The incidence of early-onset colorectal cancer (CRC), which occurs in individuals <50 years of age, has been increasing worldwide and particularly in high-income countries. The reasons for this increase remain unknown but plausible hypotheses include greater exposure to potential risk factors, such as a Western-style diet, obesity, physical inactivity and antibiotic use, especially during the early prenatal to adolescent periods of life. These exposures can not only cause genetic and epigenetic alterations in colorectal epithelial cells but also affect the gut microbiota and host immunity. Early-onset CRCs have differential clinical, pathological and molecular features compared with later-onset CRCs. Certain existing resources can be utilized to elucidate the aetiology of early-onset CRC and inform the development of effective prevention, early detection and therapeutic strategies; however, additional life-course cohort studies spanning childhood and young adulthood, integrated with prospective biospecimen collections, omics biomarker analyses and a molecular pathological epidemiology approach, are needed to better understand and manage this disease entity. In this Perspective, we summarize our current understanding of early-onset CRC and discuss how we should strategize future research to improve its prevention and clinical management.
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The authors thank Tyler Twombly (Program in Molecular Pathological Epidemiology, Department of Pathology, Brigham and Women’s Hospital, Boston, USA) for proofreading of the manuscript. The work of the authors is supported by US NIH grants (R35 CA197735 and R01 CA248857 to S.O., R21 CA230873 to S.O. and K.W., R01 CA205406 to K.N., R03 CA197879 to K.W., and R37 CA246175 to Y.C.), a Cancer Research UK Grand Challenge Award (UK C10674/A27140 to M.G., K.N. and S.O.), an Investigator Initiated Grant from the American Institute for Cancer Research (AICR) to K.W., and by a US Department of Defense grant (CA160344 to K.N.). K.N. and M.G. have received support from the Project P Fund. The work of M.G. has been supported by a Stand Up to Cancer Colorectal Cancer Dream Team Translational Research Grant (SU2C-AACR-DT22-17) administered by the American Association for Cancer Research, a scientific partner of SU2C. The work of T.U. has been supported by an Overseas Research Fellowship grant (201960541) from the Japan Society for the Promotion of Science, the Uehara Memorial Foundation and the Yasuda Medical Foundation. The work of K.F. has been supported by fellowship grants from the Uehara Memorial Foundation and the Grant of The Clinical Research Promotion Foundation (2018). The content of this manuscript is solely the responsibility of the authors and does not necessarily represent the official views of the NIH.
K.N. has received institutional research funding from Evergrande Group, Genentech, Gilead Sciences, Pharmavite, Revolution Medicines, Tarrex Biopharma and Trovagene, and has served on advisory boards for Array Biopharma, Bayer and Seattle Genetics. M.G. has received research funding from Bristol-Myers Squibb and Merck. The other authors declare no competing interests.
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Child Health and Development Studies (CHDS): http://www.chdstudies.org/
Colon Cancer Family Registry (CCFR) Cohort: https://www.coloncfr.org/
Growing Up in New Zealand: https://www.growingup.co.nz/
Growing Up Today Study 2 (GUTS2): https://nhs2survey.org/gutswordpress/index.php/about/history/
Millennium Cohort Study: https://cls.ucl.ac.uk/cls-studies/millennium-cohort-study/
National Children’s Study: https://www.nichd.nih.gov/research/supported/NCS
Nurses’ Health Study 3 (NHS3): https://www.nhs3.org/
ORIGINS Project: https://originsproject.telethonkids.org.au/
SEER Cancer Statistics Review 1975–2017: https://seer.cancer.gov/csr/1975_2017/
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Akimoto, N., Ugai, T., Zhong, R. et al. Rising incidence of early-onset colorectal cancer — a call to action. Nat Rev Clin Oncol 18, 230–243 (2021). https://doi.org/10.1038/s41571-020-00445-1
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