Circulating tryptophan-kynurenine pathway metabolites are associated with all-cause mortality among patients with stage I-III colorectal cancer.

Alterations within the tryptophan-kynurenine metabolic pathway have been linked to the etiology of colorectal cancer (CRC), but the relevance of this pathway for prognostic outcomes in CRC patients needs further elucidation. Therefore, we investigated associations between circulating concentrations of tryptophan-kynurenine pathway metabolites and all-cause mortality among CRC patients. This study utilizes data from 2102 stage I-III CRC patients participating in six prospective cohorts involved in the international FOCUS Consortium. Preoperative circulating concentrations of tryptophan, kynurenine, kynurenic acid (KA), 3-hydroxykynurenine (HK), xanthurenic acid (XA), 3-hydroxyanthranilic acid (HAA), anthranilic acid (AA), picolinic acid (PA), and quinolinic acid (QA) were measured by liquid chromatography-tandem mass spectrometry. Using Cox proportional hazards regression, we examined associations of above-mentioned metabolites with all-cause mortality, adjusted for potential confounders. During a median follow-up of 3.2 years (interquartile range: 2.2-4.9), 290 patients (13.8%) deceased. Higher blood concentrations of tryptophan, XA, and PA were associated with a lower risk of all-cause mortality (per doubling in concentrations: tryptophan: HR = 0.56; 95%CI:0.41,0.76, XA: HR = 0.74; 95%CI:0.64,0.85, PA: HR = 0.76; 95%CI:0.64,0.92), while higher concentrations of HK and QA were associated with an increased risk of death (per doubling in concentrations: HK: HR = 1.80; 95%CI:1.47,2.21, QA: HR = 1.31; 95%CI:1.05,1.63). A higher kynurenine-to-tryptophan ratio, a marker of cell-mediated immune activation, was associated with an increased risk of death (per doubling: HR = 2.07; 95%CI:1.52,2.83). In conclusion, tryptophan-kynurenine pathway metabolites may be prognostic markers of survival in CRC patients.

Prognostic value of post-operative iron biomarkers in colorectal cancer: population-based patient cohort.

BACKGROUND: Post-operative anaemia is linked to iron deficiency. We investigated the prognostic value of post-operative iron biomarkers in colorectal cancer (CRC). METHODS: Ferritin, transferrin, iron, and transferrin saturation (TS%) were measured from blood collected at a single time-point post-surgery in 2769 CRC patients. Associations between iron biomarkers with cancer-specific survival (CSS) and overall survival (OS) were assessed using Cox regression with hazard ratios (HR), stratified by post-operative time of blood collection (<1-month/≥1-month). RESULTS: After a median follow-up of 9.5 years, 52.6% of patients had died. For iron biomarkers assessed <1-month post-surgery, higher compared to normal TS% was associated with shorter CSS (HR [95% CI] = 2.36 [1.25-4.46]), and higher iron levels with better OS (upper vs. median tertile: HR [95% CI] = 0.79 [0.65-0.97]). When assessed ≥1-month post-surgery, elevated ferritin was associated with poor CSS (high vs. normal: HR [95% CI] = 1.44 [1.10-1.87]), and low TS% with worse CSS (low vs. normal: HR [95% CI] = 1.60 [1.24-2.06]). Similar but weaker associations were observed for OS. CONCLUSION: Monitoring of serum ferritin and TS% beyond 1-month post-surgery may be relevant for risk stratification of patients with operable CRC. Future studies should validate our findings.

Genetic risk impacts the association of menopausal hormone therapy with colorectal cancer risk.

BACKGROUND: Menopausal hormone therapy (MHT), a common treatment to relieve symptoms of menopause, is associated with a lower risk of colorectal cancer (CRC). To inform CRC risk prediction and MHT risk-benefit assessment, we aimed to evaluate the joint association of a polygenic risk score (PRS) for CRC and MHT on CRC risk. METHODS: We used data from 28,486 postmenopausal women (11,519 cases and 16,967 controls) of European descent. A PRS based on 141 CRC-associated genetic variants was modeled as a categorical variable in quartiles. Multiplicative interaction between PRS and MHT use was evaluated using logistic regression. Additive interaction was measured using the relative excess risk due to interaction (RERI). 30-year cumulative risks of CRC for 50-year-old women according to MHT use and PRS were calculated. RESULTS: The reduction in odds ratios by MHT use was larger in women within the highest quartile of PRS compared to that in women within the lowest quartile of PRS (p-value = 2.7 × 10-8). At the highest quartile of PRS, the 30-year CRC risk was statistically significantly lower for women taking any MHT than for women not taking any MHT, 3.7% (3.3%-4.0%) vs 6.1% (5.7%-6.5%) (difference 2.4%, P-value = 1.83 × 10-14); these differences were also statistically significant but smaller in magnitude in the lowest PRS quartile, 1.6% (1.4%-1.8%) vs 2.2% (1.9%-2.4%) (difference 0.6%, P-value = 1.01 × 10-3), indicating 4 times greater reduction in absolute risk associated with any MHT use in the highest compared to the lowest quartile of genetic CRC risk. CONCLUSIONS: MHT use has a greater impact on the reduction of CRC risk for women at higher genetic risk. These findings have implications for the development of risk prediction models for CRC and potentially for the consideration of genetic information in the risk-benefit assessment of MHT use.

Excess Weight, Polygenic Risk Score, and Findings of Colorectal Neoplasms at Screening Colonoscopy.

INTRODUCTION: Excess weight is an established risk factor of colorectal cancer (CRC). However, evidence is lacking on how its impact varies by polygenic risk at different stages of colorectal carcinogenesis. METHODS: We assessed the individual and joint associations of body mass index (BMI) and polygenic risk scores (PRSs) with findings of colorectal neoplasms among 4,784 participants of screening colonoscopy. Adjusted odds ratios (aORs) for excess weight derived by multiple logistic regression were converted to genetic risk equivalents (GREs) to quantify the impact of excess weight compared with genetic predisposition. RESULTS: Overweight and obesity (BMI 25-<30 and ≥30 kg/m 2 ) were associated with increased risk of any colorectal neoplasm (aOR [95% confidence interval, CI] 1.26 [1.09-1.45] and 1.47 [1.24-1.75]). Obesity was associated with increased risk of advanced colorectal neoplasm (aOR [95% CI] 1.46 [1.16-1.84]). Dose-response relationships were seen for the PRS (stronger for advanced neoplasms than any neoplasms), with no interaction with BMI, suggesting multiplicative effects of both factors. Obese participants with a PRS in the highest tertile had a 2.3-fold (95% CI 1.7-3.1) and 2.9-fold (95% CI 1.9-4.3) increased risk of any colorectal neoplasm and advanced colorectal neoplasm, respectively. The aOR of obesity translated into a GRE of 38, meaning that its impact was estimated to be equivalent to the risk caused by 38 percentiles higher PRS for colorectal neoplasm. DISCUSSION: Excess weight and polygenic risk are associated with increased risk of colorectal neoplasms in a multiplicative manner. Maintaining normal weight is estimated to have an equivalent effect as having 38 percentiles lower PRS.

Characterization of additive gene-environment interactions for colorectal cancer risk.

BACKGROUND: Colorectal cancer (CRC) is a common, fatal cancer. Identifying subgroups who may benefit more from intervention is of critical public health importance. Previous studies have assessed multiplicative interaction between genetic risk scores and environmental factors, but few have assessed additive interaction, the relevant public health measure. METHODS: Using resources from colorectal cancer consortia including 45,247 CRC cases and 52,671 controls, we assessed multiplicative and additive interaction (relative excess risk due to interaction, RERI) using logistic regression between 13 harmonized environmental factors and genetic risk score including 141 variants associated with CRC risk. RESULTS: There was no evidence of multiplicative interaction between environmental factors and genetic risk score. There was additive interaction where, for individuals with high genetic susceptibility, either heavy drinking [RERI = 0.24, 95% confidence interval, CI, (0.13, 0.36)], ever smoking [0.11 (0.05, 0.16)], high BMI [female 0.09 (0.05, 0.13), male 0.10 (0.05, 0.14)], or high red meat intake [highest versus lowest quartile 0.18 (0.09, 0.27)] was associated with excess CRC risk greater than that for individuals with average genetic susceptibility. Conversely, we estimate those with high genetic susceptibility may benefit more from reducing CRC risk with aspirin/NSAID use [-0.16 (-0.20, -0.11)] or higher intake of fruit, fiber, or calcium [highest quartile versus lowest quartile -0.12 (-0.18, -0.050); -0.16 (-0.23, -0.09); -0.11 (-0.18, -0.05), respectively] than those with average genetic susceptibility. CONCLUSIONS: Additive interaction is important to assess for identifying subgroups who may benefit from intervention. The subgroups identified in this study may help inform precision CRC prevention.

Automated curation of large-scale cancer histopathology image datasets using deep learning.

BACKGROUND: Artificial intelligence (AI) has numerous applications in pathology, supporting diagnosis and prognostication in cancer. However, most AI models are trained on highly selected data, typically one tissue slide per patient. In reality, especially for large surgical resection specimens, dozens of slides can be available for each patient. Manually sorting and labelling whole-slide images (WSIs) is a very time-consuming process, hindering the direct application of AI on the collected tissue samples from large cohorts. In this study we addressed this issue by developing a deep-learning (DL)-based method for automatic curation of large pathology datasets with several slides per patient. METHODS: We collected multiple large multicentric datasets of colorectal cancer histopathological slides from the United Kingdom (FOXTROT, N = 21,384 slides; CR07, N = 7985 slides) and Germany (DACHS, N = 3606 slides). These datasets contained multiple types of tissue slides, including bowel resection specimens, endoscopic biopsies, lymph node resections, immunohistochemistry-stained slides, and tissue microarrays. We developed, trained, and tested a deep convolutional neural network model to predict the type of slide from the slide overview (thumbnail) image. The primary statistical endpoint was the macro-averaged area under the receiver operating curve (AUROCs) for detection of the type of slide. RESULTS: In the primary dataset (FOXTROT), with an AUROC of 0.995 [95% confidence interval [CI]: 0.994-0.996] the algorithm achieved a high classification performance and was able to accurately predict the type of slide from the thumbnail image alone. In the two external test cohorts (CR07, DACHS) AUROCs of 0.982 [95% CI: 0.979-0.985] and 0.875 [95% CI: 0.864-0.887] were observed, which indicates the generalizability of the trained model on unseen datasets. With a confidence threshold of 0.95, the model reached an accuracy of 94.6% (7331 classified cases) in CR07 and 85.1% (2752 classified cases) for the DACHS cohort. CONCLUSION: Our findings show that using the low-resolution thumbnail image is sufficient to accurately classify the type of slide in digital pathology. This can support researchers to make the vast resource of existing pathology archives accessible to modern AI models with only minimal manual annotations.

Contributions of early detection and cancer prevention to colorectal cancer mortality reduction by screening colonoscopy: a validated modeling study.

BACKGROUND AND AIMS: Screening colonoscopy, recommended every 10 years, reduces mortality from colorectal cancer (CRC) by early detection of prevalent but undiagnosed CRC, as well as by removal of precursor lesions. The aim of this study was to assess the relative contribution of both components to total CRC mortality reduction over time. METHODS: Using a validated multistate Markov model, we simulated hypothetical cohorts of 100,000 individuals aged 55 to 64 years with and without screening at baseline. Main outcomes included proportions of prevented CRC deaths arising from (asymptomatic) CRC already present at baseline and from newly developed CRC during 15 years of follow-up, and mortality rate ratios of screened versus nonscreened groups over time. RESULTS: Early detection of prevalent cases accounted for 52%, 30%, and 18% of deaths prevented by screening colonoscopy within 5, 10, and 15 years, respectively. Relative reduction of mortality was estimated to be much larger for mortality from incident cancers than for mortality from cancers that were already present and detected early at screening endoscopy and for total CRC mortality (ie, 88% versus 67% and 79%, respectively, within 10 years from screening). CONCLUSIONS: Reduction of CRC mortality mainly arises from early detection of prevalent cancers during the early years after screening colonoscopy, but prevention of incident cases accounts for the majority of prevented deaths in the longer run. Prevention of incident cases leads to sustained strong reduction of CRC mortality, possibly warranting an extension of screening intervals.

Reevaluating the fraction of cancer attributable to excess weight: overcoming the hidden impact of prediagnostic weight loss.

OBJECTIVE: To evaluate the magnitude of the potential underestimation of the proportion of cancer cases attributable to excess weight, known as population attributable fraction (PAF), due to potential bias from prediagnostic weight loss already present at baseline of cohort studies and to overcome it as much as possible. METHODS: Data from the UK Biobank cohort participants aged 40-69 without prior cancer diagnosis were analyzed. We assessed the magnitude of associations of excess weight with the incidence of obesity-related cancers combined, and separately for gastrointestinal (GI) and other cancers. Using multivariable Cox proportional hazards models, hazard ratios (HR) and their 95% confidence intervals (CI), and PAFs for excess weight at baseline were estimated for various periods of time after weight measurements. FINDINGS: Of 458,660 participants, 20,218 individuals developed obesity-related cancers during a median 11.0-year follow-up, comprising 8,460 GI, and 11,765 non-GI cancers. PAFs were much higher for cancers occurring more than four years after recruitment than for cancers occurring within the initial four years: 17.7% versus 7.2%, 21.4% versus 11.7% for GI, non-GI and all obesity-related cancers combined, respectively. With respect to total cancer (including cancers with no established relationship with excess weight), PAFs were estimated as 5.1% and 8.8% for the 0-4 and 4-14-year periods of follow-up. CONCLUSION: The proportion of cancers attributable to excess weight is likely substantially larger than previously estimated based on cohort studies with short follow-up time or no or only limited exclusion of the early years of follow-up from the analyses.

The underestimated preventive effects of flexible sigmoidoscopy screening: re-analysis and meta-analysis of randomized trials.

Flexible sigmoidoscopy (FS), which is less invasive, resource intensive and costly than colonoscopy, is among the recommended screening options for colorectal cancer (CRC). Four large randomized trials consistently reported statistically significant, albeit modest effects of screening by FS on CRC incidence. However, their effect estimates included cancers that were already prevalent at recruitment and could not have been prevented by screening. We performed a re-analysis and meta-analysis of two of the trials (including the largest one) to estimate reduction of truly incident cases by a single FS offered between 55 and 64 years of age among the "at risk study population" without prevalent CRC at recruitment. In meta-analyses of data reported after more than 15 years of follow-up, relative risk (95% CI) in intention-to-screen and per-protocol analyses were 0.71 (0.66-0.76) and 0.59 (0.55-0.65) for any CRC, and 0.52 (0.47-0.57) and 0.34 (0.30-0.39) for distal CRC, respectively. These results indicate much stronger effects than those suggested by the original reports and imply that a single screening FS can prevent approximately two out of three distal incident CRC cases within 15 + years of follow-up.

Breast cancer screening programmes and self-reported mammography use in European countries.

Mammography screening has been shown to be able to reduce breast cancer mortality, leading most European countries to implement mammography-based screening programmes. In our study, we analysed key characteristics of breast cancer screening programmes and mammography use in European countries. Information on screening programmes were obtained from the 2017 European Union (EU) screening report, websites from governments and cancer registries, and through literature search in PubMed (studies published up to 20 June 2022). Data on self-reported mammography use in the past 2 years were obtained from Eurostat and had been derived from the European health interview survey (cross-sectional survey), conducted in the 27 EU countries, Iceland, Norway, Serbia, Turkey and the UK in 2013 to 2015 and 2018 to 2020. Data were analysed for each country according to their human development index (HDI). By 2022, all included countries besides Bulgaria and Greece had introduced an organised mammography-based screening programme; Romania and Turkey had only pilot programmes. Screening programmes differ substantially across countries, particularly in timing of implementation (e.g., in Sweden, the Netherlands before 1990; Belgium, France between 2000 and 2004; Denmark, Germany between 2005 and 2009; Austria, Slovakia after 2010). Self-reported mammography use also differed considerably across countries, and went along with HDI-from <36% in all countries with HDI <0.85 to >70% in most countries with HDI >0.90. The data call for efforts to improve mammography screening use across Europe, particularly in countries with lower development levels where breast cancer mortality rates are also among the highest in the region.

Overall and age-specific risk advancement periods of colorectal cancer for men vs women: Implications for gender-sensitive screening offers?

Colorectal cancer (CRC) incidence and mortality are higher among men than among women. We aimed to estimate overall and age-specific risk advancement periods (RAPs) for men compared to women, which quantify how many years earlier comparable levels of risk are reached by men. RAPs were derived by Cox regression models among 331 224 participants aged 40 to 69 at baseline of the UK Biobank with no previous diagnosis of CRC and no previous CRC screening examination who were followed with respect to CRC incidence for up to 13 years. Men were at substantially higher risk of CRC than women in age groups 50 to 59 and 60 to 69, with RAPs (95% confidence intervals) as high as 8.7 (4.5-13.0) and 6.2 (4.5-7.9), respectively. These RAPs were higher than those for family history of CRC in these age groups. By contrast, no significant sex difference but a major impact of family history was seen in age group 40 to 49 (P-value for interaction between sex and age = .00079). The observed patterns suggest that consideration of gender-specific starting ages of screening might be warranted in countries in which screening offers start at ages above 50 years.

Making colonoscopy-based screening more efficient: A "gateopener" approach.

Screening colonoscopy for early detection and prevention of colorectal cancer (CRC) is mostly used inefficiently. Here, we assessed the potential of an innovative approach to colonoscopy-based screening, by use of a single, low threshold fecal immunochemical test (FIT) as a "gateopener" for screening colonoscopy. Using COSIMO, a validated simulation model, we modeled scenarios including either direct invitation to screening colonoscopy or an alternative approach involving mailing a single ("gateopener") FIT along with an invitation to colonoscopy contingent on a FIT value above a low threshold yielding a 50% positivity rate (ie, every other pretest will be positive). Under plausible assumptions on screening offer adherence, we found that such "gateopener screening" (use of screening colonoscopy contingent on a positive, low threshold gateopener FIT) approximately doubled cancer detection rates vs conventional screening. In those spared from screening colonoscopy due to a negative gateopener FIT pretest, numbers needed to screen were 10-times higher vs those for individuals with a positive FIT, peaking in >2000 and >3800 (hypothetically) needed colonoscopies to detect one case of cancer in men and women, respectively. Gateopener screening resulted in 42%-51% and 59%-65% more prevented CRC cases and deaths, respectively. In summary, by directing colonoscopy capacities to those most likely to benefit, offering screening colonoscopy contingent on a "gateopener" low-threshold FIT would substantially enhance efficiency of colonoscopy screening.

Genome-wide study of genetic polymorphisms predictive for outcome from first-line oxaliplatin-based chemotherapy in colorectal cancer patients.

We conducted the first large genome-wide association study to identify novel genetic variants that predict better (or poorer) prognosis in colorectal cancer patients receiving standard first-line oxaliplatin-based chemotherapy vs chemotherapy without oxaliplatin. We used data from two phase III trials, NCCTG N0147 and NCCTG N9741 and a population-based patient cohort, DACHS. Multivariable Cox proportional hazards models were employed, including an interaction term between each SNP and type of treatment for overall survival (OS) and progression-free survival. The analysis was performed for studies individually, and the results were combined using fixed-effect meta-analyses separately for resected stage III colon cancer (3098 patients from NCCTG N0147 and 549 patients from DACHS) and mCRC (505 patients from NCCTG N9741 and 437 patients from DACHS). We further performed gene-based analysis as well as in silico bioinformatics analysis for CRC-relevant functional genomic annotation of identified loci. In stage III colon cancer patients, a locus on chr22 (rs11912167) was associated with significantly poorer OS after oxaliplatin-based chemotherapy vs chemotherapy without oxaliplatin (Pinteraction < 5 × 10-8 ). For mCRC patients, three loci on chr1 (rs1234556), chr12 (rs11052270) and chr15 (rs11858406) were found to be associated with differential OS (P < 5 × 10-7 ). The locus on chr1 located in the intronic region of RCSD1 was replicated in an independent cohort of 586 mCRC patients from ALGB/SWOG 80405 (Pinteraction = .04). The GWA gene-based analysis yielded for RCSD1 the most significant association with differential OS in mCRC (P = 6.6 × 10-6 ). With further investigation into its biological mechanisms, this finding could potentially be used to individualize first-line treatment and improve clinical outcomes.

The underestimated impact of excess body weight on colorectal cancer risk: Evidence from the UK Biobank cohort.

BACKGROUND: The association between excess weight and colorectal cancer (CRC) risk may have been underestimated due to potential weight loss during pre-clinical sojourn time of CRC. We aimed to investigate this association and the corresponding population attributable fraction (PAF), accounting for prediagnostic weight loss. METHODS: Data from the UK Biobank prospective cohort were used. Multivariable adjusted hazard ratios (HR) and their 95% confidence intervals (CI) for various periods of follow-up and the corresponding PAF of excess weight were calculated. RESULTS: During a median of 10.0 years of follow-up, of 453,049 participants, 4794 developed CRC. The excess weight-CRC association became substantially stronger with including increasing lengths of follow-up in the analyses and further excluding the initial years of follow-up. HRs (95% CIs) for overweight and obesity were 1.06 (0.97-1.16) and 1.14 (1.03-1.26) after 7 years of follow-up, 1.13 (1.05-1.21) and 1.23 (1.14-1.33) when including complete follow-up length, and 1.26 (1.12-1.43) and 1.42 (1.24-1.63) when excluding the initial 7 years of follow-up. The corresponding PAFs of excess weight were estimated as 6.8%, 11.3%, and 19.0%, respectively. CONCLUSIONS: Comprehensive consideration of the potential effect of prediagnostic weight loss discloses a much stronger impact of excess body weight on CRC risk than previously assumed.

Probing the diabetes and colorectal cancer relationship using gene - environment interaction analyses.

BACKGROUND: Diabetes is an established risk factor for colorectal cancer. However, the mechanisms underlying this relationship still require investigation and it is not known if the association is modified by genetic variants. To address these questions, we undertook a genome-wide gene-environment interaction analysis. METHODS: We used data from 3 genetic consortia (CCFR, CORECT, GECCO; 31,318 colorectal cancer cases/41,499 controls) and undertook genome-wide gene-environment interaction analyses with colorectal cancer risk, including interaction tests of genetics(G)xdiabetes (1-degree of freedom; d.f.) and joint testing of Gxdiabetes, G-colorectal cancer association (2-d.f. joint test) and G-diabetes correlation (3-d.f. joint test). RESULTS: Based on the joint tests, we found that the association of diabetes with colorectal cancer risk is modified by loci on chromosomes 8q24.11 (rs3802177, SLC30A8 - ORAA: 1.62, 95% CI: 1.34-1.96; ORAG: 1.41, 95% CI: 1.30-1.54; ORGG: 1.22, 95% CI: 1.13-1.31; p-value3-d.f.: 5.46 × 10-11) and 13q14.13 (rs9526201, LRCH1 - ORGG: 2.11, 95% CI: 1.56-2.83; ORGA: 1.52, 95% CI: 1.38-1.68; ORAA: 1.13, 95% CI: 1.06-1.21; p-value2-d.f.: 7.84 × 10-09). DISCUSSION: These results suggest that variation in genes related to insulin signaling (SLC30A8) and immune function (LRCH1) may modify the association of diabetes with colorectal cancer risk and provide novel insights into the biology underlying the diabetes and colorectal cancer relationship.

Genome-wide Modeling of Polygenic Risk Score in Colorectal Cancer Risk.

Accurate colorectal cancer (CRC) risk prediction models are critical for identifying individuals at low and high risk of developing CRC, as they can then be offered targeted screening and interventions to address their risks of developing disease (if they are in a high-risk group) and avoid unnecessary screening and interventions (if they are in a low-risk group). As it is likely that thousands of genetic variants contribute to CRC risk, it is clinically important to investigate whether these genetic variants can be used jointly for CRC risk prediction. In this paper, we derived and compared different approaches to generating predictive polygenic risk scores (PRS) from genome-wide association studies (GWASs) including 55,105 CRC-affected case subjects and 65,079 control subjects of European ancestry. We built the PRS in three ways, using (1) 140 previously identified and validated CRC loci; (2) SNP selection based on linkage disequilibrium (LD) clumping followed by machine-learning approaches; and (3) LDpred, a Bayesian approach for genome-wide risk prediction. We tested the PRS in an independent cohort of 101,987 individuals with 1,699 CRC-affected case subjects. The discriminatory accuracy, calculated by the age- and sex-adjusted area under the receiver operating characteristics curve (AUC), was highest for the LDpred-derived PRS (AUC = 0.654) including nearly 1.2 M genetic variants (the proportion of causal genetic variants for CRC assumed to be 0.003), whereas the PRS of the 140 known variants identified from GWASs had the lowest AUC (AUC = 0.629). Based on the LDpred-derived PRS, we are able to identify 30% of individuals without a family history as having risk for CRC similar to those with a family history of CRC, whereas the PRS based on known GWAS variants identified only top 10% as having a similar relative risk. About 90% of these individuals have no family history and would have been considered average risk under current screening guidelines, but might benefit from earlier screening. The developed PRS offers a way for risk-stratified CRC screening and other targeted interventions.

Associations of Body Mass Index at Different Ages With Early-Onset Colorectal Cancer.

BACKGROUND & AIMS: Incidence of colorectal cancer (CRC) in younger adults is increasing in many countries. Given the established association of body mass index (BMI) with CRC risk and the increasing obesity prevalence among younger generations, we aimed to evaluate the association of BMI at different ages during early adulthood with early-onset CRC. METHODS: Among 6602 patients with CRC and 7950 matched controls who were recruited in 2003-2020 in the Darmkrebs: Chancen der Verhütung durch Screening study, a population-based case-control study from Germany, 747 patients and 621 controls were younger than 55 years and included in this analysis. Self-reported height and weight at ages 20 years and 30 years and at approximately 10 years before diagnosis or interview were recorded in personal interviews. Associations of BMI with early-onset CRC were estimated using multiple logistic regression. RESULTS: Compared with participants with BMI <25 kg/m2, those with BMI ≥30 kg/m2 (obesity) at ages 20 years and 30 years and approximately 10 years before diagnosis or interview had 2.56- (95% confidence interval, 1.20-5.44), 2.06- (confidence interval, 1.25-3.40), and 1.88- (95% confidence interval, 1.30-2.73) fold risk of early-onset CRC. The association of BMI with early-onset CRC risk was particularly pronounced among, and essentially restricted to, the majority of participants with no previous colonoscopy. CONCLUSIONS: Obesity at early adulthood is strongly associated with increased risk of early-onset CRC. German Clinical Trials Register ID: DRKS00011793.

Polygenic Risk Score for Defining Personalized Surveillance Intervals After Adenoma Detection and Removal at Colonoscopy.

BACKGROUND & AIMS: Polygenic risk scores (PRSs) could help to define personalized colorectal cancer (CRC) screening strategies. The aim of this study was to evaluate whether a PRS, along with adenoma characteristics, could help to define more personalized and risk-adapted surveillance intervals. METHODS: In a population-based, case-control study from Germany, detailed information on previous colonoscopies and a PRS based on 140 CRC-related, single-nucleotide polymorphisms was obtained from 4696 CRC cases and 3709 controls. Participants were classified as having low, medium, or high genetic risk according to tertiles of PRSs among controls. We calculated the absolute risk of CRC based on the PRS and colonoscopy history and findings. RESULTS: We observed major variations of CRC risk according to the PRS, including among individuals with detection and removal of adenomas at colonoscopy. For instance, the estimated 10-year absolute risk of CRC for 50-year-old men and women with no polyps, for whom repeat screening colonoscopy is recommended after 10 years only, was 0.2%. Equivalent absolute risks were estimated for people with low-risk adenomas and low PRS. However, the same levels of absolute risk were reached within 3 to 5 years by those with low-risk adenomas and high PRS and with high-risk adenomas irrespective of the PRS. CONCLUSIONS: Consideration of genetic predisposition to CRC risk, as determined by a PRS, could help to define personalized, risk-adapted surveillance intervals after detection and removal of adenomas at screening colonoscopy. However, whether the risk variation is strong enough to direct clinical risk stratification needs to be explored further.

Molecular Characteristics of Early-Onset Colorectal Cancer According to Detailed Anatomical Locations: Comparison With Later-Onset Cases.

INTRODUCTION: 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. METHODS: 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. RESULTS: 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. DISCUSSION: Our findings support biogeographical and pathogenic heterogeneity of colorectal carcinomas in different colorectal subsites and age groups.

Weakly supervised annotation-free cancer detection and prediction of genotype in routine histopathology.

Deep learning is a powerful tool in computational pathology: it can be used for tumor detection and for predicting genetic alterations based on histopathology images alone. Conventionally, tumor detection and prediction of genetic alterations are two separate workflows. Newer methods have combined them, but require complex, manually engineered computational pipelines, restricting reproducibility and robustness. To address these issues, we present a new method for simultaneous tumor detection and prediction of genetic alterations: The Slide-Level Assessment Model (SLAM) uses a single off-the-shelf neural network to predict molecular alterations directly from routine pathology slides without any manual annotations, improving upon previous methods by automatically excluding normal and non-informative tissue regions. SLAM requires only standard programming libraries and is conceptually simpler than previous approaches. We have extensively validated SLAM for clinically relevant tasks using two large multicentric cohorts of colorectal cancer patients, Darmkrebs: Chancen der Verhütung durch Screening (DACHS) from Germany and Yorkshire Cancer Research Bowel Cancer Improvement Programme (YCR-BCIP) from the UK. We show that SLAM yields reliable slide-level classification of tumor presence with an area under the receiver operating curve (AUROC) of 0.980 (confidence interval 0.975, 0.984; n = 2,297 tumor and n = 1,281 normal slides). In addition, SLAM can detect microsatellite instability (MSI)/mismatch repair deficiency (dMMR) or microsatellite stability/mismatch repair proficiency with an AUROC of 0.909 (0.888, 0.929; n = 2,039 patients) and BRAF mutational status with an AUROC of 0.821 (0.786, 0.852; n = 2,075 patients). The improvement with respect to previous methods was validated in a large external testing cohort in which MSI/dMMR status was detected with an AUROC of 0.900 (0.864, 0.931; n = 805 patients). In addition, SLAM provides human-interpretable visualization maps, enabling the analysis of multiplexed network predictions by human experts. In summary, SLAM is a new simple and powerful method for computational pathology that could be applied to multiple disease contexts. © 2021 The Authors. The Journal of Pathology published by John Wiley & Sons, Ltd. on behalf of The Pathological Society of Great Britain and Ireland.