To further dissect the genetic architecture of colorectal cancer (CRC), we performed whole-genome sequencing of 1,439 cases and 720 controls, imputed discovered sequence variants and Haplotype Reference Consortium panel variants into genome-wide association study data, and tested for association in 34,869 cases and 29,051 controls. Findings were followed up in an additional 23,262 cases and 38,296 controls. We discovered a strongly protective 0.3% frequency variant signal at CHD1. In a combined meta-analysis of 125,478 individuals, we identified 40 new independent signals at P < 5 × 10-8, bringing the number of known independent signals for CRC to ~100. New signals implicate lower-frequency variants, Krüppel-like factors, Hedgehog signaling, Hippo-YAP signaling, long noncoding RNAs and somatic drivers, and support a role for immune function. Heritability analyses suggest that CRC risk is highly polygenic, and larger, more comprehensive studies enabling rare variant analysis will improve understanding of biology underlying this risk and influence personalized screening strategies and drug development.

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.

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

Identifying stage II patients with colorectal cancer (CRC) at higher risk of progression is a clinical priority in order to optimize the advantages of adjuvant chemotherapy while avoiding unnecessary toxicity. Recently, the intensity and the quality of the host immune response in the tumor microenvironment have been reported to have an important role in tumorigenesis and an inverse association with tumor progression. This association is well established in microsatellite instable CRC. In this work, we aim to assess the usefulness of measures of T-cell infiltration as prognostic biomarkers in 640 stage II, CRC tumors, 582 of them confirmed microsatellite stable. We measured both the quantity and clonality index of T cells by means of T-cell receptor (TCR) immunosequencing in a discovery dataset (95 patients with colon cancer diagnosed at stage II and microsatellite stable, median age 67, 30% women) and replicated the results in 3 additional series of stage II patients from 2 countries. Series 1 and 2 were recruited in Barcelona, Spain and included 112 fresh frozen (FF, median age 69, 44% women) and 163 formalin-fixed paraffin-embedded (FFPE, median age 67, 39% women) samples, respectively. Series 3 included 270 FFPE samples from patients recruited in Haifa, Northern Israel, as part of a large case-control study of CRC (median age 73, 46% women). Median follow-up time was 81.1 months. Cox regression models were fitted to evaluate the prognostic value of T-cell abundance and Simpson clonality of TCR variants adjusting by sex, age, tumor location, and stage (IIA and IIB). In the discovery dataset, higher TCR abundance was associated with better prognosis (hazard ratio [HR] for ≥Q1 = 0.25, 95% CI 0.10–0.63, P = 0.003). A functional analysis of gene expression on these tumors revealed enrichment in pathways related to immune response. Higher values of clonality index (lower diversity) were not associated with worse disease-free survival, though the HR for ≥Q3 was 2.32 (95% CI 0.90–5.97, P = 0.08). These results were replicated in an independent FF dataset (TCR abundance: HR = 0.30, 95% CI 0.12–0.72, P = 0.007; clonality: HR = 3.32, 95% CI 1.38–7.94, P = 0.007). Also, the association with prognosis was tested in 2 independent FFPE datasets. The same association was observed with TCR abundance (HR = 0.41, 95% CI 0.18–0.93, P = 0.03 and HR = 0.56, 95% CI 0.31–1, P = 0.042, respectively, for each FFPE dataset). However, the clonality index was associated with prognosis only in the FFPE dataset from Israel (HR = 2.45, 95% CI 1.39–4.32, P = 0.002). Finally, a combined analysis combining all microsatellite stable (MSS) samples demonstrated a clear prognosis value both for TCR abundance (HR = 0.39, 95% CI 0.26–0.57, P = 1.3e-06) and the clonality index (HR = 2.13, 95% CI 1.44–3.15, P = 0.0002). These associations were also observed when variables were considered continuous in the models (HR per log2 of TCR abundance = 0.85, 95% CI 0.78–0.93, P = 0.0002; HR per log2 or clonality index = 1.16, 95% CI 1.03–1.31, P = 0.016). This is a retrospective study, and samples had been preserved with different methods. Validation series lack complete information about microsatellite instability (MSI) status and pathology assessment. The Molecular Epidemiology of Colorectal Cancer (MECC) study had information about overall survival instead of progression-free survival. Results from this study demonstrate that tumor lymphocytes, assessed by TCR repertoire quantification based on a sequencing method, are an independent prognostic factor in microsatellite stable stage II CRC.

Purpose: Mutations in the CDH1 gene confer up to an 80% lifetime risk of diffuse gastric cancer and up to a 60% lifetime risk of lobular breast cancer. Testing for CDH1 mutations is recommended for individuals who meet the International Gastric Cancer Linkage Consortium (IGCLC) guidelines. However, the interpretation of unexpected CDH1 mutations identified in patients who do not meet IGCLC criteria or do not have phenotypes suggestive of hereditary diffuse gastric cancer is clinically challenging. This study aims to describe phenotypes of CDH1 mutation carriers identified through multigene panel testing (MGPT) and to offer informed recommendations for medical management. Patients and Methods: This cross-sectional prevalence study included all patients who underwent MGPT between March 2012 and September 2014 from a commercial laboratory (n = 26,936) and an academic medical center cancer genetics clinic (n = 318) to estimate CDH1 mutation prevalence and associated clinical phenotypes. CDH1 mutation carriers were classified as IGCLC positive (met criteria), IGCLC partial phenotype, and IGCLC negative. Results: In the laboratory cohort, 16 (0.06%) of 26,936 patients were identified as having a pathogenic CDH1 mutation. In the clinic cohort, four (1.26%) of 318 had a pathogenic CDH1 mutation. Overall, 65% of mutation carriers did not meet the revised testing criteria published in 2015. All three CDH1 mutation carriers who had risk-reducing gastrectomy had pathologic evidence of diffuse gastric cancer despite not having met IGCLC criteria. Conclusion: The majority of CDH1 mutations identified on MGPT are unexpected and found in individuals who do not fit the accepted diagnostic testing criteria. These test results alter the medical management of CDH1-positive patients and families and provide opportunities for early detection and risk reduction.

Background: Colorectal cancer (CRC) is the fifth most common cancer in Africa, with significant differences in incidence, biology and clinical behavior from other populations. Materials and Methods: We studied prevalence and clinicopathological features of microsatellite instability (MSI) and young onset CRC in 83 archival samples from the University of Ibadan, Nigeria. Results: Nigerian cases of CRC were MSI-high in 43% and MSI-high CRC had significantly lower histological heterogeneity than microsatellite-stable CRC (20% vs. 55% respectively, p=0.046). Presence of signet ring cell differentiation (10-50% of tumor) was significantly higher in younger patients with CRC (<50 years) (odds ratio(OR)=5.93, 95% confidence interval(CI)=1.17-29.95, p=0.038). Poor differentiation (34%), invasive growth (96%), and high prevalence of mucinous (10%) and signet ring cell adenocarcinomas (4%) were among distinct features of Nigerian patients with CRC. Conclusion: MSI-high CRC is more common in West Africa and more detailed molecular and genetic analysis is warranted as CRC incidence and mortality continue to increase in the Sub-Saharan Africa.