Shonaka T, Tani C, Mizukami S, Koro D, Iwata H, Ohara M, Tanabe H, Makita Y, Tanino M, Yokoo H. Clinical and molecular heterogeneity of microsatellite instability-high colorectal cancer in older adults. World J Gastrointest Oncol 2026; 18(11): 123709 [DOI: 10.4251/wjgo.123709]
Corresponding Author of This Article
Tatsuya Shonaka, MD, PhD, Division of Gastroenterological and Transplantation Surgery, Department of Surgery, Asahikawa Medical University, 2-1 Midorigaoka-Higashi, Asahikawa 078-8510, Japan. shonaka@asahikawa-med.ac.jp
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Gastroenterology & Hepatology
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Shonaka T, Tani C, Mizukami S, Koro D, Iwata H, Ohara M, Tanabe H, Makita Y, Tanino M, Yokoo H. Clinical and molecular heterogeneity of microsatellite instability-high colorectal cancer in older adults. World J Gastrointest Oncol 2026; 18(11): 123709 [DOI: 10.4251/wjgo.123709]
Tatsuya Shonaka, Chikayoshi Tani, Shoichiro Mizukami, Daisuke Koro, Hiroyoshi Iwata, Mizuho Ohara, Hideki Yokoo, Division of Gastroenterological and Transplantation Surgery, Department of Surgery, Asahikawa Medical University, Asahikawa 078-8510, Japan
Hiroki Tanabe, Division of Gastroenterology, Department of Internal Medicine, Asahikawa Medical University, Asahikawa 078-8510, Japan
Hiroki Tanabe, Yoshio Makita, Department of Genetic Counseling, Asahikawa Medical University Hospital, Asahikawa 078-8510, Japan
Mishie Tanino, Department of Pathology, Asahikawa Medical University Hospital, Asahikawa 078-8510, Japan
Author contributions: Shonaka T, Tani C, and Mizukami S contributed to study conception and design; Koro D, Iwata H, and Ohara M collected and analyzed data; Tanabe H and Makita Y provided genetic counseling and advice; Tanino M performed pathological diagnosis and mismatch repair immunostaining for pathological evaluation; Shonaka T wrote the first draft of this manuscript; Yokoo H supervised the study. All the authors critically reviewed, commented on, and approved the final manuscript.
AI contribution statement: Portions of this manuscript were edited using AI tools (specifically Gemini) solely for language refinement. The authors carefully reviewed and verified all AI-assisted outputs and take full responsibility for the scientific content of the manuscript.
Supported by Akiyama Life Science Foundation.
Institutional review board statement: The study was reviewed and approved by the Ethics Committee of Asahikawa Medical University, No. 24011.
Informed consent statement: Informed consent was obtained from all patients via an opt-out framework, in accordance with the institutional ethical requirements and the Declaration of Helsinki. Patient data were fully anonymized to protect personal information.
Conflict-of-interest statement: All the authors report no relevant conflicts of interest for this article.
STROBE statement: The authors have read the STROBE Statement-checklist of items, and the manuscript was prepared and revised according to the STROBE Statement-checklist of items.
Data sharing statement: The datasets supporting the conclusions of this study are available from the corresponding author upon request. Owing to ethical and confidentiality constraints, the raw datasets are not publicly available.
Corresponding author: Tatsuya Shonaka, MD, PhD, Division of Gastroenterological and Transplantation Surgery, Department of Surgery, Asahikawa Medical University, 2-1 Midorigaoka-Higashi, Asahikawa 078-8510, Japan. shonaka@asahikawa-med.ac.jp
Received: May 27, 2026 Revised: June 26, 2026 Accepted: July 16, 2026 Published online: November 15, 2026 Processing time: 154 Days and 4.7 Hours
Abstract
BACKGROUND
Although universal screening for Lynch syndrome is gaining increased support, the clinical utility of microsatellite instability (MSI) testing in older patients remains controversial. Consequently, MSI-high (MSI-H) colorectal cancer (CRC) in older adults is generally considered a sporadic disease driven by aging, and the actual molecular heterogeneity in this population remains underappreciated.
AIM
To define age-specific clinicopathological MSI-H CRC features in an aging East Asian population and challenge the assumption of uniformly sporadic older MSI-H CRC.
METHODS
Data of 573 consecutive patients who underwent surgical resection for primary CRC between 2013 and 2025 were retrospectively analyzed. MSI status was determined using five mononucleotide markers or mismatch repair immunohistochemistry. The patients were stratified into older (≥ 71 years; n = 289) and younger (≤ 70 years; n = 284) groups.
RESULTS
The prevalence of MSI-H CRC was comparable across groups: 7.4% in the older group and 7.6% in the younger group (P = 1.0). Although the older group had significantly more BRAF mutations (P < 0.001), the molecular landscape was heterogeneous. Of the older MSI-H patients, 28.6% (6/21) exhibited non-sporadic, atypical profiles, including four BRAF wild-type cases with MLH1 deficiency and two with MSH2 or MSH6 deficiencies. A 72-year-old patient with an MSH6 mutation was definitively diagnosed with Lynch syndrome, a condition that would have remained undetected under the conventional age-restricted screening guidelines.
CONCLUSION
Although limited by a small sample size, nearly 30% of older patients with MSI-H CRC in our cohort exhibit atypical molecular profiles, suggesting that older age does not uniformly imply sporadic disease. Relying strictly on age to triage patients carries a risk of missing Lynch syndrome. Further larger studies are needed to confirm whether reflex MLH1 promoter methylation analysis should be performed regardless of age to optimize precision medicine.
Core Tip: While microsatellite instability-high colorectal cancer in older adults is widely considered sporadic, our real-world data revealed that 28.6% (6/21) of older adults with microsatellite instability-high exhibited atypical molecular profiles, including BRAF wild-type/MLH1 and MSH2/MSH6 deficiencies. Age-based assumptions can lead to missed diagnoses of Lynch syndrome, as demonstrated in the 72-year-old patient in our study. Therefore, reflex MLH1 promoter methylation analysis should be routinely performed regardless of age to optimize precision medicine and facilitate life-saving cascade screening of family members.
