Chan, Andrew T

Background: Considering the pathophysiological importance of the intestine-passing microbiota, we hypothesized that the mutational and microbial profiles of colorectal cancer might gradually change along detailed anatomical locations and that these trends might differ by the age of diagnosis and the microsatellite instability (MSI) status. Methods: We assessed somatic mutations and selected bacterial species in colorectal carcinomas along the cecum, ascending colon, transverse colon, descending colon, sigmoid colon, and rectum, utilizing targeted sequencing data ( N = 5685) from the Genetics and Epidemiology of Colorectal Cancer Consortium and tissue microbial data ( N = 1389) from the Health Professionals Follow-up Study and Nurses’ Health Study. Results: There were decreasing trends from the cecum to rectum in the prevalence of gene mutations in the IGF/PI3K, receptor tyrosine kinase (RTK)/RAS, TGFB, and WNT signaling pathways (all P trend < 0.0001), as well as high levels of Bacteroides fragilis ( P trend < 0.0001) and high levels of Fusobacterium nucleatum ( P trend = 0.0029) (but not enterotoxigenic Bacteroides fragilis or pks+ Escherichia coli ). Conversely, TP53 pathway mutations showed an increasing cecum-to-rectum trend ( P trend < 0.0001). Similar to later-onset cases diagnosed at ages 50 years and older, in early-onset cases diagnosed under the age of 50 years, we found generally decreasing cecum-to-rectum trends of IGF/PI3K, RTK/RAS, TGFB, and WNT pathway mutations and an increasing cecum-to-rectum trend in TP53 pathway mutations. By contrast, the cecum-to-rectum prevalence-changing trends in IGF/PI3K, RTK/RAS, TGFB, and TP53 pathway mutations were present in non–MSI-high tumors but not in MSI-high tumors (all P interaction < 0.0052). Conclusion: Non–MSI-high colorectal cancers exhibited decreasing cecum-to-rectum trends of IGF/PI3K, RTK/RAS, and TGFB pathway mutations (and an increasing trend of TP53 pathway mutations), in contrast to MSI-high tumors that demonstrated no such trends. Our study highlights the importance of detailed colorectal subsite information combined with tumor molecular and microbial characteristics in colorectal cancer research.

Abstract Background Physical activity is associated with lower colorectal cancer (CRC) risk, but its association with molecular subtypes defined by genetic and epigenetic alterations of the disease is unclear. Such information may enhance the understanding of the mechanisms related to the benefits of physical activity. Methods Pooled observational (cases: n = 5386; controls: n = 6798; studies n = 5) and genome-wide association data (cases: n = 8178; controls: n = 10 472; studies n = 5) were used. We used multivariable logistic regression models and Mendelian randomization to assess the association between physical activity and the risk of CRC subtypes defined by individual tumor markers (and marker combinations), namely microsatellite instability status, CpG island methylator phenotype status, and BRAF and KRAS mutations. We used case-only analysis to test for differences between molecular subtypes. We applied Bonferroni correction to account for multiple tests. Results In the pooled observational analysis, higher levels of physical activity were associated with lower CRC risk (Obs-per 1SD, odds ratio [OR] = 0.94, 95% confidence interval [CI] = 0.90 to 0.97), with an association that was stronger in males (Obs-per 1SD, OR = 0.91, 95% CI = 0.87 to 0.96) than in females (Obs-per 1SD, OR = 0.97, 95% CI = 0.91 to 1.03; Pinteraction = .04). Higher physical activity was associated with a lower risk of CRC across all molecular subtypes, especially in males. There was no difference in the associations by subtypes by pooled observational or Mendelian randomization analyses. The findings did not differ by study design, anatomical site, and early or late age onset of CRC. Conclusions Our findings suggest that physical activity is not differentially associated with the 4 major molecular subtypes involved in colorectal carcinogenesis, indicating that its benefits extend broadly across colorectal cancer pathogenesis.

Abstract Background: Waist circumference (WC) and its allometric counterpart, “a body shape index” (ABSI), are risk factors for colorectal cancer; however, it is uncertain whether associations with these body measurements are limited to specific molecular subtypes of the disease. Methods: Data from 2,772 colorectal cancer cases and 3,521 controls were pooled from four cohort studies within the Genetics and Epidemiology of Colorectal Cancer Consortium. Four molecular markers (BRAF mutation, KRAS mutation, CpG island methylator phenotype, and microsatellite instability) were analyzed individually and in combination (Jass types). Multivariable logistic and multinomial logistic models were used to assess the associations of WC and ABSI with overall colorectal cancer risk and, in case-only analyses, to evaluate heterogeneity by molecular subtype, respectively. Results: Higher WC (ORper 5 cm = 1.06, 95% confidence interval, 1.04–1.09) and ABSI (ORper 1-SD = 1.07, 95% confidence interval, 1.00–1.14) were associated with elevated colorectal cancer risk. There was no evidence of heterogeneity between the molecular subtypes. No difference was observed regarding the influence of WC and ABSI on the four major molecular markers in proximal colon, distal colon, and rectal cancers, as well as in early- and late-onset colorectal cancers. Associations did not differ in the Jass-type analysis. Conclusions: Higher WC and ABSI were associated with elevated colorectal cancer risk; however, they do not differentially influence all four major molecular mutations involved in colorectal carcinogenesis but underscore the importance of maintaining a healthy body weight in colorectal cancer prevention. Impact: The proposed results have potential utility in colorectal cancer prevention.

Regular, long-term aspirin use may act synergistically with genetic variants, particularly those in mechanistically relevant pathways, to confer a protective effect on colorectal cancer (CRC) risk. We leveraged pooled data from 52 clinical trial, cohort, and case-control studies that included 30,806 CRC cases and 41,861 controls of European ancestry to conduct a genome-wide interaction scan between regular aspirin/nonsteroidal anti-inflammatory drug (NSAID) use and imputed genetic variants. After adjusting for multiple comparisons, we identified statistically significant interactions between regular aspirin/NSAID use and variants in 6q24.1 (top hit rs72833769 ), which has evidence of influencing expression of TBC1D7 (a subunit of the TSC1-TSC2 complex, a key regulator of MTOR activity), and variants in 5p13.1 (top hit rs350047 ), which is associated with expression of PTGER4 (codes a cell surface receptor directly involved in the mode of action of aspirin). Genetic variants with functional impact may modulate the chemopreventive effect of regular aspirin use, and our study identifies putative previously unidentified targets for additional mechanistic interrogation.

Abstract Background: The genotoxin colibactin causes a tumor single-base substitution (SBS) mutational signature, SBS88. It is unknown whether epidemiologic factors’ association with colorectal cancer risk and survival differs by SBS88. Methods: Within the Genetic Epidemiology of Colorectal Cancer Consortium and Colon Cancer Family Registry, we measured SBS88 in 4,308 microsatellite stable/microsatellite instability low tumors. Associations of epidemiologic factors with colorectal cancer risk by SBS88 were assessed using multinomial regression (N = 4,308 cases, 14,192 controls; cohort-only cases N = 1,911), and with colorectal cancer–specific survival using Cox proportional hazards regression (N = 3,465 cases). Results: 392 (9%) tumors were SBS88 positive. Among all cases, the highest quartile of fruit intake was associated with lower risk of SBS88-positive colorectal cancer than SBS88-negative colorectal cancer [odds ratio (OR) = 0.53, 95% confidence interval (CI) 0.37-0.76; OR = 0.75, 95% CI 0.66–0.85, respectively, Pheterogeneity = 0.047]. Among cohort studies, associations of body mass index (BMI), alcohol, and fruit intake with colorectal cancer risk differed by SBS88. BMI ≥30 kg/m2 was associated with worse colorectal cancer–specific survival among those SBS88-positive [hazard ratio (HR) = 3.40, 95% CI 1.47–7.84], but not among those SBS88-negative (HR = 0.97, 95% CI 0.78–1.21, Pheterogeneity = 0.066). Conclusions: Most epidemiologic factors did not differ by SBS88 for colorectal cancer risk or survival. Higher BMI may be associated with worse colorectal cancer–specific survival among those SBS88-positive; however, validation is needed in samples with whole-genome or whole-exome sequencing available. Impact: This study highlights the importance of identification of tumor phenotypes related to colorectal cancer and understanding potential heterogeneity for risk and survival.

Abstract Background: 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. Methods: 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 &gt; 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. Results: 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. Conclusions: DEPTH can identify candidate susceptibility regions for colorectal cancer not identified using conventional analyses of larger datasets. Impact: DEPTH has potential as a powerful complementary tool to conventional GWAS analyses for discovering susceptibility regions within the genome.

Abstract Colorectal cancer risk can be impacted by genetic, environmental, and lifestyle factors, including diet and obesity. Gene-environment interactions (G × E) can provide biological insights into the effects of obesity on colorectal cancer risk. Here, we assessed potential genome-wide G × E interactions between body mass index (BMI) and common SNPs for colorectal cancer risk using data from 36,415 colorectal cancer cases and 48,451 controls from three international colorectal cancer consortia (CCFR, CORECT, and GECCO). The G × E tests included the conventional logistic regression using multiplicative terms (one degree of freedom, 1DF test), the two-step EDGE method, and the joint 3DF test, each of which is powerful for detecting G × E interactions under specific conditions. BMI was associated with higher colorectal cancer risk. The two-step approach revealed a statistically significant G×BMI interaction located within the Formin 1/Gremlin 1 (FMN1/GREM1) gene region (rs58349661). This SNP was also identified by the 3DF test, with a suggestive statistical significance in the 1DF test. Among participants with the CC genotype of rs58349661, overweight and obesity categories were associated with higher colorectal cancer risk, whereas null associations were observed across BMI categories in those with the TT genotype. Using data from three large international consortia, this study discovered a locus in the FMN1/GREM1 gene region that interacts with BMI on the association with colorectal cancer risk. Further studies should examine the potential mechanisms through which this locus modifies the etiologic link between obesity and colorectal cancer. Significance: This gene-environment interaction analysis revealed a genetic locus in FMN1/GREM1 that interacts with body mass index in colorectal cancer risk, suggesting potential implications for precision prevention strategies.

Screening for colorectal cancer (CRC) is effective in reducing CRC related mortality. Current screening methods include endoscopy based and biomarker based approaches. This guideline is a joint official statement of the Asian Pacific Association of Gastroenterology (APAGE) and the Asian Pacific Society of Digestive Endoscopy (APSDE), developed in response to the increasing use of, and accumulating supportive evidence for the role of, non-invasive biomarkers for the diagnosis of CRC and its precursor lesions. A systematic review of 678 publications and a two stage Delphi consensus process involving 16 clinicians in various disciplines was undertaken to develop 32 evidence based and expert opinion based recommendations for the use of faecal immunochemical tests, faecal based tumour biomarkers or microbial biomarkers, and blood based tumour biomarkers for the detection of CRC and adenoma. Comprehensive up-to-date guidance is provided on indications, patient selection and strengths and limitations of each screening tool. Future research to inform clinical applications are discussed alongside objective measurement of research priorities. This joint APAGE–APSDE practice guideline is intended to provide an up-to-date guide to assist clinicians worldwide in utilising non-invasive biomarkers for CRC screening; it has particular salience for clinicians in the Asia-Pacific region.

Abstract Background: Tobacco smoking is an established risk factor for colorectal cancer. However, genetically defined population subgroups may have increased susceptibility to smoking-related effects on colorectal cancer. Methods: A genome-wide interaction scan was performed including 33,756 colorectal cancer cases and 44,346 controls from three genetic consortia. Results: Evidence of an interaction was observed between smoking status (ever vs. never smokers) and a locus on 3p12.1 (rs9880919, P = 4.58 × 10−8), with higher associated risk in subjects carrying the GG genotype [OR, 1.25; 95% confidence interval (CI), 1.20–1.30] compared with the other genotypes (OR &lt;1.17 for GA and AA). Among ever smokers, we observed interactions between smoking intensity (increase in 10 cigarettes smoked per day) and two loci on 6p21.33 (rs4151657, P = 1.72 × 10−8) and 8q24.23 (rs7005722, P = 2.88 × 10−8). Subjects carrying the rs4151657 TT genotype showed higher risk (OR, 1.12; 95% CI, 1.09–1.16) compared with the other genotypes (OR &lt;1.06 for TC and CC). Similarly, higher risk was observed among subjects carrying the rs7005722 AA genotype (OR, 1.17; 95% CI, 1.07–1.28) compared with the other genotypes (OR &lt;1.13 for AC and CC). Functional annotation revealed that SNPs in 3p12.1 and 6p21.33 loci were located in regulatory regions, and were associated with expression levels of nearby genes. Genetic models predicting gene expression revealed that smoking parameters were associated with lower colorectal cancer risk with higher expression levels of CADM2 (3p12.1) and ATF6B (6p21.33). Conclusions: Our study identified novel genetic loci that may modulate the risk for colorectal cancer of smoking status and intensity, linked to tumor suppression and immune response. Impact: These findings can guide potential prevention treatments.

Abstract Background: Associations between candidate germline genetic variants and treatment outcome of oxaliplatin, a drug commonly used for patients with colorectal cancer, have been reported but not robustly established. This study aimed to construct polygenic hazard scores (PHSs) as predictive markers for oxaliplatin treatment outcome by using a supervised principal component approach (PCA). Methods: Genome-wide association analysis for overall survival, including interaction terms (SNP*treatment type) was carried out using two phase III trials, 3,098 resected stage III colon cancer (rCC) patients of NCCTG N0147 and 506 metastatic colorectal cancer (mCRC) patients of NCCTG N9741, separately. SNPs showing interaction with genome-wide significance (P &lt; 5 × 10–8) were selected for PCA to derive a PHS. PHS interaction with treatment was included in Cox regression models to predict outcome. Replication of prediction models was performed in an independent cohort, DACHS. Results: The two PHSs based on the first two principal components of selected SNPs (15SNPs for rCC and 13SNPs for mCRC) were used to construct interaction terms with treatment type and included in models adjusted for clinical covariables. However, in the DACHS study, the addition of the two PHS terms to clinical models did not improve the prediction error in either patients with rCC or mCRC. PHS interaction was also not replicated. Conclusions: The PHSs derived using principal components efficiently combined multiple predictive SNPs for estimating likelihood of benefit from oxaliplatin versus other treatment but could not be replicated. Impact: These results highlight the potential but also challenges in generating evidence for a predictive polygenic score for oxaliplatin efficacy.