Distinct molecular pathways in colorectal precursor lesions: Correlation of KRAS, BRAF mutations and microsatellite instability with histomorphology
KRAS, BRAF and MSI in colorectal precursor lesions
DOI:
https://doi.org/10.5281/zenodo.18968382Keywords:
BRAF, colorectal polyps, KRAS, microsatellite instabilityAbstract
Objective: This study aimed to investigate the clinicopathological and molecular characteristics of colorectal precursor lesions and to evaluate the presence of KRAS and BRAF mutations and microsatellite instability (MSI) according to the 2019 World Health Organization (WHO) classification.
Methods: A total of 48 colorectal precursor lesions obtained during colonoscopy were analysed, including 12 conventional adenomas, 24 serrated polyps (12 hyperplastic polyps [HP], 7 sessile serrated lesions [SSL], 5 traditional serrated adenomas [TSA]) and 12 lesions with dual morphological features (9 TSA/tubulovillous adenoma [TSA/TVA], 3 SSL/HP). Real-time PCR was utilised to evaluate KRAS (codons 12, 13, 61), BRAF V600E mutations and MSI status (BAT25, BAT26, NR21, NR24, MONO27). Statistical comparisons were performed using Fisher's exact test.
Results: KRAS mutations were detected in 45.8% (22/48) of all lesions, with a higher frequency observed in conventional adenomas (50%) compared to serrated polyps (37.5%), although this difference did not reach statistical significance (p=0.499). KRAS-mutant polyps exhibited a significantly larger size compared to KRAS wild-type polyps (17.07 mm vs. 12.24 mm; p=0.028). BRAF V600E mutations were identified in 31.3% (15/48) of lesions and were significantly associated with serrated polyps (58.4%) compared with conventional adenomas (0%) (p=0.01). BRAF-mutant polyps exhibited a tendency to be of smaller size in comparison to wild-type polyps, demonstrating borderline statistical significance (p=0.055). Among serrated subtypes, KRAS mutations predominated in TSAs (100%) and goblet-rich HPs, whereas BRAF mutations were most frequent in SSLs (85.7%) and microvesicular HPs (80%). MSI was detected in a single TSA/TVA lesion (2%), which is a noteworthy finding given its rarity.
Conclusion: Distinct molecular alterations have been shown to correlate with specific morphological subtypes of colorectal precursor lesions. KRAS mutations have been observed to be associated with larger lesion size and conventional or TSA-related pathways, whereas BRAF mutations have been shown to characterise the serrated pathway. Molecular profiling has been demonstrated to provide valuable adjunctive information for the classification and risk stratification of colorectal precursor lesions under the 2019 WHO framework.
References
1.Howlader N, Noone AM, Krapcho M, Neyman N, Aminou R, Waldron W, et al. SEER cancer statistics review, 1975–2009. Bethesda: National Cancer Institute; 2009.
2.Nagtegaal ID, Odze RD, Klimstra D, Paradis V, Rugge M, Schirmacher P, et al. The 2019 WHO classification of tumours of the digestive system. Histopathology. 2020;76:182–8.
3.Nguyen LH, Goel A, Chung DC. Pathways of colorectal carcinogenesis. Gastroenterology. 2020;158:291–302.
4.Hagen R, Srivastava A, Anderson JC. The serrated pathway and colorectal cancer: what the gastroenterologist should know. Expert Rev Gastroenterol Hepatol. 2025;19:593–606.
5.Currais P, Rosa I, Claro I. Colorectal cancer carcinogenesis: From bench to bedside. World J Gastrointest Oncol. 2022;14:654.
6.Marcellinaro R. Colorectal cancer: current updates and future perspectives. J Clin Med. 2023;13:40.
7.Dunne PD, Arends MJ. Molecular pathological classification of colorectal cancer—an update. Virchows Arch. 2024;484:273–85.
8.Torlakovic E, Skovlund E, Snover DC, Torlakovic G, Nesland JM. Morphologic reappraisal of serrated colorectal polyps. Am J Surg Pathol. 2003;27:65–81.
9.Kim KM, Lee JH, Kim YS, Park SJ, Kim JH, Lee HS, et al. Clinical significance of p53 protein expression and TP53 variation status in colorectal cancer. BMC Cancer. 2022;22:940.
10.Aiderus A, Barker N, Tergaonkar V. Serrated colorectal cancer: preclinical models and molecular pathways. Trends Cancer. 2024;10:76–91.
11.Wankhede D, Singh R, Kumar S, Gupta R, Patel P, Sharma A, et al. Clinical significance of combined tumour-infiltrating lymphocytes and microsatellite instability status in colorectal cancer: a systematic review and network meta-analysis. Lancet Gastroenterol Hepatol. 2024;9:609–19.
12.Smits LJH, van Lanschot MCJ, Carvalho B, Coupé VMH, van den Broek E, Nagtegaal ID, et al. Diagnostic variability in the histopathological assessment of advanced colorectal adenomas and early colorectal cancer in a screening population. Histopathology. 2022;80:790–8.
13.Takeda M, Yamamoto H, Tanaka T, Suzuki H, Sato Y, Itoh F, et al. The role of KRAS mutations in colorectal cancer: biological insights, clinical implications, and future therapeutic perspectives. Cancers (Basel). 2025;17:428.
14.Park PH, Kim YS, Lee JH, Choi YJ, Kim HJ, Park SJ, et al. Association between gut microbiota and CpG island methylator phenotype in colorectal cancer. Gut Microbes. 2024;16:2363012.
15.Rex DK, Ahnen DJ, Baron JA, Batts KP, Burke CA, Burt RW, et al. Serrated lesions of the colorectum: review and recommendations from an expert panel. Am J Gastroenterol. 2012;107:1315–30.
16.Mezzapesa M, Rossi R, Bianchi F, De Luca A, Ricciardiello L, Lanza G, et al. Serrated colorectal lesions: an up-to-date review from histological pattern to molecular pathogenesis. Int J Mol Sci. 2022;23:4461.
17.Inoue A, Okamoto K, Fujino Y, Nakagawa T, Muguruma N, Sannomiya K, et al. BRAF mutation and accumulated gene methylation in sessile serrated adenoma/polyp and cancer. Br J Cancer. 2015;112:403–12.
18.Nakamura F, Yamamoto H, Takahashi T, Suzuki H, Tanaka T, Itoh F, et al. Colorectal carcinoma occurring via the adenoma–carcinoma pathway in patients with serrated polyposis syndrome. J Gastroenterol. 2022;57:286–99.
19.Yamamoto H, Imai K, Tanaka T, Suzuki H, Takahashi T, Itoh F, et al. Microsatellite instability: A 2024 update. Cancer Sci. 2024;115:1738–48.
20.Sninsky JA, Smith RA, Jones KR, Brown LM, Patel V, Greenwald P, et al. Risk factors for colorectal polyps and cancer. Gastrointest Endosc Clin N Am. 2022;32:195–213.
21.Bettington ML, Walker NI, Rosty C, Brown IS, Clouston AD, McKeone DM, et al. Clinicopathological and molecular analysis of traditional serrated adenomas. Mod Pathol. 2015;28:414–27.
22.Bettington ML, Chetty R. Traditional serrated adenoma: an update. Hum Pathol. 2015;46:933–8.
23.Chen Y, Wang X, Li J, Zhang H, Liu Y, Zhao Q, et al. Traditional serrated adenomas associated with risk of subsequent high-risk polyps and colorectal cancer. Am J Gastroenterol. 2022;117:S14309.
24.Wang JD, Liu Y, Zhang H, Chen X, Li Q, Zhao Y, et al. The histologic features, molecular features, detection and management of serrated polyps: a review. Front Oncol. 2024;14:1356250.
25.Li Q, Zhang Y, Wang H, Liu X, Chen J, Zhao L, et al. Signaling pathways involved in colorectal cancer: pathogenesis and targeted therapy. Signal Transduct Target Ther. 2024;9:266.
Downloads
Published
How to Cite
Issue
Section
License
Copyright (c) 2026 The Injector
This work is licensed under a Creative Commons Attribution-NonCommercial 4.0 International License.
The journal is licensed under a 