Microsatellite instability (MSI) is one of the subgroups based on the new molecular classification of gastric cancer (GC). In this study, we analyzed the role of KRAS status in MSI GC and the impact of MSI status on KRAS mutation. We performed analysis on 595 GC patients. Polymerase chain reaction (PCR) was used for the screening of KRAS mutation (exon 2) and 5 quasi-monomorphic mononucleotide repeats, namely, BAT-26, BAT-25, NR -24, NR-21, and NR-27 were used to determine the MSI status. The KRAS and MSI status were then compared with clinicopathologic data of the GC patients. MSI GC was found in 20.3% of all cases. KRAS mutation was seen in 24 patients; 18 were MSI (75%) and 6 were microsatellite stable (MSS) (25%). MSI GC patients with KRAS mutation were older and mostly female, but MSS presented more advanced T and N stage of the disease, more cardia tumors, and adjuvant treatment. Five-year survival was 72.2% for KRAS mutation patients with MSI and 0% for MSS (p < 0.001). Although KRAS mutations in GC are linked with MSI in the majority of cases, KRAS mutations with MSS status presented with a poor prognosis and a worse outcome. In multivariate analysis, MSI was associated with better survival (p < 0.001) but KRAS was with worse survival (p = 0.304). Our study suggests that KRAS mutations are based on MSI status rather than different codon subtypes of mutation, and such a division could be used to determine the GC patient outcome.
Stomach cancer KRAS mutation Mismatch repair deficiency Molecular Prognosis
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This work was supported by:
Istituto Toscano Tumori (ITT) grant entitled Gene expression profiles and therapy of gastric cancer- (Grant No. ITT-2007).
European Union’s Seventh Framework Programme (FP7), GastricGlycoExplorer under grant agreement n°  (Karol Polom, Franco Roviello).
Compliance with Ethical Standards
Conflict of Interest
The authors declare they have no conflict of interest.
All procedures followed were in accordance with the ethical standards of the responsible committee on human experimentation (institutional and national) and with the Helsinki Declaration of 1964 and later versions. Informed consent or substitute for it was obtained from all patients for being included in the study.
Ferlay J, Soerjomataram I, Dikshit R et al (2015) Cancer incidence and mortality worldwide: sources, methods and major patterns in GLOBOCAN 2012. Int J Cancer 136(5):E359–E366CrossRefGoogle Scholar
Marrelli D, Połom K, de Manzoni G, Morgagni P, Baiocchi GL, Roviello F. (2015) Multimodal treatment of non-cardia gastric cancer in West: where are we going? World J Gastroenterol 21(26):7954–7969Google Scholar
Roviello G, Polom K, Petrioli R et al (2016) Monoclonal antibodies-based treatment in gastric cancer: current status and future perspectives. Tumour Biol 37(1):127–140CrossRefGoogle Scholar
Bang, YJ, Van Cutsem E, Feyereislova A et al. (2010) Trastuzumab in combination with chemotherapy versus chemotherapy alone for treatment of HER2-positive advanced gastric or gastro-oesophageal junction cancer (ToGA): a phase 3, open-label, randomised controlled trial. Lancet 376(9742):687–697Google Scholar
Cancer Genome Atlas Research Network et al (2014) Comprehensive molecular characterization of gastric adenocarcinoma. Nature 513(7517):202–209CrossRefGoogle Scholar
Cristescu R, Lee J, Nebozhyn M et al (2015) Molecular analysis of gastric cancer identifies subtypes associated with distinct clinical outcomes. Nat Med 21(5):449–456CrossRefGoogle Scholar
Isa N (2014) Evidence based radiation oncology with existing technology. Rep Pract Oncol Radiother 19(6):259–266CrossRefGoogle Scholar
Polom W, Markuszewski M, Rho YS, Matuszewski M (2014) Usage of invisible near infrared light (NIR) fluorescence with indocyanine green (ICG) and methylene blue (MB) in urological oncology. Part 1. Cent Europe J Urol 67(2):142–148Google Scholar
Yamamoto H, Adachi Y, Taniguchi H et al (2012) Interrelationship between microsatellite instability and microRNA in gastrointestinal cancer. World J Gastroenterol 18:2745–2755CrossRefGoogle Scholar
Beghelli S, de Manzoni G, Barbi S et al (2006) Microsatellite instability in gastric cancer is associated with better prognosis in only stage II cancers. Surgery 139:347–356CrossRefGoogle Scholar
Corso G, Pedrazzani C, Marrelli D, Pascale V, Pinto E, Roviello F (2009) Correlation of microsatellite instability at multiple loci with long-term survival in advanced gastric carcinoma. Arch Surg 144:722–727CrossRefGoogle Scholar
Marrelli D, Polom K, Pascale V et al (2016) Strong Prognostic Value of Microsatellite Instability in Intestinal Type Non-cardia Gastric Cancer. Ann Surg Oncol 23(3):943–950CrossRefGoogle Scholar
Polom K, Marano L, Marrelli D, De Luca R, Roviello G, Savelli V, Tan P, Roviello F (2017) Meta-analysis of microsatellite instability on clinicopathological characteristics and overall survival in gastric cancer. Br J Surg. https://doi.org/10.1002/bjs.10663
Misale S, Yaeger R, Hobor S et al (2012) Emergence of KRAS mutations and acquired resistance to anti-EGFR therapy in colorectal cancer. Nature 486(7404):532–536CrossRefGoogle Scholar
Heindl S, Eggenstein E, Keller S et al (2012) Relevance of MET activation and genetic alterations of KRAS and E-cadherin for cetuximab sensitivity of gastric cancer cell lines. J Cancer Res Clin Oncol 138(5):843–858CrossRefGoogle Scholar
Shi M, Shi H, Ji J et al (2014) Cetuximab inhibits gastric cancer growth in vivo, independent of KRAS status. Curr Cancer Drug Targets 14(2):217–224CrossRefGoogle Scholar
Lee SH, Lee JW, Soung YH et al (2003) BRAF and KRAS mutations in stomach cancer. Oncogene 22(44):6942–6945CrossRefGoogle Scholar
Brennetot C, Duval A, Hamelin R et al (2003) Frequent Ki-ras mutations in gastric tumors of the MSI phenotype. Gastroenterology 125(4):1282CrossRefGoogle Scholar
Oliveira C, Pinto M, Duval A et al (2003) BRAF mutations characterize colon but not gastric cancer with mismatch repair deficiency. Oncogene 22(57):9192–9196CrossRefGoogle Scholar
Oliveira C, Velho S, Moutinho C et al (2007) KRAS and BRAF oncogenic mutations in MSS colorectal carcinoma progression. Oncogene 26:158–163CrossRefGoogle Scholar
Boland CR, Thibodeau SN, Hamilton SR et al (1998) A National Cancer Institute workshop on microsatellite instability for cancer detection and familial predisposition: development of international criteria for the determination of microsatellite instability in colorectal cancer. Cancer Res 58(22):5248–5257Google Scholar
Janjigian YY, Werner D, Pauligk C et al (2012) Prognosis of metastatic gastric and gastroesophageal junction cancer by HER2 status: a European and USA International collaborative analysis. Ann Oncol 23(10):2656–2662CrossRefGoogle Scholar
Fuchs CS, Tomasek J, Yong CJ et al (2014) Ramucirumab monotherapy for previously treated advanced gastric or gastro-oesophageal junction adenocarcinoma (REGARD): an international, randomised, multicentre, placebo-controlled, phase 3 trial. Lancet 383(9911):31–39CrossRefGoogle Scholar
Gao J, Aksoy BA, Dogrusoz U et al (2013) Integrative analysis of complex cancer genomics and clinical profiles using the cBioPortal. Sci Signal 6(269):pl1CrossRefGoogle Scholar
Cerami E, Gao J, Dogrusoz U et al (2012) The cBio cancer genomics portal: an open platform for exploring multidimensional cancer genomics data. Canc Discov 2(5):401–404CrossRefGoogle Scholar
Queirós P, Pinheiro H, Carvalho J et al (2015) KRAS mutations in microsatellite instable gastric tumours: impact of targeted treatment and intratumoural heterogeneity. Virchows Arch 467(4):383–392CrossRefGoogle Scholar
van Grieken NC, Aoyama T, Chambers PA, et al. (2013) KRAS and BRAF mutations are rare and related to DNA mismatch repair deficiency in gastric cancer from the East and the West: results from a large international multicentre study. Br J Cancer 108(7):1495–1501. doi: https://doi.org/10.1038/bjc.2013.109
Zhao W, Chan TL, Chu KM et al (2004) Mutations of BRAF and KRAS in gastric cancer and their association with microsatellite instability. Int J Cancer 108(1):167–169CrossRefGoogle Scholar
Duggan BD, Felix JC, Muderspach LI et al (1994) Microsatellite instability in sporadic endometrial carcinoma. J Natl Cancer Inst 86:1216–1221CrossRefGoogle Scholar
de Cuba EM, Snaebjornsson P, Heideman DA et al (2016) Prognostic value of BRAF and KRAS mutation status in stage II and III microsatellite instable colon cancers. Int J Cancer 138(5):1139–1145CrossRefGoogle Scholar
Yokota T, Shibata N, Ura T et al (2010) Cycleave polymerase chain reaction method is practically applicable for V-Ki-ras2 Kirsten rat sarcoma viral oncogene homolog (KRAS)/V-raf murine sarcoma viral oncogene homolog B1 (BRAF) genotyping in colorectal cancer. Transl Res 156:98–105CrossRefGoogle Scholar
Warneke VS, Behrens HM, Haag J et al (2013) Prognostic and putative predictive biomarkers of gastric cancer for personalized medicine. Diagn Mol Pathol 22(3):127–137CrossRefGoogle Scholar