Polygenic Risk Scores for Follow Up After Colonoscopy and Polypectomy: Another Tool for Risk Stratification and Planning Surveillance?

Abstract

Colorectal cancer (CRC) screening is recommended for adults in the United States aged ≥45 years.1Davidson K.W. Barry M.J. et al.U.S. Preventive Services Task ForceScreening for colorectal cancer: US Preventive Services Task Force recommendation statement.JAMA. 2021; 325: 1965-1977Crossref PubMed Scopus (257) Google Scholar Screening for CRC offers the opportunity for reducing CRC incidence through detection and removal of polyps, such as adenomas and sessile serrated lesions, and mortality through early detection and treatment. Post-polypectomy, evidence suggests that some individuals, such as those with advanced adenomas (defined as having an adenoma with size ≥1 cm, villous/tubulovillous histology, or high-grade dysplasia) remain at increased risk for developing CRC.2Gupta S. Lieberman D. Anderson J.C. et al.Recommendations for follow-up after colonoscopy and polypectomy: a consensus update by the US Multi-Society Task Force on Colorectal Cancer.Gastroenterology. 2020; 158: 1131-1153Abstract Full Text Full Text PDF PubMed Scopus (128) Google Scholar However, risk among these patients is not uniform nor linear. According to estimated risk based on the number, size, and histology of baseline polyps, the US Multi-Society Task Force on Colorectal Cancer recommends repeat colonoscopy in 1–10 years.2Gupta S. Lieberman D. Anderson J.C. et al.Recommendations for follow-up after colonoscopy and polypectomy: a consensus update by the US Multi-Society Task Force on Colorectal Cancer.Gastroenterology. 2020; 158: 1131-1153Abstract Full Text Full Text PDF PubMed Scopus (128) Google Scholar A limitation of the current approach is that risk stratification is imprecise, with current guidelines having sensitivity and specificity for predicting metachronous advanced neoplasia estimated to be 59%–81% and 43%–58%, respectively.3Liu L. Messer K. Baron J.A. et al.A prognostic model for advanced colorectal neoplasia recurrence.Cancer Causes Control. 2016; 27: 1175-1185Crossref PubMed Scopus (11) Google Scholar, 4Martínez M.E. Baron J.A. Lieberman D.A. et al.A pooled analysis of advanced colorectal neoplasia diagnoses after colonoscopic polypectomy.Gastroenterology. 2009; 136: 832-841Abstract Full Text Full Text PDF PubMed Scopus (438) Google Scholar, 5Laiyemo A.O. Murphy G. Albert P.S. et al.Postpolypectomy colonoscopy surveillance guidelines: predictive accuracy for advanced adenoma at 4 years.Ann Intern Med. 2008; 148: 419-426Crossref PubMed Google Scholar, 6Pinsky P.F. Schoen R.E. Weissfeld J.L. et al.The yield of surveillance colonoscopy by adenoma history and time to examination.Clin Gastroenterol Hepatol. 2009; 7: 86-92Abstract Full Text Full Text PDF PubMed Scopus (87) Google Scholar, 7Chung S.J. Kim Y.S. Yang S.Y. et al.Five-year risk for advanced colorectal neoplasia after initial colonoscopy according to the baseline risk stratification: a prospective study in 2452 asymptomatic Koreans.Gut. 2011; 60: 1537-1543Crossref PubMed Scopus (138) Google Scholar, 8Stegeman I. de Wijkerslooth T.R. Stoop E.M. et al.Colorectal cancer risk factors in the detection of advanced adenoma and colorectal cancer.Cancer Epidemiol. 2013; 37: 278-283Crossref PubMed Scopus (35) Google Scholar As such, novel strategies are needed to improve risk stratification and planning surveillance after polypectomy. Genome-wide association studies have identified associations between common genetic variants, single nucleotide polymorphisms (SNPs), and the risk of developing CRC. Proponents argue that one powerful application of genetic markers is the use of polygenic risk scores (PRS) to improve prediction for complex disease risk. PRSs, based on panels of risk SNPs that are weighted according to their magnitude of association with disease risk, have the potential to revolutionize primary and secondary prevention of cancer through improved risk stratification and subsequent management. Indeed, PRSs have been shown in previous research to have potential for predicting risk for CRC, and for guiding the age of initiation for CRC screening.9Thomas M. Sakoda L.C. Hoffmeister M. et al.Genome-wide modeling of polygenic risk score in colorectal cancer risk.Am J Hum Genet. 2020; 107: 432-444Abstract Full Text Full Text PDF PubMed Scopus (51) Google Scholar, 10Archambault A.N. Su Y.R. Jeon J. et al.Cumulative burden of colorectal cancer-associated genetic variants is more strongly associated with early-onset vs late-onset cancer.Gastroenterology. 2020; 158: 1274-1286Abstract Full Text Full Text PDF PubMed Scopus (63) Google Scholar, 11Archambault A.N. Jeon J. Lin Y. et al.Risk stratification for early-onset colorectal cancer using a combination of genetic and environmental risk scores: an international multi-center study.J Natl Cancer Inst. 2022; 114: 528-539PubMed Google Scholar As such, PRSs might also have utility for guiding risk stratification after polypectomy, but have not been widely studied to date for this indication. In this issue of Clinical Gastroenterology and Hepatology, Guo et al12Guo F. Edelmann D. Cardoso R. et al.Polygenic risk score for defining personalized surveillance intervals after adenoma detection and removal at colonoscopy.Clin Gastroenterol Hepatol. 2023; 21: 210-219Abstract Full Text Full Text PDF Google Scholar aimed to address this evidence gap by examining whether a PRS, along with adenoma characteristics, could improve risk stratification of individuals after polyp removal. They conducted a population-based case-control study in Germany among 4696 CRC cases, and 3709 CRC-free control subjects. The study population included individuals with and without prior colonoscopy. Primary exposure of interest was a PRS that tallied the number of risk alleles a patient carried for 140 SNPs previously associated with CRC risk among populations of European ancestry. Subjects were classified as having low, medium, or high genetic risk based on the tertile distribution of the PRS, and the relationship between PRS category (the primary predictor) and CRC (primary outcome) was examined. Cumulative absolute CRC risk at 3-, 5-, and 10-year intervals, stratified by baseline colonoscopy status (no colonoscopy, normal colonoscopy, low-risk adenoma, high-risk adenoma) and PRS (low, medium, and high) was modeled. The study population was nearly 40% women, with more than 60% aged 60 years or older. Cases were more likely than control subjects to have lower education, family history of CRC, smoking exposure, increased BMI, and lack of exposure to nonsteroidal anti-inflammatory drugs or hormone-replacement therapy. Additionally, colonoscopy exposure was less common among cases (69.9%) versus control subjects (30.1%). Several findings are of note. Across all individuals, increasing PRS was associated with increasing CRC risk, consistent with prior work.9Thomas M. Sakoda L.C. Hoffmeister M. et al.Genome-wide modeling of polygenic risk score in colorectal cancer risk.Am J Hum Genet. 2020; 107: 432-444Abstract Full Text Full Text PDF PubMed Scopus (51) Google Scholar, 10Archambault A.N. Su Y.R. Jeon J. et al.Cumulative burden of colorectal cancer-associated genetic variants is more strongly associated with early-onset vs late-onset cancer.Gastroenterology. 2020; 158: 1274-1286Abstract Full Text Full Text PDF PubMed Scopus (63) Google Scholar, 11Archambault A.N. Jeon J. Lin Y. et al.Risk stratification for early-onset colorectal cancer using a combination of genetic and environmental risk scores: an international multi-center study.J Natl Cancer Inst. 2022; 114: 528-539PubMed Google Scholar Also consistent with prior research, having normal colonoscopy, colonoscopy with hyperplastic polyps, or colonoscopy with low-risk adenoma (1-2 adenomas <10 mm in size) was associated with substantially reduced CRC risk compared with having no colonoscopy at up to 10 years follow-up. When estimating cumulative and relative CRC risks at 3, 5, and 10 years, more variation by PRS category was seen among those with no exposure to colonoscopy than among those with exposure to colonoscopy, regardless of baseline polypectomy finding. For example, low versus high PRS scores were associated with cumulative 10-year CRC risk of 0.8 versus 2.1% for men and 0.5 versus 1.3% for women after no exposure to colonoscopy, and 0.4 versus 1.0% for men and 0.3 versus 0.8% for women after colonoscopy with high-risk adenoma removal. The range of cumulative risk variation for low versus high PRS for individuals with normal colonoscopy, colonoscopy with hyperplastic polyps, or colonoscopy with low-risk adenoma was smaller than observed for those with colonoscopy with high-risk adenoma or no exposure to colonoscopy, although the point estimates for cumulative risk were consistently higher for those with high PRS versus low PRS within each baseline colonoscopy finding category. These findings show that increasing PRS is clearly associated with increased CRC risk among individuals without exposure to colonoscopy. The findings also suggest that among individuals with colonoscopy exposure, PRS may continue to contribute to risk variation, although on a smaller absolute scale. Overall, the study was well done, with the main limitations being small sample size within colonoscopy finding subcategories, reducing power to assess differences in CRC risk within categories across PRS risk score levels, and a focus on a PRS derived from a population of only European descent such that the PRS may have substantially lower performance in other ancestral groups. Strengths of the study include a population-based design, and using previously validated SNPs in their PRS, enhancing potential for generalizability. Overall, these findings are consistent with the hypothesis that heritable genetic factors contribute to CRC risk after exposure to colonoscopy and polypectomy. The findings of Guo et al12Guo F. Edelmann D. Cardoso R. et al.Polygenic risk score for defining personalized surveillance intervals after adenoma detection and removal at colonoscopy.Clin Gastroenterol Hepatol. 2023; 21: 210-219Abstract Full Text Full Text PDF Google Scholar may be considered in the larger context of attempts to optimize risk stratification and surveillance of individuals after colonoscopy. Mechanisms driving CRC risk after polypectomy may be broadly categorized into biologic factors and colonoscopy quality factors (Figure 1). Several biologic factors have been shown to be associated with risk for CRC after polypectomy, including increasing age; male sex; comorbid conditions (eg, metabolic syndrome and diabetes); and exposures, such as medications (eg, aspirin and nonsteroidal anti-inflammatory drugs), smoking, and lower physical activity.4Martínez M.E. Baron J.A. Lieberman D.A. et al.A pooled analysis of advanced colorectal neoplasia diagnoses after colonoscopic polypectomy.Gastroenterology. 2009; 136: 832-841Abstract Full Text Full Text PDF PubMed Scopus (438) Google Scholar,13Kim T.J. Kim J.E. Choi Y.H. et al.Obesity-related parameters and colorectal adenoma development.Gastroenterology. 2017; 52: 1221-1229Google Scholar, 14Kim M.C. Jung S.W. Kim C.S. et al.Metabolic syndrome is associated with increased risk of recurrent colorectal adenomas in Korean men.Int J Obes (Lond). 2012; 36: 1007-1011Crossref PubMed Scopus (23) Google Scholar, 15Kim N.H. Park J.H. Park D.I. et al.Metabolic syndrome is a risk factor for adenoma occurrence at surveillance colonoscopy: a single-center experience in Korea.Medicine (Baltimore). 2016; 95: e4454Crossref PubMed Scopus (18) Google Scholar, 16Figueiredo J.C. Crockett S.D. Snover D.C. et al.Smoking-associated risks of conventional adenomas and serrated polyps in the colorectum.Cancer Causes Control. 2015; 26: 377-386Crossref PubMed Scopus (43) Google Scholar, 17Molmenti C.L. Hibler E.A. Ashbeck E.L. et al.Sedentary behavior is associated with colorectal adenoma recurrence in men.Cancer Causes Control. 2014; 25: 1387-1395Crossref PubMed Scopus (21) Google Scholar, 18Dulai P.S. Singh S. Marquez E. et al.Chemoprevention of colorectal cancer in individuals with previous colorectal neoplasia: systematic review and network meta-analysis.BMJ. 2016; 355: i6188Crossref PubMed Scopus (59) Google Scholar Diet likely plays a role as a biologic factor given its overall proven role in driving CRC risk, although interventional and observational studies to date of the role of diet in influencing postpolypectomy CRC risk have not shown a close association.19Kunzmann A.T. Coleman H.G. Huang W.Y. et al.Fruit and vegetable intakes and risk of colorectal cancer and incident and recurrent adenomas in the PLCO cancer screening trial.Int J Cancer. 2016; 138: 1851-1861Crossref PubMed Scopus (24) Google Scholar, 20Sardo Molmenti C.L. Steck S.E. Thomson C.A. et al.Dietary inflammatory index and risk of colorectal adenoma recurrence: a pooled analysis.Nutr Cancer. 2017; 69: 238-247Crossref PubMed Scopus (14) Google Scholar, 21Lanza E. Yu B. Murphy G. et al.The polyp prevention trial continued follow-up study: no effect of a low-fat, high-fiber, high-fruit, and -vegetable diet on adenoma recurrence eight years after randomization.Cancer Epidemiol Biomarkers Prev. 2007; 16: 1745-1752Crossref PubMed Scopus (74) Google Scholar, 22Schatzkin A. Lanza E. Corle D. et al.Lack of effect of a low-fat, high-fiber diet on the recurrence of colorectal adenomas. Polyp Prevention Trial Study Group.N Engl J Med. 2000; 342: 1149-1155Crossref PubMed Scopus (829) Google Scholar Family history of CRC increases risk for metachronous advanced neoplasia after polypectomy.23Jacobs E.T. Gupta S. Baron J.A. et al.Family history of colorectal cancer in first-degree relatives and metachronous colorectal adenoma.Am J Gastroenterol. 2018; 113: 899-905Crossref PubMed Scopus (13) Google Scholar Considered together with the finding of Guo et al12Guo F. Edelmann D. Cardoso R. et al.Polygenic risk score for defining personalized surveillance intervals after adenoma detection and removal at colonoscopy.Clin Gastroenterol Hepatol. 2023; 21: 210-219Abstract Full Text Full Text PDF Google Scholar that CRC-associated SNPs, as summarized by a PRS, genetic predisposition can be postulated to be a useful tool for postpolypectomy CRC risk stratification, and the clinical utility for PRS in the setting of postpolypectomy patients may be further enhanced with the additional discovery and validation of additional CRC risk SNPs. Evidence that colonoscopy quality drives CRC risk is growing. Inadequate bowel preparation has been associated with increased risk for incident CRC after polypectomy.24Atkin W. Wooldrage K. Brenner A. et al.Adenoma surveillance and colorectal cancer incidence: a retrospective, multicentre, cohort study.Lancet Oncol. 2017; 18: 823-834Abstract Full Text Full Text PDF PubMed Scopus (128) Google Scholar Colonoscopist skill is also a factor, because incomplete examination has been associated with increased risk for incident CRC,24Atkin W. Wooldrage K. Brenner A. et al.Adenoma surveillance and colorectal cancer incidence: a retrospective, multicentre, cohort study.Lancet Oncol. 2017; 18: 823-834Abstract Full Text Full Text PDF PubMed Scopus (128) Google Scholar and achieving complete polyp excision has been shown to be challenging, particularly for larger adenomas and sessile serrated lesions.25Pohl H. Srivastava A. Bensen S.P. et al.Incomplete polyp resection during colonoscopy-results of the complete adenoma resection (CARE) study.Gastroenterology. 2013; 144: 74-80Abstract Full Text Full Text PDF PubMed Scopus (485) Google Scholar Colonoscopist skill, as measured by the adenoma detection rate (ADR), has previously been well established to be associated with CRC risk after normal colonoscopy,26Corley D.A. Jensen C.D. Marks A.R. et al.Adenoma detection rate and risk of colorectal cancer and death.N Engl J Med. 2014; 370: 1298-1306Crossref PubMed Scopus (1128) Google Scholar,27Kaminski M.F. Wieszczy P. Rupinski M. et al.Increased rate of adenoma detection associates with reduced risk of colorectal cancer and death.Gastroenterology. 2017; 153: 98-105Abstract Full Text Full Text PDF PubMed Scopus (247) Google Scholar and recent evidence shows increasing ADR is associated with decreasing risk for incident CRC28Wieszczy P. Kaminski M.F. Franczyk R. et al.Colorectal cancer incidence and mortality after removal of adenomas during screening colonoscopies.Gastroenterology. 2020; 158: 875-883Abstract Full Text Full Text PDF PubMed Scopus (71) Google Scholar and advanced metachronous neoplasia after adenoma removal.29Gupta S. Bustamante R. Earles A. et al.Impact of polyp features and colonoscopist adenoma detection rate on post-polypectomy risk for metachronous advanced neoplasia.Gastroenterology. 2020; 158 (S-641-S-642)Abstract Full Text PDF Google Scholar The growing understanding of the potential biologic and quality mechanisms that contribute to CRC risk after polypectomy may help to improve risk stratification of individuals after polypectomy, and ultimately, better guide surveillance intervals. As mentioned previously, current guideline recommendations for follow-up after colonoscopy and polypectomy have suboptimal sensitivity and specificity for identifying individuals with metachronous advanced neoplasia. Risk stratification models to date have mainly considered demographic and polyp characteristics, and have not achieved excellent performance.3Liu L. Messer K. Baron J.A. et al.A prognostic model for advanced colorectal neoplasia recurrence.Cancer Causes Control. 2016; 27: 1175-1185Crossref PubMed Scopus (11) Google Scholar,28Wieszczy P. Kaminski M.F. Franczyk R. et al.Colorectal cancer incidence and mortality after removal of adenomas during screening colonoscopies.Gastroenterology. 2020; 158: 875-883Abstract Full Text Full Text PDF PubMed Scopus (71) Google Scholar,30van Heijningen E.M. Lansdorp-Vogelaar I. Kuipers E.J. et al.Features of adenoma and colonoscopy associated with recurrent colorectal neoplasia based on a large community-based study.Gastroenterology. 2013; 144: 1410-1418Abstract Full Text Full Text PDF PubMed Scopus (68) Google Scholar,31Lee J.Y. Park H.W. Kim M.J. et al.Prediction of the risk of a metachronous advanced colorectal neoplasm using a novel scoring system.Dig Dis Sci. 2016; 61: 3016-3025Crossref PubMed Scopus (10) Google Scholar A novel model considering demographic characteristics, polyp features, presence of diabetes, exposure to smoking, and colonoscopist ADR was recently shown to achieve improved sensitivity and specificity for identifying individuals with metachronous advanced neoplasia compared with 2020 US Multi-Society Task Force on Colorectal Cancer recommendations, but still did not reach excellent discriminatory performance.29Gupta S. Bustamante R. Earles A. et al.Impact of polyp features and colonoscopist adenoma detection rate on post-polypectomy risk for metachronous advanced neoplasia.Gastroenterology. 2020; 158 (S-641-S-642)Abstract Full Text PDF Google Scholar In summary, work to date on risk stratification suggests that multiple factors associated with metachronous CRC risk can be identified, and that models incorporating these factors can improve risk stratification. Work by Guo et al12Guo F. Edelmann D. Cardoso R. et al.Polygenic risk score for defining personalized surveillance intervals after adenoma detection and removal at colonoscopy.Clin Gastroenterol Hepatol. 2023; 21: 210-219Abstract Full Text Full Text PDF Google Scholar and others also underscores that single factors, such as a PRS alone, are unlikely to be adequate to achieve optimal risk stratification. However, work by Guo et al12Guo F. Edelmann D. Cardoso R. et al.Polygenic risk score for defining personalized surveillance intervals after adenoma detection and removal at colonoscopy.Clin Gastroenterol Hepatol. 2023; 21: 210-219Abstract Full Text Full Text PDF Google Scholar and others also suggests that there is an opportunity to leverage well-established biologic and quality factors, such as age, sex, and extent of examination, and emerging factors, such as information on genetic predisposition and colonoscopist ADR, to develop even better, more comprehensive models for risk stratification. Although questionnaire-based, clinical and PRS-based tools seem to be clinically useful, incorporating additional blood-based markers (eg, information from the blood epigenome)32Gebhard C. Mulet-Lazaro R. Glatz D. et al.Aberrant DNA methylation patterns in microsatellite stable human colorectal cancers define a new marker panel for the CpG island methylator phenotype.Int J Cancer. 2022; 150: 617-625Crossref PubMed Scopus (2) Google Scholar,33Nassar F.J. Msheik Z.S. Nasr R.R. et al.Methylated circulating tumor DNA as a biomarker for colorectal cancer diagnosis, prognosis, and prediction.Clin Epigenetics. 2021; 13: 111Crossref PubMed Scopus (14) Google Scholar may provide a novel path toward improving further CRC risk prediction. Innovations in strategies for risk stratification may enable a new era of precision surveillance that might ultimately allow some low-risk patients to be offered long intervals between colonoscopy or even the option of noninvasive surveillance, such as with a fecal immunochemical test, and high-risk patients to receive tailored recommendations for close interval colonoscopy surveillance. Ultimately, continued work in this area has great potential to improve the effectiveness and efficiency of post-polypectomy surveillance. Polygenic Risk Score for Defining Personalized Surveillance Intervals After Adenoma Detection and Removal at ColonoscopyClinical Gastroenterology and HepatologyVol. 21Issue 1PreviewPolygenic 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. Full-Text PDF Open Access