Correlation between microsatellite instability and RAS gene mutation and stage Ⅲ colorectal cancer

Niu,Wenbo; Wang,Guiying; Feng,Jun; Li,Zheng; Li,Chenhui; Shan,Baoen

doi:10.3892/ol.2018.9611

Correlation between microsatellite instability and RAS gene mutation and stage Ⅲ colorectal cancer

Authors:
- Wenbo Niu
- Guiying Wang
- Jun Feng
- Zheng Li
- Chenhui Li
- Baoen Shan
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Affiliations: Department of Surgery Ⅱ, The Fourth Hospital of Hebei Medical University, Shijiazhuang, Hebei 050000, P.R. China, Center of Scientific Research, The Fourth Hospital of Hebei Medical University, Shijiazhuang, Hebei 050000, P.R. China
Published online on: October 23, 2018 https://doi.org/10.3892/ol.2018.9611
Pages: 332-338
Copyright: © Niu et al. This is an open access article distributed under the terms of Creative Commons Attribution License.

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Abstract

Correlation between RAS gene mutation and microsatellite instability (MSI) status in cancer tissues and clinicopathological parameters of patients with stage Ⅲ colorectal cancer (CRC) were investigated. Tissues were collected from 180 patients diagnosed with stage Ⅲ CRC in the Department of Gastrointestinal Surgery of the Fourth Hospital of Hebei Medical University from 2012 to 2016. RAS gene mutations in paraffin sections were detected by PCR and Sanger sequencing. Expression of mismatch repair proteins MLH1, MSH2, MSH6 and PMS2 was detected by immunohistochemistry, and MSI status was determined based on the positive and negative expression combinations of the above proteins, and the correlation with clinicopathological parameters of CRC was analyzed. Mutation rates of KRAS and NRAS were 48.33% (87/180) and 2.78% (5/180), respectively. Mutation rate of p.G12D in codon 12 of exon 2 in KRAS gene was the highest (31/87, 35.63%). Mutation rate of p.G12D in codon 12 of exon 2 in NRAS gene was the highest (2/5, 40%). Mutation rate of KRAS gene in right colon was higher than that in left colon and rectum (p<0.05), and mutation rate in N2b phase was higher than that in N2a and N1 phases (p<0.01). In low degree of microsatellite instability (MSI‑L) and high degree of microsatellite instability (MSI‑H) status, negative MKH1 protein expression was dominant (18/32, 56.25%). MSI‑H in CRC patients aged ≥50 years was higher than that of CRC patients <50 years. Rates of MSI‑H in N1, N2a, and N2b were 1.75, 12.82, and 1.11% (p<0.05). Mutation rate of KRAS gene in MSI‑H status of stage Ⅲ CRC patients was significantly higher than that in MSI‑L/microsatellite stability (MSS) (p<0.05). Mutation of RAS gene and the status of MSI are involved in the occurrence and development of stage Ⅲ CRC. Detection of RAS gene has important significance for the individual treatment of CRC in clinic.

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1	Martins C, Sousa P, Araújo T, Castro-Poças F and Pedroto I: Mediastinal mass in a patient with colorectal cancer: A diagnostic challenge. GE Port J Gastroenterol. 24:193–197. 2017. View Article : Google Scholar : PubMed/NCBI
2	Cermak K, Thill V, Simoens CH, Smets D, Ngongang CH and da Costa PM: Surgical resection for colon cancer: laparoscopic assisted vs. open colectomy. Hepatogastroenterology. 55:412–417. 2008.PubMed/NCBI
3	Heo JH, Ryu CG, Jung EJ, Paik JH and Hwang DY: Clinical significance of preoperative virtual colonoscopy for evaluation of the proximal colon in patient with obstructive colorectal cancer. Ann Coloproctol. 33:130–133. 2017. View Article : Google Scholar : PubMed/NCBI
4	Wicha MS: Targeting self-renewal, an Achilles' heel of cancer stem cells. Nat Med. 20:14–15. 2014. View Article : Google Scholar : PubMed/NCBI
5	Jiricny J: The multifaceted mismatch-repair system. Nat Rev Mol Cell Biol. 7:335–346. 2006. View Article : Google Scholar : PubMed/NCBI
6	Iyer RR, Pluciennik A, Burdett V and Modrich PL: DNA mismatch repair: Functions and mechanisms. Chem Rev. 106:302–323. 2006. View Article : Google Scholar : PubMed/NCBI
7	Barberán S, Fraguas S and Cebrià F: The EGFR signaling pathway controls gut progenitor differentiation during planarian regeneration and homeostasis. Development. 143:2089–2102. 2016. View Article : Google Scholar : PubMed/NCBI
8	Saafan H, Foerster S, Parra-Guillen ZP, Hammer E, Michaelis M, Cinatl J Jr, Völker U, Fröhlich H, Kloft C and Ritter CA: Utilising the EGFR interactome to identify mechanisms of drug resistance in non-small cell lung cancer - proof of concept towards a systems pharmacology approach. Eur J Pharm Sci. 94:20–32. 2016. View Article : Google Scholar : PubMed/NCBI
9	Tang Y, Zhou H, Chen A, Pittman RN and Field J: The Akt proto-oncogene links Ras to Pak and cell survival signals. J Biol Chem. 275:9106–9109. 2000. View Article : Google Scholar : PubMed/NCBI
10	Di Nicolantonio F, Martini M, Molinari F, Sartore-Bianchi A, Arena S, Saletti P, De Dosso S, Mazzucchelli L, Frattini M, Siena S, et al: Wild-type BRAF is required for response to panitumumab or cetuximab in metastatic colorectal cancer. J Clin Oncol. 26:5705–5712. 2008. View Article : Google Scholar : PubMed/NCBI
11	Trojan J, Mineur L, Tomášek J, Rouleau E, Fabian P, de Maglio G, García-Alfonso P, Aprile G, Taylor A, Kafatos G, et al: Panitumumab use in metastatic colorectal cancer and patterns of KRAS testing: Results from a Europe-wide physician survey and medical records review. PLoS One. 10:e01407172015. View Article : Google Scholar : PubMed/NCBI
12	Hu J, Yan WY, Xie L, Cheng L, Yang M, Li L, Shi J, Liu BR and Qian XP: Coexistence of MSI with KRAS mutation is associated with worse prognosis in colorectal cancer. Medicine (Baltimore). 95:e56492016. View Article : Google Scholar : PubMed/NCBI
13	Sideris M and Papagrigoriadis S: Molecular biomarkers and classification models in the evaluation of the prognosis of colorectal cancer. Anticancer Res. 34:2061–2068. 2014.PubMed/NCBI
14	Slik K, Kurki S, Korpela T, Carpén O, Korkeila E and Sundström J: Ezrin expression combined with MSI status in prognostication of stage II colorectal cancer. PLoS One. 12:e01854362017. View Article : Google Scholar : PubMed/NCBI
15	Ciardiello F and Tortora G: EGFR antagonists in cancer treatment. N Engl J Med. 358:1160–1174. 2008. View Article : Google Scholar : PubMed/NCBI
16	Neumann J, Zeindl-Eberhart E, Kirchner T and Jung A: Frequency and type of KRAS mutations in routine diagnostic analysis of metastatic colorectal cancer. Pathol Res Pract. 205:858–862. 2009. View Article : Google Scholar : PubMed/NCBI
17	Shemirani AI, Haghighi MM, Milanizadeh S, Taleghani MY, Fatemi SR, Damavand B, Akbari Z and Zali MR: The role of kras mutations and MSI status in diagnosis of colorectal cancer. Gastroenterol Hepatol Bed Bench. 4:70–75. 2011.PubMed/NCBI
18	Vilar E and Gruber SB: Microsatellite instability in colorectal cancer-the stable evidence. Nat Rev Clin Oncol. 7:153–162. 2010. View Article : Google Scholar : PubMed/NCBI
19	Philip P, Ernst P and Wantzin GL: Karyotypes in infectious mononucleosis. Scand J Haematol. 15:201–206. 1975. View Article : Google Scholar : PubMed/NCBI
20	Kambara T, Simms LA, Whitehall VL, Spring KJ, Wynter CV, Walsh MD, Barker MA, Arnold S, McGivern A, Matsubara N, et al: BRAF mutation is associated with DNA methylation in serrated polyps and cancers of the colorectum. Gut. 53:1137–1144. 2004. View Article : Google Scholar : PubMed/NCBI
21	Ye JX, Liu Y, Qin Y, Zhong HH, Yi WN and Shi XY: KRAS and BRAF gene mutations and DNA mismatch repair status in Chinese colorectal carcinoma patients. World J Gastroenterol. 21:1595–1605. 2015. View Article : Google Scholar : PubMed/NCBI
22	Omidifar N, Geramizadeh B and Mirzai M: K-ras mutation in colorectal cancer, a report from Southern Iran. Iran J Med Sci. 40:454–460. 2015.PubMed/NCBI
23	Fujiyoshi K, Yamamoto G, Takahashi A, Arai Y, Yamada M, Kakuta M, Yamaguchi K, Akagi Y, Nishimura Y, Sakamoto H, et al: High concordance rate of KRAS/BRAF mutations and MSI-H between primary colorectal cancer and corresponding metastases. Oncol Rep. 37:785–792. 2017. View Article : Google Scholar : PubMed/NCBI
24	Martinetti D, Costanzo R, Kadare S, Alimehmeti M, Colarossi C, Canzonieri V, Berretta M and Memeo L: KRAS and BRAF mutational status in colon cancer from Albanian patients. Diagn Pathol. 9:1872014. View Article : Google Scholar : PubMed/NCBI
25	Kawazoe A, Shitara K, Fukuoka S, Kuboki Y, Bando H, Okamoto W, Kojima T, Fuse N, Yamanaka T, Doi T, et al: A retrospective observational study of clinicopathological features of KRAS NRAS, BRAF and PIK3CA mutations in Japanese patients with metastatic colorectal cancer. BMC Cancer. 15:2582015. View Article : Google Scholar : PubMed/NCBI
26	Ogura T, Kakuta M, Yatsuoka T, Nishimura Y, Sakamoto H, Yamaguchi K, Tanabe M, Tanaka Y and Akagi K: Clinicopathological characteristics and prognostic impact of colorectal cancers with NRAS mutations. Oncol Rep. 32:50–56. 2014. View Article : Google Scholar : PubMed/NCBI
27	Yamane LS, Scapulatempo-Neto C, Alvarenga L, Oliveira CZ, Berardinelli GN, Almodova E, Cunha TR, Fava G, Colaiacovo W, Melani A, et al: KRAS and BRAF mutations and MSI status in precursor lesions of colorectal cancer detected by colonoscopy. Oncol Rep. 32:1419–1426. 2014. View Article : Google Scholar : PubMed/NCBI
28	Fleming M, Ravula S, Tatishchev SF and Wang HL: Colorectal carcinoma: Pathologic aspects. J Gastrointest Oncol. 3:153–173. 2012.PubMed/NCBI