Clinical and Translational Gastroenterology

Evaluating the Use of Environmental and Polygenic Risk Scores to Inform Colorectal Cancer Risk-Based Surveillance Intervals

INTRODUCTION: United States Multi-Society Task Force colonoscopy surveillance intervals are based solely on adenoma characteristics, without accounting for other risk factors. We investigated whether a risk model including demographic, environmental, and genetic risk factors could individualize surveillance intervals under an “equal management of equal risks” framework. METHODS: Using 14,069 individuals from the Prostate, Lung, Colorectal, and Ovarian Cancer Screening Trial who had a diagnostic colonoscopy following an abnormal flexible sigmoidoscopy, we modeled the risk of colorectal cancer, considering the diagnostic colonoscopy finding, baseline risk factors (e.g., age and sex), 19 lifestyle and environmental risk factors, and a polygenic risk score for colorectal cancer. Ten-year absolute cancer risks for each diagnostic colonoscopy finding (advanced adenomas [N = 2,446], ≥3 non-advanced adenomas [N = 483], 1–2 non-advanced adenomas [N = 4,400], and no adenoma [N = 7,183]) were used as implicit risk thresholds for recommended surveillance intervals. RESULTS: The area under the curve for the model including colonoscopy findings, baseline characteristics, and polygenic risk score was 0.658. Applying the equal management of equal risks framework, 28.2% of individuals with no adenoma and 42.7% of those with 1–2 non-advanced adenomas would be considered high risk and assigned a significantly shorter surveillance interval than currently recommended. Among individuals who developed cancer within 10 years, 52.4% with no adenoma and 48.3% with 1–2 non-advanced adenomas would have been considered high risk and assigned a shorter surveillance interval. DISCUSSION: Using a personalized risk-based model has the potential to identify individuals with no adenoma or 1–2 non-advanced adenomas, who are higher risk and may benefit from shorter surveillance intervals.

Homologous Recombination Repair Truncations Predict Hypermutation in Microsatellite Stable Colorectal and Endometrial Tumors

INTRODUCTION: Somatic mutations in BRCA1/2 and other homologous recombination repair (HRR) genes have been associated with sensitivity to PARP inhibitors and/or platinum agents in several cancers, whereas hypermutant tumors caused by alterations in POLE or mismatch repair genes have demonstrated robust responses to immunotherapy. We investigated the relationship between somatic truncations in HRR genes and hypermutation in colorectal cancer (CRC) and endometrial cancer (EC). METHODS: We analyzed the mutational spectra associated with somatic BRCA1/2 truncations in multiple genomic cohorts (N = 2,335). From these results, we devised a classifier incorporating HRR genes to predict hypermutator status among microsatellite stable (MSS) tumors. Using additional genomic cohorts (N = 1,439) and functional in vivo assays, we tested the classifier to disambiguate POLE variants of unknown significance and identify MSS hypermutators without somatic POLE exonuclease domain mutations. RESULTS: Hypermutator phenotypes were prevalent among CRCs with somatic BRCA1/2 truncations (50/62, 80.6%) and ECs with such mutations (44/47, 93.6%). The classifier predicted MSS hypermutators with a cumulative true-positive rate of 100% in CRC and 98.0% in EC and a false-positive rate of 0.07% and 0.63%. Validated by signature analyses of tumor exomes and in vivo assays, the classifier accurately reassigned multiple POLE variants of unknown significance as pathogenic and identified MSS hypermutant samples without POLE exonuclease domain mutations. DISCUSSION: Somatic truncations in HRR can accurately fingerprint MSS hypermutators with or without known pathogenic exonuclease domain mutations in POLE and may serve as a low-cost biomarker for immunotherapy decisions in MSS CRC and EC.

Risk of Cervical Cancer in Inflammatory Bowel Disease: A Meta-Analysis of Population-Based Studies

INTRODUCTION: There is increased risk of several malignancies in inflammatory bowel disease (IBD). However, evidence regarding risk of cervical cancer in IBD is conflicting. We aimed to investigate the risk of cervical cancer in IBD by undertaking a systematic review and meta-analysis of unselected, population-based studies. METHODS: MEDLINE, EMBASE, and Cochrane Library were searched using Medical Subject Heading terms, and 2 reviewers independently screened results. Pooled hazard ratios (HRs) were calculated using random effects model meta-analysis for risk of cervical cancer in IBD. Subgroup meta-analysis was undertaken to assess risk of cervical cancer by IBD subtype (Crohn's disease and ulcerative colitis), treatment exposure, and grade of lesion. RESULTS: We screened 1,393 articles to identify 5 population-based studies, including 74,310 patients with IBD and 2,029,087 reference patients, across 5 different countries. Pooled random effects model meta-analysis of these studies did not show statistically significant increased risk for cervical cancer in IBD compared with reference populations (HR: 1.24; 95% confidence interval [CI]: 0.94–1.63). Meta-analysis by grade of lesion showed increased risk of low-grade cervical lesions (HR: 1.15; 95% CI: 1.04–1.28). Meta-analysis by disease subtype indicated no statistically significant increased risk in Crohn's disease (HR: 1.36; 95% CI: 0.83–2.23) or ulcerative colitis (HR: 0.95; 95% CI: 0.72–1.25) or in patients treated with antitumor necrosis factor (HR: 1.19; 95% CI: 0.64–2.21) or thiopurines (HR: 0.96; 95% CI: 0.60–1.50). DISCUSSION: This meta-analysis of high-quality, unselected population-based studies shows no statistically significant increased risk of cervical cancer in patients with IBD. There is, however, increased risk of low-grade cervical lesions compared with the general population.