Incidence Of Kras Mutations In Colon Adenocarcinomas And Its Association With Lymph Node Metastases

Öz

Objective: Colon adenocarcinoma, one of the most frequent malignant tumors of the gastrointestinal system, is a major cause of morbidity and mortality. As KRAS mutations are encountered in 30-40% of colorectal carcinomas, a mutation screening is required before therapy commences. In this study, we aim to determine KRAS codon 12, 13 and 61 mutations in moderately differentiated colon adenocarcinomas and assess whether these mutations are associated with lymph node metastases.

Materials and methods: A total of 120 moderately differentiated colorectal carcinomas, 60 with lymph node metastases and 60 without, were included. Samples underwent PCR with appropriate primers and Sanger sequencing was carried out to determine their KRAS mutation status.

Results: Out of the 120 cases included in our study, 40 carried codon 12, 5 carried codon 13 mutations. In total, 37.5% of cases had a KRAS mutation (45/120). No mutation was detected in codon 61.

Conclusion: Our study has not shown a significant association between the presence of KRAS mutations and lymph node metastasis. This study was conducted in a limited number of patients and in a pre-defined, small area; but can be used as a preliminary step for multicenter and larger studies.

Anahtar Kelimeler

• colon adenocarcinoma,kras,lymph node metastases

Kolon Adenokarsinomlarinda Kras Mutasyonlarinin Sikliği Ve Lenf Nodu Metastazi İle İlişkisi

Öz

Amaç: Gastrointestinal sistemin en yaygın malignitesi olan kolon kanserleri mortalite ve morbiditenin ana nedenlerinden biridir. Kolorektal kanserlerin %30-40’ında KRAS gen mutasyonu izlendiğinden tedaviye başlamadan önce mutasyon taraması önemlidir. Bu çalışmadaki amacımız orta derece diferansiye kolon adenokarsinomlarında KRAS kodon 12, 13, 61 mutasyon durumunu belirlemek ve bu mutasyonların lenf nodu metastazı ile ilişkisini araştırmaktır.

Gereç ve yöntem: Fırat Üniversitesi Tıp Fakültesi Tıbbi Patoloji Anabilim Dalı arşivinden seçilen 60 adet lenf nodu metastazlı ve 60 adet lenf nodu metastazı olmayan toplam 120 adet orta derecede diferansiye kolon adenokarsinomu örneğinden uygun primer çiftleri PZR ile çoğaltılıp sekans analizi ile KRAS mutasyon durumu belirlenmiştir.

Bulgular: Çalışmamıza alınan 120 olguda 40 tanesi kodon 12 de ve 5 tanesi kodon 13 de olmak üzere %37.5 (45/120) oranında KRAS mutasyonu izlendi. KRAS kodon 61 de mutasyona rastlanmadı.

Sonuç: Çalışmamızda KRAS mutasyon durumu ile lenf nodu metastazı arasında anlamlı bir ilişki bulunmadı. Bu çalışma küçük bir alanda öncesinde tanı almış sınırlı sayıda olguda yapıldı; ancak çok merkezli ve daha geniş çalışmalar için bir ön izlenim taşıma özelliğindedir.

Anahtar Kelimeler

• Kolon adenokarsinomu,kras,lenf nodu metastazı

Kaynakça

1. REFERENCES 1.Kumar V, Abbas A, Fausto N, Aster J. Robbins and cotran pathologic basis of disease, professional edition e-book. Elsevier Health Sciences, 2014; 810-15.
2. 2.Haggar FA, Boushey RP. Colorectal cancer epidemiology incidence, mortality, survival and risk factors. Clin Colon Rectal Surg 2009;22(4):191-97.
3. 3.Jemal A, Siegel R, Ward E, Hao Y, Xu J, Murray T et al. Cancer statics. Ca Cancer J Clinic 2008;58(2):71-96.
4. 4.Kumar V, Abbas A, Fausto N, Aster J. Robbins and cotran pathologic basis of disease, professional edition e-book. Elsevier Health Sciences, 2014; 809-10.
5. 5.Martinez JD, Parker MT, Fultz KE, Ignantenko NA, Gerner EW. Molecular biology of cancer. Burger’s medicinal chemistry and drug discovery. Wiley&Sons, 2003;1-32.
6. 6.Jıang Y, Mackley H, Cheng H, Ajani JA. Use of K-ras as a predictive biomarker for selecting anti-EGF receptor pathway treatment. Biomark Med 2010;4(4):534-41.
7. 7.De Roock W, Claes B, Bernasconi D, De Schutter J, Biesmans B, Fountzilas G et al. Effects of KRAS, BRAF, NRAS and PIK3Ca mutations on the efficacy of cetuximab plus chemothrapy in chemotherapy-refractory metastatic colorectal cancer: a retrospective consortium analysis. Lancet Oncol 2010;11(8):753-62.
8. 8.Panagiotis P, Antonio C, Francesco T, Giuseppe P, Grazia P. KRAS mutational concordance between primary and metastatic colorectal adenocarcinoma. Oncol Lett 2014;8(4):1422-26.

9. 9.Saif MW, Shah M. K-ras mutations in colorectal cancer: a practice changing discovery. Clin Adv Hematol Oncol 2009;7(1):45-53, 64.
10. 10.Andreyev HJ, Norman AR, Cunningham D, Oates J, Dix BR, Iacopetta BJ et al. Kirsten ras mutations in patients with colorectal cancer: the ''Rascal II study''. Br J Cancer 2001;85(5):692-96.
11. 11.Messner I, Cadeddu G, Huckenbeck W, Knowles HJ, Gabbert HE, Baldus SE et al. KRAS p.G13D mutations are associated with sensitivity to anti-EGFR antibody treatment in colorectal cancer cell lines. J Cancer Res Clin Oncol 2013;139(2):201-9.
12. 12.Linardou H, Dahabreh IJ, Kanaloupiti D, Siannis F, Bafaloukos D, Kosmidis P et al. Assessment of somatic KRAS mutations as a mechanism associated with resistance to EGFR-targeted agents: a systematic review and meta-analysis of studies in advanced non-small-cell lung cancer and metastatic colorectal cancer. Lancet Oncol 2008;9(10):962-72.
13. 13.Dahabreh IJ, Terasawa T, Castaldi PJ, Trikalinos TA. Systematic review: anti-epidermal growth factor receptor treatment effect modification by KRAS mutations in advanced colorectal cancer. Ann Intern Med 2011;154(1):37-49.
14. 14.Tol J, Punt CJ. Monoclonal antibodies in the treatment of metastatic colorectal cancer: a review. Clin Ther 2010;32(3):437-53.
15. 15.Wolpin BM, Mayer RJ. Systemic treatment of colorectal cancer. Gastroenterology 2008;134(5):1296-1310.
16. 16.Allegra CJ, Jessup JM., Somerfield MR, Hamilton SR, Hammond EH, Hayes DF et al. American society of clinical oncology provisional clinical opinion: testing for KRAS gene mutations in patients with metastatic colorectal carcinoma to predict response to anti-epidermal growth factor receptor monoclonal antibody therapy. J Clin Oncol 2009;27(12):2091-96.
17. 17.Bazan V, Migliavacca M, Zanna I, Tubiolo C, Grassi N, Latteri NA et al. Spesific codon 13 K-ras mutations are predictive of clinical outcome in colorectal cancer patients, whereas codon 12 K-ras mutations are associated with musinocus histotype. Annals of Oncology 2002;13(9):1438-46.
18. 18.Mannan A, Hahn-Strömberg V. K-ras mutations are correlated to lymph node metastasis and tumor stage, but not to the growth pattern of colon carcinoma. APMIS 2012;120(6):459-68.
19. 19.Li Z, Chen Y, Wang D, He L, Suo J. Detection of KRAS mutations and their associantions with clinicopathological features and survival in chinese colorectal cancer patients. Journal of International Medical Research 2012;40:1589-98.
20. 20.Grimminger PP, Danenberg P, Dellas K, Arnold D, Rödel C, Machiels JP et al. Biomarker for cetuximab-based neoadjuvant radiochemotherapy in localy advanced rectal cancer. Clin Cancer Res 2011;17(10):3469-77.
21. 21.Imamura Y, Morikowa T, Liao X, Lochhead P, Kuchiba A, Yamauchi M et al.Spesific mutations in KRAS codon 12 and codon 13, and patients prognosis in 1075 BRAF wild type colorectal cancer. Clin Cancer Res 2012;18(17):4753-63.
22. 22.Cercek A, Saltz L. Beyond KRAS: other markers and potential treatment strategies for KRAS mutant and wild-type patients. Curr Treat Options Oncol 2011;12(2):126-35.
23. 23.Dienstmann R, Tabernero J. BRAF as a target for cancer therapy, Anticancer Agents Med Chem 2011;11(3):285-95.
24. 24.Di Fiore, F, Sesboüe R, Michel P, Sabourin JC, Frebourg T, Molecular determinants of anti-EGFR sensitivity and resistance in metastatic colorectal cancer. Br J Cancer 2010;103(12):1765-72.
25. 25.Franklin WA, Haney J, Sugita M, Bemis L, Jimeno A, Messersmith WA. KRAS mutation: comparison of testing methods and tissue sampling techniques in colon cancer. J Mol Diagn 2010;12(1):43-50.
26. 26.Tsiatis AC, Norris-Kirby A, Rich RG, Hafez MJ, Gocke CD, Eshleman JR et al. Comparison of sanger sequencing, pyrosequencing, and melting curve analysis for the detection of KRAS mutations: diagnostic and clinical implications. J Mol Diagn 2010;12(4):425-32.
27. 27.Bando H, Yoshino T, Yuki S, Shinozaki E, nishina T, Kadowaki S et al. Clinical outcome of Japanese metastatic colorectal cancer patients harboring the KRAS p.G13D mutation treated with cetuximab+irinotecan. Jpn J Clin Oncol 2012;42(12):1146-51.
28. 28.Miranda E, Bianchi P, Destro A, Morenghi E, Malesci A, Santoro A et al. Genetic and epigenetic altertions in primary colorectal cancers and related lymph node and liver metastases. Wiley Online Library 2013;119:266-76.
29. 29.Kodaz H, Hacibekiroğlu I, Erdoğan B, Türkmen E, Tozkır H, Albayrak D et al. Association between spesific KRAS mutations and the clinicopathogical characterictics of colorectal tumors. Mol Clin Oncol 2015;3(1):179-84.
30. 30.Esteller M, Gonzalez S, Risques RA, Marcuello E, Mangues R, Germa JR et al. KRAS and p16 aberrations cancer poor prognosis in human colorectal cancer. J Clin Oncol 2001;19(2):299-304.