DEPendency of association on the number of Top Hits (DEPTH) is an approach to identify candidate susceptibility regions by considering the risk signals from overlapping groups of sequential variants ...across the genome.
We applied a DEPTH analysis using a sliding window of 200 SNPs to colorectal cancer data from the Colon Cancer Family Registry (CCFR; 5,735 cases and 3,688 controls), and Genetics and Epidemiology of Colorectal Cancer Consortium (GECCO; 8,865 cases and 10,285 controls) studies. A DEPTH score > 1 was used to identify candidate susceptibility regions common to both analyses. We compared DEPTH results against those from conventional genome-wide association study (GWAS) analyses of these two studies as well as against 132 published susceptibility regions.
Initial DEPTH analysis revealed 2,622 (CCFR) and 3,686 (GECCO) candidate susceptibility regions, of which 569 were common to both studies. Bootstrapping revealed 40 and 49 candidate susceptibility regions in the CCFR and GECCO data sets, respectively. Notably, DEPTH identified at least 82 regions that would not be detected using conventional GWAS methods, nor had they been identified by previous colorectal cancer GWASs. We found four reproducible candidate susceptibility regions (2q22.2, 2q33.1, 6p21.32, 13q14.3). The highest DEPTH scores were in the human leukocyte antigen locus at 6p21 where the strongest associated SNPs were rs762216297, rs149490268, rs114741460, and rs199707618 for the CCFR data, and rs9270761 for the GECCO data.
DEPTH can identify candidate susceptibility regions for colorectal cancer not identified using conventional analyses of larger datasets.
DEPTH has potential as a powerful complementary tool to conventional GWAS analyses for discovering susceptibility regions within the genome.
Early-onset colorectal cancer diagnosed before the age of 50 years has been increasing. Likely reflecting the pathogenic role of the intestinal microbiome, which gradually changes across the entire ...colorectal length, the prevalence of certain tumor molecular characteristics gradually changes along colorectal subsites. Understanding how colorectal tumor molecular features differ by age and tumor location is important in personalized patient management.
Using 14,004 cases with colorectal cancer including 3,089 early-onset cases, we examined microsatellite instability (MSI), CpG island methylator phenotype (CIMP), and KRAS and BRAF mutations in carcinomas of the cecum, ascending colon, transverse colon, descending colon, sigmoid colon, and rectum and compared early-onset cases with later-onset cases.
The proportions of MSI-high, CIMP-high, and BRAF -mutated early-onset tumors were lowest in the rectum (8.8%, 3.4%, and 3.5%, respectively) and highest in the ascending colon (46% MSI-high; 15% CIMP-high) or transverse colon (8.6% BRAF -mutated) (all Ptrend <0.001 across the rectum to ascending colon). Compared with later-onset tumors, early-onset tumors showed a higher prevalence of MSI-high status and a lower prevalence of CIMP-high status and BRAF mutations in most subsites. KRAS mutation prevalence was higher in the cecum compared with that in the other subsites in both early-onset and later-onset tumors ( P < 0.001). Notably, later-onset MSI-high tumors showed a continuous decrease in KRAS mutation prevalence from the rectum (36%) to ascending colon (9%; Ptrend <0.001), followed by an increase in the cecum (14%), while early-onset MSI-high cancers showed no such trend.
Our findings support biogeographical and pathogenic heterogeneity of colorectal carcinomas in different colorectal subsites and age groups.
Risk variants identified so far for colorectal cancer explain only a small proportion of familial risk of this cancer, particularly in Asians.
We performed a genome-wide association study (GWAS) of ...colorectal cancer in East Asians, including 23,572 colorectal cancer cases and 48,700 controls. To identify novel risk loci, we selected 60 promising risk variants for replication using data from 58,131 colorectal cancer cases and 67,347 controls of European descent. To identify additional risk variants in known colorectal cancer loci, we performed conditional analyses in East Asians.
An indel variant, rs67052019 at 1p13.3, was found to be associated with colorectal cancer risk at
× 10
in Asians (
per allele deletion = 1.13, 95% confidence interval = 1.08-1.18). This association was replicated in European descendants using a variant (rs2938616) in complete linkage disequilibrium with rs67052019 (
= 7.7 × 10
). Of the remaining 59 variants, 12 showed an association at
< 0.05 in the European-ancestry study, including rs11108175 and rs9634162 at
< 5 × 10
and two variants with an association near the genome-wide significance level (rs60911071,
= 5.8 × 10
; rs62558833,
= 7.5 × 10
) in the combined analyses of Asian- and European-ancestry data. In addition, using data from East Asians, we identified 13 new risk variants at 11 loci reported from previous GWAS.
In this large GWAS, we identified three novel risk loci and two highly suggestive loci for colorectal cancer risk and provided evidence for potential roles of multiple genes and pathways in the etiology of colorectal cancer. In addition, we showed that additional risk variants exist in many colorectal cancer risk loci identified previously.
Our study provides novel data to improve the understanding of the genetic basis for colorectal cancer risk.
Clustering of breast and colorectal cancer has been observed within some families and cannot be explained by chance or known high-risk mutations in major susceptibility genes. Potential shared ...genetic susceptibility between breast and colorectal cancer, not explained by high-penetrance genes, has been postulated. We hypothesized that yet undiscovered genetic variants predispose to a breast-colorectal cancer phenotype.
To identify variants associated with a breast-colorectal cancer phenotype, we analyzed genome-wide association study (GWAS) data from cases and controls that met the following criteria: cases (n = 985) were women with breast cancer who had one or more first- or second-degree relatives with colorectal cancer, men/women with colorectal cancer who had one or more first- or second-degree relatives with breast cancer, and women diagnosed with both breast and colorectal cancer. Controls (n = 1769), were unrelated, breast and colorectal cancer-free, and age- and sex- frequency-matched to cases. After imputation, 6,220,060 variants were analyzed using the discovery set and variants associated with the breast-colorectal cancer phenotype at P<5.0E-04 (n = 549, at 60 loci) were analyzed for replication (n = 293 cases and 2,103 controls).
Multiple correlated SNPs in intron 1 of the ROBO1 gene were suggestively associated with the breast-colorectal cancer phenotype in the discovery and replication data (most significant; rs7430339, Pdiscovery = 1.2E-04; rs7429100, Preplication = 2.8E-03). In meta-analysis of the discovery and replication data, the most significant association remained at rs7429100 (P = 1.84E-06).
The results of this exploratory analysis did not find clear evidence for a susceptibility locus with a pleiotropic effect on hereditary breast and colorectal cancer risk, although the suggestive association of genetic variation in the region of ROBO1, a potential tumor suppressor gene, merits further investigation.
Protective associations of fruits, vegetables, and fiber intake with colorectal cancer risk have been shown in many, but not all epidemiologic studies. One possible reason for study heterogeneity is ...that dietary factors may have distinct effects by colorectal cancer molecular subtypes. Here, we investigate the association of fruit, vegetables, and fiber intake with four well-established colorectal cancer molecular subtypes separately and in combination. Nine observational studies including 9,592 cases with molecular subtypes for microsatellite instability (MSI), CpG island methylator phenotype (CIMP), and somatic mutations in
and
genes, and 7,869 controls were analyzed. Both case-only logistic regression analyses and polytomous logistic regression analyses (with one control set and multiple case groups) were used. Higher fruit intake was associated with a trend toward decreased risk of
-mutated tumors OR 4th vs. 1st quartile = 0.82 (95% confidence interval, 0.65-1.04) but not
-wildtype tumors 1.09 (0.97-1.22);
difference as shown in case-only analysis = 0.02. This difference was observed in case-control studies and not in cohort studies. Compared with controls, higher fiber intake showed negative association with colorectal cancer risk for cases with microsatellite stable/MSI-low, CIMP-negative,
-wildtype, and
-wildtype tumors (
range from 0.03 to 3.4e-03), which is consistent with the traditional adenoma-colorectal cancer pathway. These negative associations were stronger compared with MSI-high, CIMP-positive,
-mutated, or
-mutated tumors, but the differences were not statistically significant. These inverse associations for fruit and fiber intake may explain, in part, inconsistent findings between fruit or fiber intake and colorectal cancer risk that have previously been reported. SIGNIFICANCE: These analyses by colorectal cancer molecular subtypes potentially explain the inconsistent findings between dietary fruit or fiber intake and overall colorectal cancer risk that have previously been reported.
Obesity is an established risk factor for colorectal cancer (CRC), but the evidence for the association is inconsistent across molecular subtypes of the disease.
We pooled data on body mass index ...(BMI), tumor microsatellite instability status, CpG island methylator phenotype status, BRAF and KRAS mutations, and Jass classification types for 11 872 CRC cases and 11 013 controls from 11 observational studies. We used multinomial logistic regression to estimate odds ratios (OR) and 95% confidence intervals (CI) adjusted for covariables.
Higher BMI was associated with increased CRC risk (OR per 5 kg/m2 = 1.18, 95% CI = 1.15 to 1.22). The positive association was stronger for men than women but similar across tumor subtypes defined by individual molecular markers. In analyses by Jass type, higher BMI was associated with elevated CRC risk for types 1-4 cases but not for type 5 CRC cases (considered familial-like/Lynch syndrome microsatellite instability-H, CpG island methylator phenotype-low or negative, BRAF-wild type, KRAS-wild type, OR = 1.04, 95% CI = 0.90 to 1.20). This pattern of associations for BMI and Jass types was consistent by sex and design of contributing studies (cohort or case-control).
In contrast to previous reports with fewer study participants, we found limited evidence of heterogeneity for the association between BMI and CRC risk according to molecular subtype, suggesting that obesity influences nearly all major pathways involved in colorectal carcinogenesis. The null association observed for the Jass type 5 suggests that BMI is not a risk factor for the development of CRC for individuals with Lynch syndrome.
Folate is involved in multiple genetic, epigenetic, and metabolic processes, and inadequate folate intake has been associated with an increased risk of cancer.
We examined whether folate intake is ...differentially associated with colorectal cancer (CRC) risk according to somatic mutations in genes linked to CRC using targeted sequencing.
Participants within 2 large CRC consortia with available information on dietary folate, supplemental folic acid, and total folate intake were included. Colorectal tumor samples from cases were sequenced for the presence of nonsilent mutations in 105 genes and 6 signaling pathways (IGF2/PI3K, MMR, RTK/RAS, TGF-β, WNT, and TP53/ATM). Multinomial logistic regression models were analyzed comparing mutated/nonmutated CRC cases to controls to compute multivariable-adjusted odds ratios (ORs) with 95% confidence interval (CI). Heterogeneity of associations of mutated compared with nonmutated CRC cases was tested in case-only analyses using logistic regression. Analyses were performed separately in hypermutated and nonhypermutated tumors, because they exhibit different clinical behaviors.
We included 4339 CRC cases (702 hypermutated tumors, 16.2%) and 11,767 controls. Total folate intake was inversely associated with CRC risk (OR = 0.93; 95% CI: 0.90, 0.96). Among hypermutated tumors, 12 genes (AXIN2, B2M, BCOR, CHD1, DOCK3, FBLN2, MAP3K21, POLD1, RYR1, TET2, UTP20, and ZNF521) showed nominal statistical significance (P < 0.05) for heterogeneity by mutation status, but none remained significant after multiple testing correction. Among these genetic subtypes, the associations between folate variables and CRC were mostly inverse or toward the null, except for tumors mutated for DOCK3 (supplemental folic acid), CHD1 (total folate), and ZNF521 (dietary folate) that showed positive associations. We did not observe differential associations in analyses among nonhypermutated tumors, or according to the signaling pathways.
Folate intake was not differentially associated with CRC risk according to mutations in the genes explored. The nominally significant differential mutation effects observed in a few genes warrants further investigation.
Background
The anti‐tumor immune response plays a key role in colorectal cancer (CRC) progression and survival. The T cell‐inflamed gene expression profile (GEP) is a biomarker predicting response to ...checkpoint inhibitor immunotherapy across immunogenic cancer types, but the prognostic value in CRC is unknown. We evaluated associations with disease‐specific survival, somatic mutations, and examined its differentially expressed genes and pathways among 84 sporadic CRC patients from the Seattle Colon Cancer Family Registry.
Methods
Gene expression profiling was performed using Nanostring's nCounter PanCancer IO 360 panel. Somatic mutations were identified by a targeted DNA sequencing panel.
Results
The T cell‐inflamed GEP was positively associated with tumor mutation burden and microsatellite instability high (MSI‐H). Higher T cell‐inflamed GEP had favorable CRC‐specific survival (hazard ratio HR per standard deviation unit = 0.50, p = 0.004) regardless of hypermutation or MSI status. Analysis of recurrently mutated genes having at least 10 mutation carriers, suggested that the T cell‐inflamed GEP is positively associated with RYR1, and negatively associated with APC. However, these associations were attenuated after adjusting for hypermutation or MSI status. We also found that expression of genes RPL23, EPCAM, AREG and ITGA6, and the Wnt signaling pathway was negatively associated with the T cell‐inflamed GEP, which might indicate immune‐inhibitory mechanisms.
Conclusions
Our results show that the T cell‐inflamed GEP is a prognostic biomarker in non‐hypermutated microsatellite‐stable CRC. This also suggests that patient stratification for immunotherapy within this CRC subgroup should be explored further. Moreover, reported immune‐inhibitory gene expression signals may suggest targets for therapeutic combination with immunotherapy.
T cell‐inflamed gene expression profile score, a biomarker predicting immune checkpoint inhibitor responses, is related to colorectal cancer (CRC)‐specific survival among non‐hypermutated and microsatellite stable patients, a group refractory to immunotherapy. Our finding suggests that patient stratification for immunotherapy within this CRC subgroup should be explored further.
(
) activates oncogenic signaling pathways and induces inflammation to promote colorectal carcinogenesis.
We characterized
and its subspecies in colorectal tumors and examined associations with tumor ...characteristics and colorectal cancer-specific survival. We conducted deep sequencing of
,
, and bacterial
genes in tumors from 1,994 patients with colorectal cancer and assessed associations between
presence and clinical characteristics, colorectal cancer-specific mortality, and somatic mutations.
, which was present in 10.3% of tumors, was detected in a higher proportion of right-sided and advanced-stage tumors, particularly subspecies
. Presence of
was associated with higher colorectal cancer-specific mortality (HR, 1.97;
= 0.0004). This association was restricted to nonhypermutated, microsatellite-stable tumors (HR, 2.13;
= 0.0002) and those who received chemotherapy HR, 1.92; confidence interval (CI), 1.07-3.45;
= 0.029). Only
subspecies
, the main subspecies detected (65.8%), was associated with colorectal cancer-specific mortality (HR, 2.16;
= 0.0016), subspecies
and
were not (HR, 1.07;
= 0.86). Additional adjustment for tumor stage suggests that the effect of
on mortality is partly driven by a stage shift. Presence of
was associated with microsatellite instable tumors, tumors with
exonuclease domain mutations, and
mutations, and suggestively associated with
mutations.
, and particularly subspecies
, was associated with a higher colorectal cancer-specific mortality and specific somatic mutated genes.
Our findings identify the
subspecies
as negatively impacting colorectal cancer mortality, which may occur through a stage shift and its effect on chemoresistance.
Carriers of germline biallelic pathogenic variants in the MUTYH gene have a high risk of colorectal cancer. We test 5649 colorectal cancers to evaluate the discriminatory potential of a tumor ...mutational signature specific to MUTYH for identifying biallelic carriers and classifying variants of uncertain clinical significance (VUS). Using a tumor and matched germline targeted multi-gene panel approach, our classifier identifies all biallelic MUTYH carriers and all known non-carriers in an independent test set of 3019 colorectal cancers (accuracy = 100% (95% confidence interval 99.87-100%)). All monoallelic MUTYH carriers are classified with the non-MUTYH carriers. The classifier provides evidence for a pathogenic classification for two VUS and a benign classification for five VUS. Somatic hotspot mutations KRAS p.G12C and PIK3CA p.Q546K are associated with colorectal cancers from biallelic MUTYH carriers compared with non-carriers (p = 2 × 10
and p = 6 × 10
, respectively). Here, we demonstrate the potential application of mutational signatures to tumor sequencing workflows to improve the identification of biallelic MUTYH carriers.
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