K-ras gene mutations contribute to the pathogenesis of colorectal cancer. We characterized K-ras mutations in colorectal tumors in patients in the Kingdom of Saudi Arabia, in terms of geographic area, age, gender, histology, stage, and anatomical localization.
Methods
Medical records and paraffin-embedded tumor samples from 150 consecutive patients with histologically proven colorectal adenocarcinoma referred to two centers in Saudi Arabia were analyzed using an LCD-array kit.
Results
K-ras mutations occurred in 56% of the patients; 48.7% of the mutations were in codon 12, most commonly p.G12V and p.G12D (each 35.6% of codon 12 mutations). Codon 13 mutations occurred in 7.3% of tumors: of these, most were p.G13D (90.9%) with the remainder p.G13R (9.1%). Codon 12 mutations overall were associated significantly with stage IVb tumors (P = 0.022) and rectal tumors (P = 0.028), with a trend of an association with a sigmoid location (P = 0.054). The p.G12V mutation was significantly associated with sigmoid tumors (P = 0.021) and negatively associated with left-sided tumors (P = 0.011), with a trend of an association with age ≥70 years (P = 0.062) and rectal tumors (P = 0.063). Other clinicopathological features were not significantly associated with K-ras mutations.
Conclusions
K-ras mutations are common among the Saudi colorectal cancer population, especially pG12V and pG12D in codon 12, and are more frequent in sigmoid and rectal adenocarcinomas and stage IVB tumors.
Kingdom of Saudi Arabia, Ministry of Health Saudi Cancer Registry: Cancer incidence and survival report, Saudi Arabia 2007. Special edition: 16–23, 2012.
2.
AllegraC.J., JessupJ.M., SomerfieldM.R., HamiltonS.R., HammondE.H., HayesD.F., McAllisterP.K., MortonR.F., SchilskyR.L.: 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, 27: 2091–2096, 2009.
3.
MisaleS., YaegerR., HoborS., ScalaE., JanakiramanM., LiskaD., ValtortaE., SchiavoR., BuscarinoM., SiravegnaG., BencardinoK., CercekA., ChenC.T., VeroneseS., ZanonC., Sartore-BianchiA., GambacortaM., GallicchioM., VakianiE., BoscaroV., MedicoE., WeiserM., SienaS., Di NicolantonioF., SolitD., BardelliA.: Emergence of KRAS mutations and acquired resistance to anti-EGFR therapy in colorectal cancer. Nature, 486: 532–536, 2012.
4.
ArringtonA.K., HeinrichE.L., LeeW., DuldulaoM., PatelS., SanchezJ., Garcia-AguilarJ., KimJ.: Prognostic and predictive roles of kras mutation in colorectal cancer. Int J Mol Sci, 13: 12153–12168, 2012.
5.
WeichertW., ScheweC., LehmannA., SersC., DenkertC., BudcziesJ., StenzingerA., JoosH., LandtO., HeiserV., RöckenC., DietelM.: KRAS genotyping of paraffin-embedded colorectal cancer tissue in routine diagnostics: comparison of methods and impact of histology. J Mol Diagn, 12: 35–42, 2010.
6.
BrinkM., de GoeijA.F., WeijenbergM.P., RoemenG.M., LentjesM.H., PachenM.M., SmitsK.M., de BruïneA.P., GoldbohmR.A., van den BrandtP.A.: K-ras oncogene mutations in sporadic colorectal cancer in The Netherlands Cohort Study. Carcinogenesis, 24: 703–710, 2003.
7.
NeumannJ., Zeindl-EberhartE., KirchnerT., JungA.: Frequency and type of KRAS mutations in routine diagnostic analysis of metastatic colorectal cancer. Pathol Res Pract, 205: 858–862, 2009.
8.
Van CutsemE., KöhneC.H., LángI., FolprechtG., NowackiM.P., CascinuS., ShchepotinI., MaurelJ., CunninghamD., TejparS., SchlichtingM., ZubelA., CelikI., RougierP., CiardielloF.: Cetuximab plus irinotecan, fluorouracil, and leucovorin as first-line treatment for metastatic colorectal cancer: updated analysis of overall survival according to tumor KRAS and BRAF mutation status. J Clin Oncol, 29: 2011–2019, 2011.
9.
ZekriJ., Rizvi1A., Al-MaghrabiJ., bin SadiqB.: K-ras in colorectal cancer tumors from Saudi patients: frequency, clinco-pathological association and clinical outcome. Open Colorectal Cancer J, 5: 22–27, 2012.
10.
KarapetisC.S., Khambata-FordS., JonkerD.J., O'CallaghanC.J., TuD., TebbuttN.C., SimesR.J., ChalchalH., ShapiroJ.D., RobitailleS., PriceT.J., ShepherdL., AuH.J., LangerC., MooreM.J., ZalcbergJ.R.: K-ras mutations and benefit from cetuximab in advanced colorectal cancer. N Engl J Med, 359: 1757–1765, 2008.
11.
Al-MullaF., Milner-WhiteE.J., GoingJ.J., BirnieG.D.: Structural differences between valine-12 and aspartate-12 Ras proteins may modify carcinoma aggression. J Pathol, 187: 433–438, 1999.
Al-AllawiN.A., IsmaeelA.T., AhmedN.Y., MerzaN.S.: The frequency and spectrum of K-ras mutations among Iraqi patients with sporadic colorectal carcinoma. Indian J Cancer, 49: 163–168, 2012.
14.
DemiralayE., SaglamY., AltacaG., BilezikciB., OzdemirH.: The frequency of K-ras mutation in colorectal adenocarcinomas with absence of distant metastasis at diagnosis. Surg Sci, 3: 111–115, 2012.
15.
ZlobecI., BihlM.P., SchwarbH., TerraccianoL., LugliA.: Clinicopathological and protein characterization of BRAF- and K-RAS-mutated colorectal cancer and implications for prognosis. Int J Cancer, 127: 367–380, 2010.
16.
ZulhabriO., RahmanJ., IsmailS., IsaM.R., Wan ZurinahW.N.: Predominance of G to A codon 12 mutation K-ras gene in Dukes' B colorectal cancer. Singapore Med J, 53: 26–31, 2012.
17.
SmithG., CareyF.A., BeattieJ., WilkieM.J., LightfootT.J., CoxheadJ., GarnerR.C., SteeleR.J., WolfC.R.: Mutations in APC, Kirsten-ras, and p53-alternative genetic pathways to colorectal cancer. Proc Natl Acad Sci USA, 99: 9433–9438, 2002.
18.
ToppingD.L., CliftonP.M.: Short-chain fatty acids and human colonic function: roles of resistant starch and non starch polysaccharides. Physiol Rev, 81: 1031–1064, 2001.
19.
BreivikJ., MelingG.I., SpurklandA., RognumT.O., GaudernackG.: K-ras mutation in colorectal cancer: relations to patient age, sex and tumour location. Br J Cancer, 69: 367–371, 1994.
20.
SugimuraT.: Nutrition and dietary carcinogens. Carcinogenesis, 21: 387–395, 2000.
21.
NaguibA., MitrouP.N., GayL.J., CookeJ.C., LubenR.N., BallR.Y., McTaggartA., ArendsM.J., RodwellS.A.: Dietary, lifestyle and clinicopathological factors associated with BRAF and K-ras mutations arising in distinct subsets of colorectal cancers in the EPIC Norfolk study. BMC Cancer, 10: 99, 2010.
22.
SamowitzW.S., CurtinK., SchafferD., RobertsonM., LeppertM., SlatteryM.L.: Relationship of Ki-ras mutations in colon cancers to tumor location, stage, and survival: a population-based study, Cancer Epidemiol Biomarkers Prev, 9: 1193–1197, 2000.
23.
PoehlmannA., KuesterD., MeyerF., LippertH., RoessnerA., Schneider-StockR.: K-ras mutation detection in colorectal cancer using the pyrosequencing technique. Pathol Res Pract, 203: 489–497, 2007.
24.
WeichertW., ScheweC., LehmannA., SersC., DenkertC., BudcziesJ., StenzingerA., JoosH., LandtO., HeiserV., RöckenC., DietelM.: KRAS genotyping of paraffin-embedded colorectal cancer tissue in routine diagnostics: comparison of methods and impact of histology. J Mol Diagn, 12: 35–42, 2010.
