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      Meeting report from the joint IARC–NCI international cancer seminar series: a focus on colorectal cancer

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          Abstract

          Abstract Despite significant progress in our understanding of the etiology, biology and genetics of colorectal cancer, as well as important clinical advances, it remains the third most frequently diagnosed cancer worldwide and is the second leading cause of cancer death. Based on demographic projections, the global burden of colorectal cancer would be expected to rise by 72% from 1.8 million new cases in 2018 to over 3 million in 2040 with substantial increases anticipated in low- and middle-income countries. In this meeting report, we summarize the content of a joint workshop led by the National Cancer Institute and the International Agency for Research on Cancer, which was held to summarize the important achievements that have been made in our understanding of colorectal cancer etiology, genetics, early detection and treatment and to identify key research questions that remain to be addressed.

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          Most cited references68

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          Colorectal cancer screening for average-risk adults: 2018 guideline update from the American Cancer Society

          In the United States, colorectal cancer (CRC) is the fourth most common cancer diagnosed among adults and the second leading cause of death from cancer. For this guideline update, the American Cancer Society (ACS) used an existing systematic evidence review of the CRC screening literature and microsimulation modeling analyses, including a new evaluation of the age to begin screening by race and sex and additional modeling that incorporates changes in US CRC incidence. Screening with any one of multiple options is associated with a significant reduction in CRC incidence through the detection and removal of adenomatous polyps and other precancerous lesions and with a reduction in mortality through incidence reduction and early detection of CRC. Results from modeling analyses identified efficient and model-recommendable strategies that started screening at age 45 years. The ACS Guideline Development Group applied the Grades of Recommendations, Assessment, Development, and Evaluation (GRADE) criteria in developing and rating the recommendations. The ACS recommends that adults aged 45 years and older with an average risk of CRC undergo regular screening with either a high-sensitivity stool-based test or a structural (visual) examination, depending on patient preference and test availability. As a part of the screening process, all positive results on noncolonoscopy screening tests should be followed up with timely colonoscopy. The recommendation to begin screening at age 45 years is a qualified recommendation. The recommendation for regular screening in adults aged 50 years and older is a strong recommendation. The ACS recommends (qualified recommendations) that: 1) average-risk adults in good health with a life expectancy of more than 10 years continue CRC screening through the age of 75 years; 2) clinicians individualize CRC screening decisions for individuals aged 76 through 85 years based on patient preferences, life expectancy, health status, and prior screening history; and 3) clinicians discourage individuals older than 85 years from continuing CRC screening. The options for CRC screening are: fecal immunochemical test annually; high-sensitivity, guaiac-based fecal occult blood test annually; multitarget stool DNA test every 3 years; colonoscopy every 10 years; computed tomography colonography every 5 years; and flexible sigmoidoscopy every 5 years. CA Cancer J Clin 2018;68:250-281. © 2018 American Cancer Society.
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            Germline mutations in the proof-reading domains of POLE and POLD1 predispose to colorectal adenomas and carcinomas

            Many individuals with multiple or large colorectal adenomas, or early-onset colorectal cancer (CRC), have no detectable germline mutations in the known cancer predisposition genes. Using whole-genome sequencing, supplemented by linkage and association analysis, we identified specific heterozygous POLE or POLD1 germline variants in several multiple adenoma and/or CRC cases, but in no controls. The susceptibility variants appear to have high penetrance. POLD1 is also associated with endometrial cancer predisposition. The mutations map to equivalent sites in the proof-reading (exonuclease) domain of DNA polymerases ε and δ, and are predicted to impair correction of mispaired bases inserted during DNA replication. In agreement with this prediction, mutation carriers’ tumours were microsatellite-stable, but tended to acquire base substitution mutations, as confirmed by yeast functional assays. Further analysis of published data showed that the recently-described group of hypermutant, microsatellite-stable CRCs is likely to be caused by somatic POLE exonuclease domain mutations.
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              Long-Term Mortality after Screening for Colorectal Cancer

              In randomized trials, fecal occult-blood testing reduces mortality from colorectal cancer. However, the duration of the benefit is unknown, as are the effects specific to age and sex. In the Minnesota Colon Cancer Control Study, 46,551 participants, 50 to 80 years of age, were randomly assigned to usual care (control) or to annual or biennial screening with fecal occult-blood testing. Screening was performed from 1976 through 1982 and from 1986 through 1992. We used the National Death Index to obtain updated information on the vital status of participants and to determine causes of death through 2008. Through 30 years of follow-up, 33,020 participants (70.9%) died. A total of 732 deaths were attributed to colorectal cancer: 200 of the 11,072 deaths (1.8%) in the annual-screening group, 237 of the 11,004 deaths (2.2%) in the biennial-screening group, and 295 of the 10,944 deaths (2.7%) in the control group. Screening reduced colorectal-cancer mortality (relative risk with annual screening, 0.68; 95% confidence interval [CI], 0.56 to 0.82; relative risk with biennial screening, 0.78; 95% CI, 0.65 to 0.93) through 30 years of follow-up. No reduction was observed in all-cause mortality (relative risk with annual screening, 1.00; 95% CI, 0.99 to 1.01; relative risk with biennial screening, 0.99; 95% CI, 0.98 to 1.01). The reduction in colorectal-cancer mortality was larger for men than for women in the biennial-screening group (P=0.04 for interaction). The effect of screening with fecal occult-blood testing on colorectal-cancer mortality persists after 30 years but does not influence all-cause mortality. The sustained reduction in colorectal-cancer mortality supports the effect of polypectomy. (Funded by the Veterans Affairs Merit Review Award Program and others.).
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                Author and article information

                Journal
                Annals of Oncology
                Oxford University Press (OUP)
                0923-7534
                1569-8041
                February 05 2019
                February 05 2019
                Affiliations
                [1 ]Section of Nutrition and Metabolism, International Agency for Research on Cancer, Lyon, France
                [2 ]King Faisal Specialist Hospital and Research Center, Riyadh, Saudi Arabia
                [3 ]Section of Cancer Surveillance, International Agency for Research on Cancer, Lyon, France
                [4 ]Division of Clinical Epidemiology and Aging Research, Division of Preventive Oncology and German Cancer Consortium (DKTK), German Cancer Research Center (DKFZ), Heidelberg
                [5 ]National Center for Tumor Diseases (NCT), Heidelberg, Germany
                [6 ]Institute of Genetic Medicine, Newcastle University, Newcastle, UK
                [7 ]Center for Public Health Genomics, University of Virginia, Charlottesville
                [8 ]Clinical and Translational Epidemiology Unit, Massachusetts General Hospital, Boston, USA
                [9 ]School of Public Health, Imperial College London, London, UK
                [10 ]Harvard T.H. Chan School of Public Health, Boston
                [11 ]Division of Cancer Epidemiology and Genetics, National Cancer Institute, National Institutes of Health, Bethesda, USA
                [12 ]Division of Genetics and Epidemiology, Institute of Cancer Research, London, UK
                [13 ]Centre for Epidemiology and Biostatistics, University of Melbourne, Melbourne, Australia
                [14 ]SIRIC CARPEM, APHP European Georges Pompidou Hospital Paris, Universite Paris Descartes, Paris, France
                [15 ]Public Health Science Division, Fred Hutchinson Cancer Research Center, Seattle
                [16 ]Lineberger Comprehensive Cancer Center, UNC School of Medicine, University of North Carolina, Chapel Hill
                [17 ]Memorial Sloan Kettering Cancer Center, New York, USA
                [18 ]Section of Genetics, International Agency for Research on Cancer, Lyon, France
                Article
                10.1093/annonc/mdz044
                55ad3463-6b00-4aba-be26-db9dfd8220e1
                © 2019

                http://creativecommons.org/licenses/by-nc/4.0/

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