Pages: 1022-1029DOI: 10.46327/msrjg.1.000000000000207
Date of Publication: 30-Nov--0001
KRAS/NRAS Mutational Analysis and Clinicopathologic Correlation of Colorectal Carcinoma: A Single Institute Experience From Turkey
Author: Onenerk A. Mine, Ozdemir H. Gulnihal, Ozkara Selvinaz, Aker Vardar Fugen, Ustaalioglu Oven Basak
Category: JMSR Oncology
Background: Colorectal carcinoma (CRC) is the second most frequent cause of cancer-related death for both sexes. Clinical and pathological correlates of Kirsten rat sarcoma viral oncogene/neuroblastoma ras viral oncogene (KRAS/NRAS) mutant tumors are important for therapy response, especially in metastatic CRCs. The aim of this study is to determine the frequency of KRAS/NRAS mutations and investigate the clinicopathologic characteristics of KRAS/NRAS mutant and rat sarcoma (RAS)-wild type CRCs. Methods: Pathology archives were searched for CRCs between 2014 and 2015, retrospectively. We reevaluated tumor slides for Crohn-like infiltrate, tumor infiltrating lymphocytes, tumor budding, presence of mucinous component, and signet-ring cell morphology. Tumor grade, depth of invasion, lymph node metastases, distant metastases, lymphovascular and perineural invasion, polyp type, and DNA mismatch repair status were derived from their pathology reports. Formalin-fixed, paraffin-embedded tissues were examined for KRAS/NRAS mutation status. Mutation status and their clinicopathologic correlates were evaluated. Results: KRAS and NRAS mutations were detected in 43.6% and 10% of the CRCs, respectively. KRAS mutations were associated with multiple organ metastasis and CRCs with solid growth pattern did not harbor RAS mutations. Well differentiated CRCs were more common in NRAS mutant and RAS-wild type CRCs in comparison to RAS mutant tumors. NRAS mutant CRCs were more frequent in the left colon and rectum. Conclusion: In this study, we identified that KRAS mutations were associated with multiple organ metastasis and CRCs with solid growth pattern did not harbor RAS mutations. Also, NRAS mutant tumors were more common in the left colon and rectum concordant with the previous studies.
Keywords: colorectal carcinoma, metastatic colorectal carcinoma, KRAS, NRAS
1. Bray F, Ferlay J, Soerjomataram I, et al. Global cancer statistics 2018: GLOBOCAN estimates of incidence and mortality worldwide for 36 cancers in 185 countries. CA: a cancer journal for clinicians. 2018;68(6):394-424.
2. Siegel RL, Miller KD, Fedewa SA, et al. Colorectal cancer statistics, 2017. CA: a cancer journal for clinicians. 2017;67(3):177-93.
3. Wolpin BM, Mayer RJ. Systemic treatment of colorectal cancer. Gastroenterology. 2008;134(5):1296-310.
4. Douillard JY, Oliner KS, Siena S, et al. Panitumumab-FOLFOX4 treatment and RAS mutations in colorectal cancer. The New England journal of medicine. 2013;369(11):1023-34.
5. Bokemeyer C, Köhne CH, Ciardiello F, et al. FOLFOX4 plus cetuximab treatment and RAS mutations in colorectal cancer. European journal of cancer (Oxford, England : 1990). 2015;51(10):1243-52.
6. Provenzale D, Gupta S, Ahnen DJ, et al. NCCN Guidelines Insights: Colorectal Cancer Screening, Version 1.2018. Journal of the National Comprehensive Cancer Network : JNCCN. 2018;16(8):939-49.
7. Chang CC, Lin PC, Lin CC, et al. Molecular and Clinicopathological Differences by Age at the Diagnosis of Colorectal Cancer. International journal of molecular sciences. 2017;18(7).
8. Gong J, Cho M, Sy M, et al. Molecular profiling of metastatic colorectal tumors using next-generation sequencing: a single-institution experience. Oncotarget. 2017;8(26):42198-213.
9. Peng J, Huang D, Poston G, et al. The molecular heterogeneity of sporadic colorectal cancer with different tumor sites in Chinese patients. Oncotarget. 2017;8(30):49076-83.
10. Schirripa M, Cremolini C, Loupakis F, et al. Role of NRAS mutations as prognostic and predictive markers in metastatic colorectal cancer. International journal of cancer. 2015;136(1):83-90.
11. Lugli A, Kirsch R, Ajioka Y, et al. Recommendations for reporting tumor budding in colorectal cancer based on the International Tumor Budding Consensus Conference (ITBCC) 2016. Modern pathology : an official journal of the United States and Canadian Academy of Pathology, Inc. 2017;30(9):1299-311.
12. Sayagués JM, Del Carmen S, Del Mar Abad M, et al. Combined assessment of the TNM stage and BRAF mutational status at diagnosis in sporadic colorectal cancer patients. Oncotarget. 2018;9(35):24081-96.
13. Chang YY, Lin PC, Lin HH, et al. Mutation spectra of RAS gene family in colorectal cancer. American journal of surgery. 2016;212(3):537-44.e3.
14. Van Cutsem E, Lenz HJ, Köhne CH, et al. Fluorouracil, leucovorin, and irinotecan plus cetuximab treatment and RAS mutations in colorectal cancer. Journal of clinical oncology : official journal of the American Society of Clinical Oncology. 2015;33(7):692-700.
15. Russo AL, Borger DR, Szymonifka J, et al. Mutational analysis and clinical correlation of metastatic colorectal cancer. Cancer. 2014;120(10):1482-90.
16. Gonsalves WI, Mahoney MR, Sargent DJ, et al. Patient and tumor characteristics and BRAF and KRAS mutations in colon cancer, NCCTG/Alliance N0147. Journal of the National Cancer Institute. 2014;106(7).
17. Zahrani A, Kandil M, Badar T, et al. Clinico-pathological study of K-ras mutations in colorectal tumors in Saudi Arabia. Tumori. 2014;100(1):75-9.
18. Shen Y, Wang J, Han X, et al. Effectors of epidermal growth factor receptor pathway: the genetic profiling ofKRAS, BRAF, PIK3CA, NRAS mutations in colorectal cancer characteristics and personalized medicine. PloS one. 2013;8(12):e81628.
19. Tsai YJ, Huang SC, Lin HH, et al. Differences in gene mutations according to gender among patients with colorectal cancer. World journal of surgical oncology. 2018;16(1):128.
20. Irahara N, Baba Y, Nosho K, et al. NRAS mutations are rare in colorectal cancer. Diagnostic molecular pathology : the American journal of surgical pathology, part B. 2010;19(3):157-63.
21. Natsume S, Yamaguchi T, Takao M, et al. Clinicopathological and molecular differences between right-sided and left-sided colorectal cancer in Japanese patients. Japanese journal of clinical oncology. 2018;48(7):609-18.
22. Salem ME, Weinberg BA, Xiu J, et al. Comparative molecular analyses of left-sided colon, right-sided colon, and rectal cancers. Oncotarget. 2017;8(49):86356-68.
23. Ghidini M, Petrelli F, Tomasello G. Right Versus Left Colon Cancer: Resectable and Metastatic Disease. Current treatment options in oncology. 2018;19(6):31.
24. Samowitz WS, Curtin K, Schaffer D, et al. Relationship of Ki-ras mutations in colon cancers to tumor location, stage, and survival: a population-based study. Cancer epidemiology, biomarkers & prevention : a publication of the American Association for Cancer Research, cosponsored by the American Society of Preventive Oncology. 2000;9(11):1193-7.
25. Baldus SE, Schaefer KL, Engers R, et al. Prevalence and heterogeneity of KRAS, BRAF, and PIK3CA mutations in primary colorectal adenocarcinomas and their corresponding metastases. Clinical cancer research : an official journal of the American Association for Cancer Research. 2010;16(3):790-9.
26. Neumann J, Wehweck L, Maatz S, et al. Alterations in the EGFR pathway coincide in colorectal cancer and impact on prognosis. Virchows Archiv : an international journal of pathology. 2013;463(4):509-23.
27. Steinestel K, Lennerz JK, Eder S, et al. Invasion pattern and histologic features of tumor aggressiveness correlate with MMR protein expression, but are independent of activating KRAS and BRAF mutations in CRC. Virchows Archiv : an international journal of pathology. 2014;465(2):155-63.
28. Petrelli F, Pezzica E, Cabiddu M, et al. Tumour Budding and Survival in Stage II Colorectal Cancer: a Systematic Review and Pooled Analysis. Journal of gastrointestinal cancer. 2015;46(3):212-8.
29. Prall F, Ostwald C. High-degree tumor budding and podia-formation in sporadic colorectal carcinomas with K-ras gene mutations. Human pathology. 2007;38(11):1696-702.
30. Zlobec I, Bihl MP, Schwarb H, et al. Clinicopathological and protein characterization of BRAF- and K-RAS-mutated colorectal cancer and implications for prognosis. International journal of cancer. 2010;127(2):367-80.