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. 2023 Apr 1;118(4):712-726.
doi: 10.14309/ajg.0000000000002171. Epub 2022 Dec 30.

Molecular Characteristics of Early-Onset Colorectal Cancer According to Detailed Anatomical Locations: Comparison With Later-Onset Cases

Tomotaka Ugai  1   2 , Koichiro Haruki  1 , Tabitha A Harrison  3 , Yin Cao  4   5 , Conghui Qu  3 , Andrew T Chan  6   7   8   9 , Peter T Campbell  10 , Naohiko Akimoto  1 , Sonja Berndt  11 , Hermann Brenner  12   13   14 , Daniel D Buchanan  15   16   17 , Jenny Chang-Claude  18   19 , Kenji Fujiyoshi  1 , Steven J Gallinger  20 , Marc J Gunter  21 , Akihisa Hidaka  3 , Michael Hoffmeister  12 , Li Hsu  3 , Mark A Jenkins  22 , Roger L Milne  22   23   24 , Victor Moreno  25   26   27   28 , Polly A Newcomb  3   29 , Reiko Nishihara  1   30 , Rish K Pai  31 , Lori C Sakoda  3   32 , Martha L Slattery  33 , Wei Sun  3 , Efrat L Amitay  12 , Elizabeth Alwers  12 , Stephen N Thibodeau  34 , Amanda E Toland  35 , Bethany Van Guelpen  36   37 , Michael O Woods  38 , Syed H Zaidi  39 , John D Potter  3 , Marios Giannakis  40   41 , Mingyang Song  2   4   5   30 , Jonathan A Nowak  1 , Amanda I Phipps  3   29 , Ulrike Peters  3   29 , Shuji Ogino  1   2   41   42
Affiliations

Molecular Characteristics of Early-Onset Colorectal Cancer According to Detailed Anatomical Locations: Comparison With Later-Onset Cases

Tomotaka Ugai et al. Am J Gastroenterol. .

Abstract

Introduction: Early-onset colorectal cancer diagnosed before the age of 50 years has been increasing. Likely reflecting the pathogenic role of the intestinal microbiome, which gradually changes across the entire colorectal length, the prevalence of certain tumor molecular characteristics gradually changes along colorectal subsites. Understanding how colorectal tumor molecular features differ by age and tumor location is important in personalized patient management.

Methods: Using 14,004 cases with colorectal cancer including 3,089 early-onset cases, we examined microsatellite instability (MSI), CpG island methylator phenotype (CIMP), and KRAS and BRAF mutations in carcinomas of the cecum, ascending colon, transverse colon, descending colon, sigmoid colon, and rectum and compared early-onset cases with later-onset cases.

Results: The proportions of MSI-high, CIMP-high, and BRAF -mutated early-onset tumors were lowest in the rectum (8.8%, 3.4%, and 3.5%, respectively) and highest in the ascending colon (46% MSI-high; 15% CIMP-high) or transverse colon (8.6% BRAF -mutated) (all Ptrend <0.001 across the rectum to ascending colon). Compared with later-onset tumors, early-onset tumors showed a higher prevalence of MSI-high status and a lower prevalence of CIMP-high status and BRAF mutations in most subsites. KRAS mutation prevalence was higher in the cecum compared with that in the other subsites in both early-onset and later-onset tumors ( P < 0.001). Notably, later-onset MSI-high tumors showed a continuous decrease in KRAS mutation prevalence from the rectum (36%) to ascending colon (9%; Ptrend <0.001), followed by an increase in the cecum (14%), while early-onset MSI-high cancers showed no such trend.

Discussion: Our findings support biogeographical and pathogenic heterogeneity of colorectal carcinomas in different colorectal subsites and age groups.

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Conflict of interest statement

A.T.C. previously served as a consultant for Bayer Healthcare and Pfizer Inc. M.G. receives research funding from Bristol-Myers Squibb and Merck. A.T.C. is a Stuart and Suzanne Steele MGH Research Scholar. The other authors declare no potential conflicts of interest. The content is solely the responsibility of the authors and does not necessarily represent the official views of U.S. NIH. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.

Figures

Figure 1.
Figure 1.
Prevalence of MSI-high status, CIMP-high status, BRAF mutations, and KRAS mutations along sublocations by age groups. Abbreviations: CIMP, CpG island methylator phenotype; MSI, microsatellite instability.
Figure 2.
Figure 2.
Prevalence of CIMP-high status, BRAF mutations, and KRAS mutations along sublocations by MSI status in early-onset and later-onset cancers. Abbreviations: CIMP, CpG island methylator phenotype; MSI, microsatellite instability.
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