Challenges With Colorectal Cancer Family History Assessment—Motivation to Translate Polygenic Risk Scores Into Practice

Abstract

Polly A. NewcombView Large Image Figure ViewerDownload Hi-res image Download (PPT)Ulrike PetersView Large Image Figure ViewerDownload Hi-res image Download (PPT) In this issue of Gastroenterology, Kastrinos et al,1Kastrinos F. Samadder N.J. Burt R.W. Use of family history and genetic testing to determine risk of colorectal cancer.Gastroenterology. 2020; 158: 389-403Abstract Full Text Full Text PDF PubMed Scopus (21) Google Scholar detailed the importance of family history of colorectal cancer (CRC) for risk-based screening recommendations. Assessment of CRC family history can be used to recommend early initiation of CRC screening, increased colonoscopy surveillance, and genetic testing for CRC hereditary syndromes, such as Lynch Syndrome and Familial Adenomatous Polyposis. However, the length of time and expertise that it takes to complete comprehensive family history assessments coupled with the lack of provider reimbursement for documenting family history has contributed to many primary care providers failing to ascertain patient family history information for important familial conditions, including CRC.2Powell K.P. Christianson C.A. Hahn S.E. et al.Collection of family health history for assessment of chronic disease risk in primary care.N C Med J. 2013; 74: 279-286PubMed Google Scholar,3Christianson C.A. Powell K.P. Hahn S.E. et al.The use of a family history risk assessment tool within a community health care system: views of primary care providers.J Genet Couns. 2012; 21: 652-661Crossref PubMed Scopus (23) Google Scholar Furthermore, when cancer family history information is collected, it often lacks standard documentation in terms of the type of family history information assessed and the location and structure of the family history information in the electronic health record (EHR).4Sifri R.D. Wender R. Paynter N. Cancer risk assessment from family history: gaps in primary care practice.J Fam Pract. 2002; 51: 856PubMed Google Scholar,5Murff H.J. Greevy R.A. Syngal S. The comprehensiveness of family cancer history assessments in primary care.Community Genet. 2007; 10: 174-180Crossref PubMed Scopus (81) Google Scholar In addition to poor documentation of family history information in the electronic health record (EHR), the validity of patient self-reported family history of CRC varies according to patient demographic characteristics. In particular, minority and other underserved populations are more likely to underreport family history of CRC.6Ramsey S.D. Yoon P. Moonesinghe R. et al.Population-based study of the prevalence of family history of cancer: implications for cancer screening and prevention.Genet Med. 2006; 8: 571-575Abstract Full Text Full Text PDF PubMed Scopus (109) Google Scholar, 7Pinsky P.F. Kramer B.S. Reding D. et al.Reported family history of cancer in the prostate, lung, colorectal, and ovarian cancer screening trial.Am J Epidemiol. 2003; 157: 792-799Crossref PubMed Scopus (61) Google Scholar, 8Orom H. Cote M.L. Gonzalez H.M. et al.Family history of cancer: is it an accurate indicator of cancer risk in the immigrant population?.Cancer. 2008; 112: 399-406Crossref PubMed Scopus (26) Google Scholar This can lead to populations with the highest rates of CRC mortality, including non-hispanic blacks and Alaska Natives,9Siegel R.L. Miller K.D. Fedewa S.A. et al.Colorectal cancer statistics, 2017.CA Cancer J Clin. 2017; 67: 177-193Crossref PubMed Scopus (2812) Google Scholar being the least likely to benefit from CRC family history assessments. Further challenges derive from the fact that family history is dynamic and may change over time. Also, CRC screening has the potential to alter the association between CRC family history and CRC risk and to change family history patterns.10Newcomb P.A. Savu A. Phipps A.I. et al.Impact of colon cancer screening on family history phenotype.Epidemiology. 2012; 23: 308-310Crossref PubMed Scopus (2) Google Scholar For example, if an individual with inherited increased CRC risk undergoes regular and complete CRC precursor removal during screening and surveillance colonoscopies, this individual may never develop CRC. Thus, this individual’s family members may not be aware of their increased inherited CRC risk. One way to address the potential for increased familial CRC risk among those whose relatives had high-risk CRC precursor removal, but did not develop CRC, is to also assess family history of CRC precursors. Early studies of the association between family history of CRC precursors and CRC risk suggested an increased risk of CRC associated with a family history of CRC precursor lesions.11Cottet V. Pariente A. Nalet B. et al.Colonoscopic screening of first-degree relatives of patients with large adenomas: increased risk of colorectal tumors.Gastroenterology. 2007; 133: 1086-1092Abstract Full Text Full Text PDF PubMed Scopus (83) Google Scholar Later studies indicated that the risk associated with family history of CRC precursors varied by type of CRC precursor, with the strongest risk associated with advanced precursor lesions.12Tuohy T.M. Rowe K.G. Mineau G.P. et al.Risk of colorectal cancer and adenomas in the families of patients with adenomas: a population-based study in Utah.Cancer. 2014; 120: 35-42Crossref PubMed Scopus (56) Google Scholar Because patients have difficulty recalling details about their own history of colorectal polyps,13Kumaravel V. Heald B. Lopez R. et al.Patients do not recall important details about polyps, required for colorectal cancer prevention.Clin Gastroenterol Hepatol. 2013; 11 (e1-2): 543-547Abstract Full Text Full Text PDF PubMed Scopus (20) Google Scholar it is unlikely that they will accurately recall details about family members’ polyps. Thus, current guidelines recommend only using family history of CRC precursors to inform screening and surveillance when pathology report confirmation of advanced CRC precursors in first-degree relatives is available.14Rex D.K. Boland C.R. Dominitz J.A. et al.Colorectal Cancer Screening: Recommendations for Physicians and Patients From the U.S. Multi-Society Task Force on Colorectal Cancer.Gastroenterology. 2017; 153: 307-323Abstract Full Text Full Text PDF PubMed Scopus (356) Google Scholar Given the pitfalls of CRC family history assessment, the increased knowledge of CRC genetics, and decreased costs for non-invasive genetic testing, it is potentially the right time to begin testing the clinical utility of supplementing CRC family history with polygenic CRC risk scores, which aggregate the increasing number of identified common genetic CRC risk variants.15Huyghe J.R. Bien S.A. Harrison T.A. et al.Discovery of common and rare genetic risk variants for colorectal cancer.Nat Genet. 2019; 51: 76-87Crossref PubMed Scopus (193) Google Scholar A recent study reported that use of a polygenic risk score in the United States identified 10% of individuals having at least as high or higher risk as those with a positive family history due to the presence of a combination of known CRC genetic risk variants.16Jeon J. Du M. Schoen R.E. et al.Determining Risk of Colorectal Cancer and Starting Age of Screening Based on Lifestyle, Environmental, and Genetic Factors.Gastroenterology. 2018; 154: 2152-2164.e19Abstract Full Text Full Text PDF PubMed Scopus (152) Google Scholar Furthermore, the combination of the polygenic risk scores and family history resulted in more accurate risk stratification than consideration of either of these factors alone,16Jeon J. Du M. Schoen R.E. et al.Determining Risk of Colorectal Cancer and Starting Age of Screening Based on Lifestyle, Environmental, and Genetic Factors.Gastroenterology. 2018; 154: 2152-2164.e19Abstract Full Text Full Text PDF PubMed Scopus (152) Google Scholar and multiple studies support that adding polygenic risk scores to CRC risk prediction models significantly improved the discriminatory accuracy of these models as measured by the area under the curve.16Jeon J. Du M. Schoen R.E. et al.Determining Risk of Colorectal Cancer and Starting Age of Screening Based on Lifestyle, Environmental, and Genetic Factors.Gastroenterology. 2018; 154: 2152-2164.e19Abstract Full Text Full Text PDF PubMed Scopus (152) Google Scholar,17Gargallo-Puyuelo C.J. Lanas Á. Asunción García-Gonzalez M. Adding genetic scores to risk models in colorectal cancer.Oncotarget. 2019; 10: 4803-4804Crossref PubMed Scopus (2) Google Scholar Thus far, only a fraction of all CRC risk loci has been identified, so it is expected that the predictive power of the polygenic risk scores will further improve as more genetic risk variants are discovered and machine learning approaches are applied to very large genetic studies to refine genome-wide genetic risk scores.16Jeon J. Du M. Schoen R.E. et al.Determining Risk of Colorectal Cancer and Starting Age of Screening Based on Lifestyle, Environmental, and Genetic Factors.Gastroenterology. 2018; 154: 2152-2164.e19Abstract Full Text Full Text PDF PubMed Scopus (152) Google Scholar As the identified genetic risk variants tend to show similar risks in advanced adenoma it is likely that the polygenic risk score can be important for the prediction of both advanced adenoma and CRC.18Burnett-Hartman A.N. Passarelli M.N. Adams S.V. et al.Differences in epidemiologic risk factors for colorectal adenomas and serrated polyps by lesion severity and anatomical site.Am J Epidemiol. 2013; 177: 625-637Crossref PubMed Scopus (93) Google Scholar A current limitation of polygenic risk scores is the fact that they are primarily developed based on individuals of European descent, which leads to biases and lower predictive performance when applied to other racial/ethnic groups.19Wojcik G.L. Graff M. Nishimura K.K. et al.Genetic analyses of diverse populations improves discovery for complex traits.Nature. 2019; 570: 514-518Crossref PubMed Scopus (279) Google Scholar However, this key concern can be addressed through dedicated efforts that bring in sizable number of racially/ethnically diverse participants to develop genetic risk scores that predict CRC risk equally across our increasingly racially/ethnically diverse population. As outlined in the review by Kastrinos, et al,1Kastrinos F. Samadder N.J. Burt R.W. Use of family history and genetic testing to determine risk of colorectal cancer.Gastroenterology. 2020; 158: 389-403Abstract Full Text Full Text PDF PubMed Scopus (21) Google Scholar understanding an individual’s familial and inherited risk for CRC helps to drive CRC screening and surveillance recommendations, and by doing so reduces CRC incidence and mortality in high risk individuals. Despite the evidence supporting family history of CRC as a strong risk factor for CRC development,20Henrikson N.B. Webber E.M. Goddard K.A. et al.Family history and the natural history of colorectal cancer: systematic review.Genet med. 2015; 17: 702-712Abstract Full Text Full Text PDF PubMed Scopus (70) Google Scholar as well as guidelines stressing the importance of family history to CRC screening and surveillance recommendations,14Rex D.K. Boland C.R. Dominitz J.A. et al.Colorectal Cancer Screening: Recommendations for Physicians and Patients From the U.S. Multi-Society Task Force on Colorectal Cancer.Gastroenterology. 2017; 153: 307-323Abstract Full Text Full Text PDF PubMed Scopus (356) Google Scholar challenges to the use of CRC family history to direct tailored CRC prevention approaches remain and likely will increase as screening uptake rises. Polygenic risk scores are agnostic to CRC family history and can be used in conjunction with, or in the absence of, cancer family history to improve the accuracy of CRC risk prediction. They may also capture the limitations of family history that is necessarily silent on precursor history. Polygenic risk scores do not suffer from differential recall of family history, nor is their ability to predict CRC risk impacted by CRC prevention activities among relatives. Furthermore, the dramatic decrease in the costs of genetic testing has increased the feasibility of applying polygenic risk scores in many clinical settings. The time is now right to begin pragmatic clinical trials to test the utility of polygenic risk scores as a supplement to family history in the context of risk-based CRC screening. Author contributions: ANBH – Conceptualization, Writing-original draft; PAN – Conceptualization, Writing – review & editing; UP – Conceptualization, Writing – review & editing. Use of Family History and Genetic Testing to Determine Risk of Colorectal CancerGastroenterologyVol. 158Issue 2PreviewApproximately 35% of patients with colorectal cancer (CRC) have a family history of the disease attributed to genetic factors, common exposures, or both. Some families with a history of CRC carry genetic variants that cause CRC with high or moderate penetrance, but these account for only 5% to 10% of CRC cases. Most families with a history of CRC and/or adenomas do not carry genetic variants associated with cancer syndromes; this is called common familial CRC. Our understanding of familial predisposition to CRC and cancer syndromes has increased rapidly due to advances in next-generation sequencing technologies. Full-Text PDF