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Mutation spectra of RAS gene family in colorectal cancer

  • Yu-Yao Chang
    Affiliations
    Division of Colon and Rectal Surgery, Department of Surgery, Taipei Veterans General Hospital, 11217, No. 201, Section 2, Shipai Road, Taipei, Taiwan

    Department of Surgery, Faculty of Medicine, National Yang-Ming University, Taipei, Taiwan

    Department of Surgery, Changhua Christian Hospital, Changhua, Taiwan
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  • Pei-Ching Lin
    Affiliations
    Department of Clinical Pathology, Yang-Ming Campus, Taipei City Hospital, Taiwan
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  • Hung-Hsin Lin
    Affiliations
    Division of Colon and Rectal Surgery, Department of Surgery, Taipei Veterans General Hospital, 11217, No. 201, Section 2, Shipai Road, Taipei, Taiwan

    Department of Surgery, Faculty of Medicine, National Yang-Ming University, Taipei, Taiwan
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  • Jen-Kou Lin
    Affiliations
    Division of Colon and Rectal Surgery, Department of Surgery, Taipei Veterans General Hospital, 11217, No. 201, Section 2, Shipai Road, Taipei, Taiwan

    Department of Surgery, Faculty of Medicine, National Yang-Ming University, Taipei, Taiwan
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  • Wei-Shone Chen
    Affiliations
    Division of Colon and Rectal Surgery, Department of Surgery, Taipei Veterans General Hospital, 11217, No. 201, Section 2, Shipai Road, Taipei, Taiwan

    Department of Surgery, Faculty of Medicine, National Yang-Ming University, Taipei, Taiwan
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  • Jeng-Kai Jiang
    Affiliations
    Division of Colon and Rectal Surgery, Department of Surgery, Taipei Veterans General Hospital, 11217, No. 201, Section 2, Shipai Road, Taipei, Taiwan

    Department of Surgery, Faculty of Medicine, National Yang-Ming University, Taipei, Taiwan
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  • Shung-Haur Yang
    Affiliations
    Division of Colon and Rectal Surgery, Department of Surgery, Taipei Veterans General Hospital, 11217, No. 201, Section 2, Shipai Road, Taipei, Taiwan

    Department of Surgery, Faculty of Medicine, National Yang-Ming University, Taipei, Taiwan
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  • Wen-Yih Liang
    Affiliations
    Department of Pathology, Taipei Veterans General Hospital, Taipei, Taiwan
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  • Shih-Ching Chang
    Correspondence
    Corresponding author. Tel.: +886-2-28757544; fax: +886-2-28757639.
    Affiliations
    Division of Colon and Rectal Surgery, Department of Surgery, Taipei Veterans General Hospital, 11217, No. 201, Section 2, Shipai Road, Taipei, Taiwan

    Department of Surgery, Faculty of Medicine, National Yang-Ming University, Taipei, Taiwan
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      Highlights

      • Of the 1,519 colorectal cancer patients, 602 (39.6%), 66 (4.3%), and 26 (1.7%) were found to have KRAS, NRAS, and HRAS mutations, respectively.
      • The KRAS mutation was associated with fewer left-sided tumors, fewer poor differentiated tumors, more mucin component, and less lymphovascular invasion.
      • Patients with the NRAS mutation, but not the KRAS or HRAS mutation, had an insignificantly worse outcome.

      Abstract

      Background

      The clinicopathologic features and frequency of KRAS mutations in colorectal cancer (CRC) patients have been reported; however, the characteristics and impact of NRAS and HRAS mutations on the survival of CRC patients have seldom been addressed.

      Methods

      Under institutional review board approval, 1,519 CRC patients who underwent surgery were enrolled. Mutation status of RAS was determined by polymerase chain reaction and mass spectrophotometry.

      Results

      The frequency of KRAS, NRAS, and HRAS mutations was 39.6%, 4.3%, and 1.7%, respectively. The KRAS mutation was associated with fewer left-sided tumors, fewer poor differentiated tumors, more mucin component, and less lymphovascular invasion. The NRAS or HRAS mutations were not associated with any of the clinicopathologic features examined. After univariate analysis, only NRAS mutation was associated with patients' overall and disease-free survival. However, the association of NRAS with patients' overall and disease-free survival disappeared after stepwise elimination.

      Conclusions

      This study demonstrates the clinicopathologic characteristics of CRC patients with RAS mutations. Patients with NRAS mutation tended to have worse outcomes.

      Keywords

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      References

        • Downward J.
        Targeting RAS signalling pathways in cancer therapy.
        Nat Rev Cancer. 2003; 3: 11-22
        • Bounacer A.
        • McGregor A.
        • Skinner J.
        • et al.
        Mutant ras-induced proliferation of human thyroid epithelial cells requires three effector pathways.
        Oncogene. 2004; 23: 7839-7845
        • Diaz-Flores E.
        • Shannon K.
        Targeting oncogenic ras.
        Genes Dev. 2007; 21: 1989-1992
        • Andreyev H.J.
        • Norman A.R.
        • Cunningham D.
        • et al.
        Kirsten ras mutations in patients with colorectal cancer: the ‘RASCAL II’ study.
        Br J Cancer. 2001; 85: 692-696
        • Andreyev H.J.
        • Norman A.R.
        • Cunningham D.
        • et al.
        Kirsten ras mutations in patients with colorectal cancer: the multicenter “RASCAL” study.
        J Natl Cancer Inst. 1998; 90: 675-684
        • Vogelstein B.
        • Fearon E.R.
        • Hamilton S.R.
        • et al.
        Genetic alterations during colorectal-tumor development.
        N Engl J Med. 1988; 319: 525-532
        • Samowitz W.S.
        • 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 Epidemiol Biomarkers Prev. 2000; 9: 1193-1197
        • Lin J.K.
        • Chang S.C.
        • Wang H.S.
        • et al.
        Distinctive clinicopathological features of Ki-ras mutated colorectal cancers.
        J Surg Oncol. 2006; 94: 234-241
        • Li Z.
        • Chen Y.
        • Wang D.
        • et al.
        Detection of KRAS mutations and their associations with clinicopathological features and survival in Chinese colorectal cancer patients.
        J Int Med Res. 2012; 40: 1589-1598
        • Shen Y.
        • Wang J.
        • Han X.
        • et al.
        Effectors of epidermal growth factor receptor pathway: the genetic profiling of KRAS, BRAF, PIK3CA, NRAS mutations in colorectal cancer characteristics and personalized medicine.
        PLoS One. 2013; 8: e81628
        • Van Cutsem E.
        • Kohne C.H.
        • Hitre E.
        • et al.
        Cetuximab and chemotherapy as initial treatment for metastatic colorectal cancer.
        N Engl J Med. 2009; 360: 1408-1417
        • Lievre A.
        • Bachet J.B.
        • Boige V.
        • et al.
        KRAS mutations as an independent prognostic factor in patients with advanced colorectal cancer treated with cetuximab.
        J Clin Oncol. 2008; 26: 374-379
        • De Roock W.
        • Piessevaux H.
        • De Schutter J.
        • et al.
        KRAS wild-type state predicts survival and is associated to early radiological response in metastatic colorectal cancer treated with cetuximab.
        Ann Oncol. 2008; 19: 508-515
        • Amado R.G.
        • Wolf M.
        • Peeters M.
        • et al.
        Wild-type KRAS is required for panitumumab efficacy in patients with metastatic colorectal cancer.
        J Clin Oncol. 2008; 26: 1626-1634
        • Van Cutsem E.
        • Peeters M.
        • Siena S.
        • et al.
        Open-label phase III trial of panitumumab plus best supportive care compared with best supportive care alone in patients with chemotherapy-refractory metastatic colorectal cancer.
        J Clin Oncol. 2007; 25: 1658-1664
        • Di Fiore F.
        • Blanchard F.
        • Charbonnier F.
        • et al.
        Clinical relevance of KRAS mutation detection in metastatic colorectal cancer treated by cetuximab plus chemotherapy.
        Br J Cancer. 2007; 96: 1166-1169
        • Russo A.L.
        • Borger D.R.
        • Szymonifka J.
        • et al.
        Mutational analysis and clinical correlation of metastatic colorectal cancer.
        Cancer. 2014; 120: 1482-1490
        • Umeda Y.
        • Nagasaka T.
        • Mori Y.
        • et al.
        Poor prognosis of KRAS or BRAF mutant colorectal liver metastasis without microsatellite instability.
        J Hepatobiliary Pancreat Sci. 2013; 20: 223-233
        • Spindler K.G.
        • Appelt A.L.
        • Pallisgaard N.
        • et al.
        KRAS-mutated plasma DNA as predictor of outcome from irinotecan monotherapy in metastatic colorectal cancer.
        Br J Cancer. 2013; 109: 3067-3072
        • Karagkounis G.
        • Torbenson M.S.
        • Daniel H.D.
        • et al.
        Incidence and prognostic impact of KRAS and BRAF mutation in patients undergoing liver surgery for colorectal metastases.
        Cancer. 2013; 119: 4137-4144
        • Huang C.W.
        • Tsai H.L.
        • Chen Y.T.
        • et al.
        The prognostic values of EGFR expression and KRAS mutation in patients with synchronous or metachronous metastatic colorectal cancer.
        BMC Cancer. 2013; 13: 599
        • Sclafani F.
        • Gonzalez D.
        • Cunningham D.
        • et al.
        RAS mutations and cetuximab in locally advanced rectal cancer: results of the EXPERT-C trial.
        Eur J Cancer. 2014; 50: 1430-1436
        • Irahara N.
        • Baba Y.
        • Nosho K.
        • et al.
        NRAS mutations are rare in colorectal cancer.
        Diagn Mol Pathol. 2010; 19: 157-163
        • De Roock W.
        • Claes B.
        • Bernasconi D.
        • et al.
        Effects of KRAS, BRAF, NRAS, and PIK3CA mutations on the efficacy of cetuximab plus chemotherapy in chemotherapy-refractory metastatic colorectal cancer: a retrospective consortium analysis.
        Lancet Oncol. 2010; 11: 753-762
        • Espada J.
        • Perez-Moreno M.
        • Braga V.M.
        • et al.
        H-Ras activation promotes cytoplasmic accumulation and phosphoinositide 3-OH kinase association of beta-catenin in epidermal keratinocytes.
        J Cell Biol. 1999; 146: 967-980
        • Rodriguez-Viciana P.
        • Warne P.H.
        • Vanhaesebroeck B.
        • et al.
        Activation of phosphoinositide 3-kinase by interaction with Ras and by point mutation.
        EMBO J. 1996; 15: 2442-2451
        • Beukers W.
        • Hercegovac A.
        • Zwarthoff E.C.
        HRAS mutations in bladder cancer at an early age and the possible association with the Costello Syndrome.
        Eur J Hum Genet. 2014; 22: 837-839
        • Chiosea S.I.
        • Grandis J.R.
        • Lui V.W.
        • et al.
        PIK3CA, HRAS and PTEN in human papillomavirus positive oropharyngeal squamous cell carcinoma.
        BMC Cancer. 2013; 13: 602
        • Greene F.L.
        • Page D.L.
        • Fleming I.D.
        • et al.
        AJCC Cancer Staging Manual.
        6th ed. Springer, Chicago, IL2002
        • Cancer Genome Atlas Network
        Comprehensive molecular characterization of human colon and rectal cancer.
        Nature. 2012; 487: 330-337
        • Lin J.K.
        • Lin A.J.
        • Lin C.C.
        • et al.
        The status of EGFR-associated genes could predict the outcome and tumor response of chemo-refractory metastatic colorectal patients using cetuximab and chemotherapy.
        J Surg Oncol. 2011; 104: 661-666
        • Karapetis C.S.
        • Khambata-Ford S.
        • Jonker D.J.
        • et al.
        K-ras mutations and benefit from cetuximab in advanced colorectal cancer.
        N Engl J Med. 2008; 359: 1757-1765
        • Tortola S.
        • Marcuello E.
        • Gonzalez I.
        • et al.
        p53 and K-ras gene mutations correlate with tumor aggressiveness but are not of routine prognostic value in colorectal cancer.
        J Clin Oncol. 1999; 17: 1375-1381
        • Rashid A.
        • Zahurak M.
        • Goodman S.N.
        • et al.
        Genetic epidemiology of mutated K-ras proto-oncogene, altered suppressor genes, and microsatellite instability in colorectal adenomas.
        Gut. 1999; 44: 826-833
        • Breivik J.
        • Meling G.I.
        • Spurkland A.
        • et al.
        K-ras mutation in colorectal cancer: relations to patient age, sex and tumour location.
        Br J Cancer. 1994; 69: 367-371
        • Bando H.
        • Yoshino T.
        • Yuki S.
        • et al.
        Clinical outcome of Japanese metastatic colorectal cancer patients harbouring the KRAS p.G13D mutation treated with cetuximab + irinotecan.
        Jpn J Clin Oncol. 2012; 42: 1146-1151
        • Andreyev H.J.
        • Tilsed J.V.
        • Cunningham D.
        • et al.
        K-ras mutations in patients with early colorectal cancers.
        Gut. 1997; 41: 323-329
        • Kastrinakis W.V.
        • Ramchurren N.
        • Maggard M.
        • et al.
        K-ras status does not predict successful hepatic resection of colorectal cancer metastasis.
        Arch Surg. 1995; 130: 9-14
        • Ren J.
        • Li G.
        • Ge J.
        • et al.
        Is K-ras gene mutation a prognostic factor for colorectal cancer: a systematic review and meta-analysis.
        Dis Colon Rectum. 2012; 55: 913-923
        • Beranek M.
        • Bures J.
        • Palicka V.
        • et al.
        A relationship between K-ras gene mutations and some clinical and histologic variables in patients with primary colorectal carcinoma.
        Clin Chem Lab Med. 1999; 37: 723-727
        • Kressner U.
        • Bjorheim J.
        • Westring S.
        • et al.
        Ki-ras mutations and prognosis in colorectal cancer.
        Eur J Cancer. 1998; 34: 518-521
        • Nash G.M.
        • Gimbel M.
        • Shia J.
        • et al.
        KRAS mutation correlates with accelerated metastatic progression in patients with colorectal liver metastases.
        Ann Surg Oncol. 2010; 17: 572-578
        • Guerrero S.
        • Casanova I.
        • Farre L.
        • et al.
        K-ras codon 12 mutation induces higher level of resistance to apoptosis and predisposition to anchorage-independent growth than codon 13 mutation or proto-oncogene overexpression.
        Cancer Res. 2000; 60: 6750-6756
        • Messner I.
        • Cadeddu G.
        • Huckenbeck W.
        • 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: 201-209
        • Kumar S.S.
        • Price T.J.
        • Mohyieldin O.
        • et al.
        KRAS G13D mutation and sensitivity to cetuximab or panitumumab in a colorectal cancer cell line model.
        Gastrointest Cancer Res. 2014; 7: 23-26
        • Chen J.
        • Ye Y.
        • Sun H.
        • et al.
        Association between KRAS codon 13 mutations and clinical response to anti-EGFR treatment in patients with metastatic colorectal cancer: results from a meta-analysis.
        Cancer Chemother Pharmacol. 2013; 71: 265-272
        • Mao C.
        • Huang Y.F.
        • Yang Z.Y.
        • et al.
        KRAS p.G13D mutation and codon 12 mutations are not created equal in predicting clinical outcomes of cetuximab in metastatic colorectal cancer: a systematic review and meta-analysis.
        Cancer. 2013; 119: 714-721
        • De Roock W.
        • Jonker D.J.
        • Di Nicolantonio F.
        • et al.
        Association of KRAS p.G13D mutation with outcome in patients with chemotherapy-refractory metastatic colorectal cancer treated with cetuximab.
        JAMA. 2010; 304: 1812-1820
        • Malumbres M.
        • Barbacid M.
        RAS oncogenes: the first 30 years.
        Nat Rev Cancer. 2003; 3: 459-465
        • Ehrhardt A.
        • David M.D.
        • Ehrhardt G.R.
        • et al.
        Distinct mechanisms determine the patterns of differential activation of H-Ras, N-Ras, K-Ras 4B, and M-Ras by receptors for growth factors or antigen.
        Mol Cell Biol. 2004; 24: 6311-6323
        • Wang Y.
        • Velho S.
        • Vakiani E.
        • et al.
        Mutant N-RAS protects colorectal cancer cells from stress-induced apoptosis and contributes to cancer development and progression.
        Cancer Discov. 2013; 3: 294-307