitate efficient genotyping. The consortium developed standard approaches for selecting SNPs for study, for quality control of markers, and for ancestry analysis. The array was genotyped at selected sites and with prespecified replicate samples to permit evaluation of genotyping accuracy among centers and by ethnic background. Results: The OncoArray consortium genotyped 447,705 samples. A total of 494,763 SNPs passed quality control steps with a sample success rate of 97% of the samples. Participating sites performed ancestry analysis using a common set of markers and a scoring algorithm based on principal components analysis. Conclusions: Results from these analyses will enable researchers to identify new susceptibility loci, perform fine-mapping of new or known loci associated with either single or multiple cancers, assess the degree of overlap in cancer causation and pleiotropic effects of loci that have been identified for disease-specific risk, and jointly model genetic, environmental, and lifestyle-related exposures. Impact: Ongoing analyses will shed light on etiology and risk assessment for many types of cancer. Cancer Epidemiol Biomarkers Prev; 26(1); 126–35. ©2016 AACR.

Genome-wide association study of colorectal cancer identifies six new susceptibility loci

Genetic susceptibility to colorectal cancer is caused by rare pathogenic mutations and common genetic variants that contribute to familial risk. Here we report the results of a two-stage association study with 18,299 cases of colorectal cancer and 19,656 controls, with follow-up of the most statistically significant genetic loci in 4,725 cases and 9,969 controls from two Asian consortia. We describe six new susceptibility loci reaching a genome-wide threshold of P<5.0E-08. These findings provide additional insight into the underlying biological mechanisms of colorectal cancer and demonstrate the scientific value of large consortia-based genetic epidemiology studies.

Tumor-Infiltrating Lymphocytes, Crohn’s-Like Lymphoid Reaction, and Survival From Colorectal Cancer

BACKGROUND While clinical outcomes from colorectal cancer (CRC) are influenced by stage at diagnosis and treatment, mounting evidence suggests that an enhanced lymphocytic reaction to a tumor may also be an informative prognostic indicator. METHODS The roles of intratumoral T lymphocyte infiltration (TIL), peritumoral Crohns-like lymphoid reaction (CLR), microsatellite instability (MSI), and clinicopathological characteristics in survival from CRC were examined using 2369 incident CRCs from a population-based case-control study in northern Israel. Cox proportional hazards regression was used to estimate hazard ratios (HRs) and 95% confidence intervals (CIs) for CRC-specific and all-cause mortality in multivariable models adjusted for age, sex, ethnicity, grade, stage, and MSI. All statistical tests were two-sided. RESULTS Tumors with TIL/high-powered field (HPF) of 2 or greater were associated with a statistically significant increase in CRC-specific (P < .001) and overall survival (P < .001) compared with tumors with TIL/HPF of less than 2. Similarly, tumors with a prominent CLR experienced better CRC-specific (P < .001) and overall survival (P < .001) as compared with those with no response. High TILs (HR = 0.76, 95% CI = 0.64 to 0.89, P < .001) and a prominent CLR (HR = 0.71, 95% CI = 0.62 to 0.80, P < .001), but not MSI, were associated with a statistically significant reduction in all-cause mortality after adjustment for established prognostic factors. CONCLUSIONS TILs and CLR are both prognostic indicators for CRC after adjusting for traditional prognostic indicators.

A novel colorectal cancer risk locus at 4q32.2 identified from an international genome-wide association study

Only a fraction of colorectal cancer heritability is explained by known risk-conferring genetic variation. This study was designed to identify novel risk alleles in Europeans. We conducted a genome-wide association study (GWAS) meta-analysis of colorectal cancer in participants from a population-based case-control study in Israel (n = 1616 cases, 1329 controls) and a consortium study from the Colon Cancer Family Registry (n = 1977 cases, 999 controls). We used a two-stage (discovery-replication) GWAS design, followed by a joint meta-analysis. A combined analysis identified a novel susceptibility locus that reached genome-wide significance on chromosome 4q32.2 [rs35509282, risk allele = A (minor allele frequency = 0.09); odds ratio (OR) per risk allele = 1.53; P value = 8.2 × 10(-9); nearest gene = FSTL5]. The direction of the association was consistent across studies. In addition, we confirmed that 14 of 29 previously identified susceptibility variants were significantly associated with risk of colorectal cancer in this study. Genetic variation on chromosome 4q32.2 is significantly associated with risk of colorectal cancer in Ashkenazi Jews and Europeans in this study.

Coffee Consumption and the Risk of Colorectal Cancer.

Background: Coffee contains several bioactive compounds relevant to colon physiology. Although coffee intake is a proposed protective factor for colorectal cancer, current evidence remains inconclusive. Methods: We investigated the association between coffee consumption and risk of colorectal cancer in 5,145 cases and 4,097 controls from the Molecular Epidemiology of Colorectal Cancer (MECC) study, a population-based case–control study in northern Israel. We also examined this association by type of coffee, by cancer site (colon and rectum), and by ethnic subgroup (Ashkenazi Jews, Sephardi Jews, and Arabs). Coffee data were collected by interview using a validated, semi-quantitative food frequency questionnaire. Results: Coffee consumption was associated with 26% lower odds of developing colorectal cancer [OR (drinkers vs. non-drinkers), 0.74; 95% confidence interval (CI), 0.64–0.86; P < 0.001]. The inverse association was also observed for decaffeinated coffee consumption alone (OR, 0.82; 95% CI, 0.68–0.99; P = 0.04) and for boiled coffee (OR, 0.82; 95% CI, 0.71–0.94; P = 0.004). Increasing consumption of coffee was associated with lower odds of developing colorectal cancer. Compared with <1 serving/day, intake of 1 to <2 servings/day (OR, 0.78; 95% CI, 0.68–0.90; P < 0.001), 2 to 2.5 servings/day (OR, 0.59; 95% CI, 0.51–0.68; P < 0.001), and >2.5 servings/day (OR, 0.46; 95% CI, 0.39–0.54; P < 0.001) were associated with significantly lower odds of colorectal cancer (Ptrend < 0.001), and the dose–response trend was statistically significant for both colon and rectal cancers. Conclusions: Coffee consumption may be inversely associated with risk of colorectal cancer in a dose–response manner. Impact: Global coffee consumption patterns suggest potential health benefits of the beverage for reducing the risk of colorectal cancer. Cancer Epidemiol Biomarkers Prev; 25(4); 634–9. ©2016 AACR.

Genome-wide Association Study of Colorectal Cancer in Hispanics

Summary This manuscript describes the first large-scale genome-wide association study of colorectal cancer in Hispanics and Latinos. Our results demonstrate the broad replication of known susceptibility regions and the importance of fine-mapping in ethnic minority populations.

Tests for Gene-Environment Interactions and Joint Effects With Exposure Misclassification

The number of methods for genome-wide testing of gene-environment (G-E) interactions continues to increase, with the aim of discovering new genetic risk factors and obtaining insight into the disease-gene-environment relationship. The relative performance of these methods, assessed on the basis of family-wise type I error rate and power, depends on underlying disease-gene-environment associations, estimates of which may be biased in the presence of exposure misclassification. This simulation study expands on a previously published simulation study of methods for detecting G-E interactions by evaluating the impact of exposure misclassification. We consider 7 single-step and modular screening methods for identifying G-E interaction at a genome-wide level and 7 joint tests for genetic association and G-E interaction, for which the goal is to discover new genetic susceptibility loci by leveraging G-E interaction when present. In terms of statistical power, modular methods that screen on the basis of the marginal disease-gene relationship are more robust to exposure misclassification. Joint tests that include main/marginal effects of a gene display a similar robustness, which confirms results from earlier studies. Our results offer an increased understanding of the strengths and limitations of methods for genome-wide searches for G-E interaction and joint tests in the presence of exposure misclassification.

MicroRNA polymorphisms and risk of colorectal cancer

Background: miRNAs act as post-transcriptional regulators of gene expression. Genetic variation in miRNA-encoding sequences or their corresponding binding sites may affect the fidelity of the miRNA–mRNA interaction and subsequently alter the risk of cancer development. Methods: This study expanded the search for miRNA-related polymorphisms contributing to the etiology of colorectal cancer across the genome using a novel platform, the Axiom miRNA Target Site Genotyping Array (237,858 markers). After quality control, the study included 596 cases and 429 controls from the Molecular Epidemiology of Colorectal Cancer study, a population-based case–control study of colorectal cancer in northern Israel. The association between each marker and colorectal cancer status was examined assuming a log-additive genetic model using logistic regression adjusted for sex, age, and two principal components. Results: Twenty-three markers had P values less than 5.0E−04, and the most statistically significant association involved rs2985 (chr6:34845648; intronic of UHRF1BP1; OR = 0.66; P = 3.7E−05). Furthermore, this study replicated a previously published risk locus, rs1051690, in the 3′-untranslated region of the insulin receptor gene INSR (OR = 1.38; P = 0.03), with strong evidence of differences in INSR gene expression by genotype. Conclusions: This study is the first to examine associations between genetic variation in miRNA target sites and colorectal cancer using a genome-wide approach. Functional studies to identify allele-specific effects on miRNA binding are needed to confirm the regulatory capacity of genetic variation to influence risk of colorectal cancer. Impact: This study demonstrates the potential for an miRNA-targeted genome-wide association study to identify candidate susceptibility loci and prioritize them for functional characterization. Cancer Epidemiol Biomarkers Prev; 24(1); 65–72. ©2014 AACR.

Novel colon cancer susceptibility variants identified from a genome-wide association study in African Americans

Genome‐wide association studies (GWAS) in ethnic/racial minority populations can help to fine‐map previously identified risk regions or discover new risk loci because of the genetic diversity in these populations. We conducted a GWAS of colorectal cancer (CRC) in 6,597 African Americans (1,894 cases and 4,703 controls) (Stage 1) and followed up the most promising markers in a replication set of 2,041 participants of African descent (891 cases and 1,150 controls) (Stage 2). We identified a novel variant, rs56848936 in the gene SYMPK at 19q13.3, associated with colon cancer risk (odds ratio 0.61 for the risk allele G, p = 2.4 × 10−8). The frequency of the G allele was 0.06 in African Americans, compared to <0.01 in Europeans, Asians and Amerindians in the 1000 Genomes project. In addition, a variant previously identified through fine‐mapping in this GWAS in the region 19q13.1, rs7252505, was confirmed to be more strongly associated with CRC in the African American replication set than the variant originally reported in Europeans (rs10411210). The association between rs7252505 and CRC was of borderline significance (p = 0.05) in a Hispanic population GWAS with 1,611 CRC cases and 4,330 controls. With the three datasets combined, the odds ratio was 0.84 for the risk allele A (95% confidence interval 0.79–0.89, p = 3.7 × 10−8). This study further highlights the importance of conducting GWAS studies in diverse ancestry populations.

DNA mismatch repair deficiency and hereditary syndromes in Latino patients with colorectal cancer

The landscape of hereditary syndromes and clinicopathologic characteristics among US Latino/Hispanic individuals with colorectal cancer (CRC) remains poorly understood.