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The utility and predictive value of combinations of low penetrance genes for screening and risk prediction of colorectal cancer.

ABSTRACT: Despite the fact that colorectal cancer (CRC) is a highly treatable form of cancer if detected early, a very low proportion of the eligible population undergoes screening for this form of cancer. Integrating a genomic screening profile as a component of existing screening programs for CRC could potentially improve the effectiveness of population screening by allowing the assignment of individuals to different types and intensities of screening and also by potentially increasing the uptake of existing screening programs. We evaluated the utility and predictive value of genomic profiling as applied to CRC, and as a potential component of a population-based cancer screening program. We generated simulated data representing a typical North American population including a variety of genetic profiles, with a range of relative risks and prevalences for individual risk genes. We then used these data to estimate parameters characterizing the predictive value of a logistic regression model built on genetic markers for CRC. Meta-analyses of genetic associations with CRC were used in building science to inform the simulation work, and to select genetic variants to include in logistic regression model-building using data from the ARCTIC study in Ontario, which included 1,200 CRC cases and a similar number of cancer-free population-based controls. Our simulations demonstrate that for reasonable assumptions involving modest relative risks for individual genetic variants, that substantial predictive power can be achieved when risk variants are common (e.g., prevalence > 20%) and data for enough risk variants are available (e.g., approximately 140-160). Pilot work in population data shows modest, but statistically significant predictive utility for a small collection of risk variants, smaller in effect than age and gender alone in predicting an individual's CRC risk. Further genotyping and many more samples will be required, and indeed the discovery of many more risk loci associated with CRC before the question of the potential utility of germline genomic profiling can be definitively answered.

SUBMITTER: Hawken SJ

PROVIDER: S-EPMC2885303 | biostudies-literature |

REPOSITORIES: biostudies-literature

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Project description:ImportanceGuidelines for colorectal cancer (CRC) screening recommend an individualized approach in older adults that is informed by consideration of life expectancy and cancer risk. However, little is known about how patients perceive individualized screening recommendations.ObjectiveTo assess veterans' attitudes toward and comfort with cessation of low-value CRC screening (defined as screening in a patient for whom the benefit is expected to be small based on quantitative estimates from hypothetical risk calculators).Design, setting, and participantsThis survey study included patients older than 50 years who had undergone prior screening colonoscopy with normal results at the Veterans Affairs Ann Arbor Healthcare System. A total of 1500 surveys were mailed to potential participants from November 1, 2010, to January 1, 2012. Survey data were analyzed from January 1, 2016, to December 31, 2017.Main outcomes and measuresResponse to the question, "If you personally had serious health problems that were likely to shorten your life and your doctor did not think screening would be of much benefit based on the calculator, how comfortable would you be with not getting any more screening colonoscopies?"ResultsOf the 1500 surveys mailed, 85 were returned to sender, leaving 1415 potential respondents; 1054 of these respondents (median age range, 60-69 years; 884 [85.9%] white and 965 [94.2%] male) completed the survey (response rate, 74.5%). A total of 300 (28.7%) were not at all comfortable with cessation of low-value CRC screening, and 509 (49.3%) thought that age should never be used to decide when to stop screening. In addition, 332 (31.7%) thought it was not at all reasonable to use life expectancy calculators, and 255 (24.3%) thought it was not at all reasonable to use CRC risk calculators to guide these decisions. In ordered logistic regression analysis, factors associated with more comfort with screening cessation were (1) higher trust in physician (odds ratio [OR], 1.19; 95% CI, 1.07-1.32), (2) higher perceived health status (OR, 1.41; 95% CI, 1.23-1.61), and (3) higher barriers to screening (OR, 1.20; 95% CI, 1.11-1.30). Factors that were associated with less comfort with screening cessation included (1) greater perceived effectiveness of screening (OR, 0.86; 95% CI, 0.80-0.94) and (2) greater perceived threat of CRC (OR, 0.81; 95% CI, 0.73-0.89).Conclusions and relevanceThe findings suggest that many veterans have strong preferences against screening cessation even when given detailed information about why the benefit may be low. Efforts to tailor screening recommendations may be met by resistance unless they are accompanied by efforts to address underlying perceptions about the benefit of screening.

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The utility and predictive value of combinations of low penetrance genes for screening and risk prediction of colorectal cancer.

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