Association Between Smoking and Molecular Subtypes of Colorectal Cancer

Background: Smoking is associated with colorectal cancer (CRC) risk. Previous studies suggested this association may be restricted to certain molecular subtypes of CRC, but large-scale comprehensive analysis is lacking. Methods: A total of 9789 CRC cases and 11 231 controls of European ancestry from 11 observational studies were included. We harmonized smoking variables across studies and derived sex study-specific quartiles of pack-years of smoking for analysis. Four somatic colorectal tumor markers were assessed individually and in combination, including BRAF mutation, KRAS mutation, CpG island methylator phenotype (CIMP), and microsatellite instability (MSI) status. A multinomial logistic regression analysis was used to assess the association between smoking and risk of CRC subtypes by molecular characteristics, adjusting for age, sex, and study. All statistical tests were 2-sided and adjusted for Bonferroni correction. Results: Heavier smoking was associated with higher risk of CRC overall and stratified by individual markers (P-trend <.001). The associations differed statistically significantly between all molecular subtypes, which was the most statistically significant for CIMP and BRAF. Compared with never-smokers, smokers in the fourth quartile of pack-years had a 90% higher risk of CIMP-positive CRC (odds ratio = 1.90, 95% confidence interval = 1.60 to 2.26) but only 35% higher risk for CIMP-negative CRC (odds ratio = 1.35, 95% confidence interval = 1.22 to 1.49; P-difference = 2.1 x 10(-6)). The association was also stronger in tumors that were CIMP positive, MSI high, or KRAS wild type when combined (P-difference <.001). Conclusion: Smoking was associated with differential risk of CRC subtypes defined by molecular characteristics. Heavier smokers had particularly higher risk of CRC subtypes that were CIMP positive and MSI high in combination, suggesting that smoking may be involved in the development of colorectal tumors via the serrated pathway

Identifying colorectal cancer caused by biallelic MUTYH pathogenic variants using tumor mutational signatures

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 x 10(-23) and p = 6 x 10(-11), respectively). Here, we demonstrate the potential application of mutational signatures to tumor sequencing workflows to improve the identification of biallelic MUTYH carriers. Germline biallelic pathogenic MUTYH variants predispose patients to colorectal cancer (CRC); however, approaches to identify MUTYH variant carriers are lacking. Here, the authors evaluated mutational signatures that could distinguish MUTYH carriers in large CRC cohorts, and found MUTYH-associated somatic mutations

Landscape of somatic single nucleotide variants and indels in colorectal cancer and impact on survival

Colorectal cancer (CRC) is a biologically heterogeneous disease. To characterize its mutational profile, we conduct targeted sequencing of 205 genes for 2,105 CRC cases with survival data. Our data shows several findings in addition to enhancing the existing knowledge of CRC. We identify PRKCI, SPZ1, MUTYH, MAP2K4, FETUB, and TGFBR2 as additional genes significantly mutated in CRC. We find that among hypermutated tumors, an increased mutation burden is associated with improved CRC-specific survival (HR=0.42, 95% CI: 0.21-0.82). Mutations in TP53 are associated with poorer CRC-specific survival, which is most pronounced in cases carrying TP53 mutations with predicted 0% transcriptional activity (HR=1.53, 95% CI: 1.21-1.94). Furthermore, we observe differences in mutational frequency of several genes and pathways by tumor location, stage, and sex. Overall, this large study provides deep insights into somatic mutations in CRC, and their potential relationships with survival and tumor features. Large scale sequencing study is of paramount importance to unravel the heterogeneity of colorectal cancer. Here, the authors sequenced 205 cancer genes in more than 2000 tumours and identified additional mutated driver genes, determined that mutational burden and specific mutations in TP53 are associated with survival odds

Salicylic Acid and Risk of Colorectal Cancer: A Two-Sample Mendelian Randomization Study.

Salicylic acid (SA) has observationally been shown to decrease colorectal cancer (CRC) risk. Aspirin (acetylsalicylic acid, that rapidly deacetylates to SA) is an effective primary and secondary chemopreventive agent. Through a Mendelian randomization (MR) approach, we aimed to address whether levels of SA affected CRC risk, stratifying by aspirin use. A two-sample MR analysis was performed using GWAS summary statistics of SA (INTERVAL and EPIC-Norfolk, N = 14,149) and CRC (CCFR, CORECT, GECCO and UK Biobank, 55,168 cases and 65,160 controls). The DACHS study (4410 cases and 3441 controls) was used for replication and stratification of aspirin-use. SNPs proxying SA were selected via three methods: (1) functional SNPs that influence the activity of aspirin-metabolising enzymes; (2) pathway SNPs present in enzymes' coding regions; and (3) genome-wide significant SNPs. We found no association between functional SNPs and SA levels. The pathway and genome-wide SNPs showed no association between SA and CRC risk (OR: 1.03, 95% CI: 0.84-1.27 and OR: 1.08, 95% CI: 0.86-1.34, respectively). Results remained unchanged upon aspirin use stratification. We found little evidence to suggest that an SD increase in genetically predicted SA protects against CRC risk in the general population and upon stratification by aspirin use

Fecal Immunochemical Tests for Colorectal Cancer Screening: Is Fecal Sampling from Multiple Sites Necessary?

Fecal immunochemical tests (FITs) for hemoglobin (Hb) are increasingly used for colorectal cancer (CRC) screening. Most FIT manufacturers instruct that fecal samples from multiple parts of one bowel movement should be obtained. Our aim was to compare the FIT diagnostic performance based on fecal samples from just one versus two different sites of one bowel movement. A total of 1141 participants of screening colonoscopy provided two fecal samples from two different sites of a single bowel movement for FIT analyses. There was no statistically significant difference in the diagnostic performance of the FIT when either one or both fecal samples were used for analysis, with area under the curve (AUC) for detecting CRC ranging from 0.94 (95% confidence interval (CI) 0.84&#8211;0.99) for one FIT to 0.95 (95%CI 0.86&#8211;0.99) for a geometric mean of two FITs. The manufacturers&#8217; recommendation of sampling multiple sites of the stool aims to reduce intra-individual Hb variability and improve diagnostic performance. If no such improvement can be achieved, the recommendation for multiple-site sampling might have potential adverse effects on population adherence to FIT-based CRC screening. Our results point to a potential of increasing adherence to FIT screening by simplifying instructions for fecal sampling at no loss of the diagnostic performance

Risk Factors of Inadequate Bowel Preparation for Screening Colonoscopy

The success of a colonoscopy in detecting and removing pre-cancerous and cancerous lesions depends heavily on the quality of bowel preparation. Despite efforts, 20–44% of colonoscopy participants have an inadequate bowel preparation. We aimed to assess and compare risk factors for inadequate bowel preparation and for the presence of advanced colorectal neoplasms in routine screening practice. In this cross-sectional study, among 8125 participants of screening colonoscopy in Germany with a comprehensive assessment of sociodemographic factors, lifestyle and medical history, we examined factors associated with inadequate bowel preparation and with findings of advanced neoplasms using adjusted log-binomial regression models. Among the identified risk factors assessed, three factors were identified that were significantly associated with inadequate bowel preparation: age ≥ 70 years (adjusted prevalence ratios, aPR, 1.50 95%CI 1.31–1.71), smoking (aPR 1.29 95%CI 1.11–1.50) and abdominal symptoms (aPR 1.14 95%CI 1.02–1.27). The same risk factors were also associated with the prevalence of advanced neoplasms in our study (aPR 1.72, 1.62 and 1.44, respectively). The risk factors associated with inadequate bowel preparation in this study were also associated with a higher risk for advanced neoplasms. Inadequate bowel preparation for colonoscopy might lead to missed colorectal cancer (CRC) precursors and the late diagnosis of CRC. People at high risk of advanced neoplasms are in particular need of enhanced bowel preparation

Smoking, alcohol consumption and colorectal cancer risk by molecular pathological subtypes and pathways

Background!#!Smoking and alcohol increase risk for colorectal malignancies. However, colorectal cancer (CRC) is a heterogenic disease and associations with the molecular pathological pathways are unclear.!##!Methods!#!This population-based case-control study includes 2444 cases with first-diagnosis CRC and 2475 controls. Tumour tissue was analysed for MSI (microsatellite instability), CIMP (CpG island methylator phenotype), BRAF (B-Raf proto-oncogene serine/threonine kinase gene) and KRAS (Kirsten rat sarcoma viral oncogene homologue gene) mutations. Odds ratios (ORs) and 95% confidence intervals (95% CIs) were estimated for associations between alcohol and smoking and CRC molecular subtypes and pathways.!##!Results!#!Current smoking showed higher ORs for MSI-high (OR = 2.79, 95% CI: 1.86-4.18) compared to MSS (OR = 1.41, 1.14-1.75, p-heterogeneity (p-het) = 0.001), BRAF-mutated (mut) (OR = 2.40, 1.41-4.07) compared to BRAF-wild type (wt) (OR = 1.52, 1.24-1.88, p-het = 0.074), KRAS-wt (OR = 1.70, 1.36-2.13) compared to KRAS-mut (OR = 1.26, 0.95-1.68, p-het = 0.039) and CIMP-high (OR = 2.01, 1.40-2.88) compared to CIMP-low/negative CRC (OR = 1.50, 1.22-1.85, p-het=0.101). Current smoking seemed more strongly associated with sessile serrated pathway (CIMP-high + BRAF-mut; OR = 2.39, 1.27-4.52) than with traditional pathway CRC (MSS + CIMP-low/negative + BRAF-wt; OR = 1.50, 1.16-1.94) and no association was observed with alternate pathway CRC (MSS + CIMP-low/negative + KRAS-wt; OR = 1.08, 0.77-1.43). No heterogeneity was observed in alcohol consumption association by molecular subtypes.!##!Conclusions!#!In this large case-control study, smoking was more strongly associated with MSI-high and KRAS-wt CRC and with cases showing features of the sessile serrated pathway. Association patterns were less clear for alcohol consumption

Response to neoadjuvant treatment among rectal cancer patients in a population-based cohort

Background!#!In rectal cancer, prediction of tumor response and pathological complete response (pCR) to neoadjuvant treatment could contribute to refine selection of patients who might benefit from a delayed- or no-surgery approach. The aim of this study was to explore the association of clinical and molecular characteristics of rectal cancer with response to neoadjuvant treatment and to compare patient survival according to level of response.!##!Methods!#!Resected rectal cancer patients were selected from a population-based cohort study. Molecular tumor markers were determined from the surgical specimen. Tumor response and pCR were defined as downstaging in T or N stage and absence of tumor cells upon pathological examination, respectively. The associations of patient and tumor characteristics with tumor response and pCR were explored, and patient survival was determined by degree of response to neoadjuvant treatment.!##!Results!#!Among 1536 patients with rectal cancer, 602 (39%) received neoadjuvant treatment. Fifty-five (9%) patients presented pCR, and 239 (49%) and 250 (53%) patients showed downstaging of the T and N stages, respectively. No statistically significant associations were observed between patient or tumor characteristics and tumor response or pCR. Patients who presented any type of response to neoadjuvant treatment had significantly better cancer-specific and overall survival compared with non-responders.!##!Conclusion!#!In this study, patient characteristics were not associated with response to neoadjuvant treatment, and molecular characteristics determined after surgical resection of the tumor were not predictive of pCR or tumor downstaging. Future studies should include molecular biomarkers from biopsy samples before neoadjuvant treatment