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A Changing Spectrum of Colorectal Cancer Biology With Age

Implications for the Young Patient

Chouhan, Hanumant, M.D.1,2,3; Ferrandon, Sylvain, Ph.D.2; DeVecchio, Jennifer, B.A.2; Kalady, Matthew F., M.D.1,2,3; Church, James M., M.D.1,2

Diseases of the Colon & Rectum: January 2019 - Volume 62 - Issue 1 - p 21–26
doi: 10.1097/DCR.0000000000001188
Original Contributions: Colorectal Cancer
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BACKGROUND: The methylator pathway of colorectal carcinogenesis, characterized by CpG island hypermethylation and BRAF mutations, accounts for ≈25% of colorectal cancers. Because these cancers tend to be right sided and because DNA methylation in the right colon increases with age, we expect an increasing proportion of right-sided cancer over time. Conversely, we expect young patients (age <50 y) to have less methylated and fewer right-sided cancers

OBJECTIVE: The purpose of this study was to analyze the distribution and genetic traits of colorectal cancer from different age groups.

DESIGN: This was a retrospective cohort study.

SETTING: The study was conducted at a high-volume tertiary referral center.

PATIENTS: Patient samples included those from our colorectal cancer biobank of resected colorectal cancer specimens.

MAIN OUTCOME MEASURES: Tumor CpG island hypermethylation, microsatellite instability, and mutations in KRAS and BRAF oncogenes were analyzed in resected specimens and stratified by age and tumor location. Comparisons included age >50 or <50 years and decade of diagnosis (≤50, 51–60, 61–70, 71–80, and >81 y). Patients with IBD or hereditary syndromes were excluded.

RESULTS: A total of 497 colorectal cancers were analyzed (266 men and 231 women); 57 patients (11.5%) were ≤50 years of age. No young cancers (0/57) were hypermethylated compared with 97 (22%) of 440 cancers of patients aged >50 years (p < 0.001). An increasing percentage of tumors were CpG island phenotype high with each decade of age at diagnosis. No cancers in patients <50 years of age were microsatellite unstable compared with 91 (23.6%) of 346 for those >50 years of age. No young cancers contained a BRAF mutation compared with 46 (10.6%) of 434 in older cancers (p < 0.001). KRAS mutations were less common in young cancers compared with older cancers (13/57 (22.8%) vs 126/410 (30.7%); p < 0.01). Eleven (19.3%) of 57 young cancers were proximal compared with 228 (51.8%) of 440 (p < 0.001) older cancers.

LIMITATIONS: This study was limited by its retrospective design.

CONCLUSIONS: The lack of CpG island methylator phenotype tumors in young patients is consistent with the dominant left-sided cancer distribution seen in the young and focuses efforts to understand and prevent cancer in this age group on causes of chromosomal instability. See Video Abstract at

1 Department of Colorectal Surgery, Cleveland Clinic, Cleveland, Ohio

2 Sanford R. Weiss, M.D., Center for Hereditary Colorectal Neoplasia, Digestive Disease and Surgery Institute, Cleveland Clinic, Cleveland, Ohio

3 Department of Stem Cell and Regenerative Medicine, Lerner Research Institute, Cleveland Clinic, Cleveland, Ohio

Funding/Support: None reported.

Financial Disclosure: None reported.

Podium presentation at the meeting of The American Society of Colon and Rectal Surgeons, Nashville, TN, May 19 to 23, 2018.

Correspondence: Hanumant Chouhan, M.D., Department of Colorectal Surgery, Cleveland Clinic, 9500 Euclid Ave, A30, Cleveland, OH 44195. E-mail:

© 2019 The American Society of Colon and Rectal Surgeons