Skip to main content
Key Specialties
Cardiology Diabetology Endocrinology Gastroenterology Geriatrics and Gerontology Gynecology and Obstetrics Hematology Infectious Disease Internal Medicine Nephrology Neurology Oncology Pediatrics Respiratory Medicine Rheumatology Surgery
Congress Coverage
2024 ACC Congress 2023 ESMO Congress 2023 EASD Congress 2023 ERS Congress 2023 ESC Congress 2023 EHA Congress 2023 ASCO Annual Meeting
Clinical Collections
Advances in Alzheimer’s

At a glance: The ONWARDS insulin icodec trials

A round-up of the ONWARDS phase 3 clinical trials evaluating the novel weekly insulin icodec in people with diabetes.
ADVANCED SEARCH
Log in
Top
Diagnostic Pathology
Published in: Diagnostic Pathology 1/2014

Open Access 01-12-2014 | Research

KRAS and BRAF mutational status in colon cancer from Albanian patients

Authors: Daniela Martinetti, Rosario Costanzo, Shahin Kadare, Mehdiu Alimehmeti, Cristina Colarossi, Vincenzo Canzonieri, Massimiliano Berretta, Lorenzo Memeo

Published in: Diagnostic Pathology | Issue 1/2014

Login to get access

Abstract

Background

Numerous clinical studies have shown that anti-EGFR therapies are effective only in a subset of patients with colorectal cancer. Mutations in the KRAS and BRAF genes have been confirmed as negative predictors of the response to EGFR-targeted therapies.
In this study we evaluated KRAS and BRAF status in 159 colorectal cancer samples obtained from the University of Tirana.

Methods

We evaluated KRAS mutations in codons 12, 13, 61, 146 and in codon 600 of BRAF by direct sequencing. 90 patients were male (57%) and 69 female (43%); the patients' ages ranged from 17 to 85 (median 61.7). 24 patient were stage I, 36 stage II, 84 stage III and 15 stage IV.

Results

Out of the 159 cases, 28 (17,6%) showed KRAS mutation (13 G12D, 4 G12C, 4 G12V, 3 G12A, 2 G13 D, 1 G12S and 1 A146T), and 10 (6,3%) showed BRAF mutation (all V600E). No significant correlations between KRAS and BRAF mutations and various clinicopathological parameters was found.
This is the first report of KRAS and BRAF status in Albanian patients with colorectal carcinoma (CRC) and though the relatively small sample size might not provide enough statistics power.

Conclusions

The results of KRAS and BRAF mutation analysis could be used in the selection of patients for anti-EGFR therapy.

Virtual Slides

The virtual slide(s) for this article can be found here: http://​www.​diagnosticpathol​ogy.​diagnomx.​eu/​vs/​13000_​2014_​187
Appendix
Available only for authorised users
Literature
1.
Ferlay J, Shin HR, Bray F, Forman D, Mathers C, Parkin DM: Estimates of worldwide burden of cancer in 2008: GLOBOCAN 2008. Int J Cancer. 2010, 127: 2893-2917. 10.1002/ijc.25516.PubMedCrossRef
2.
Jemal A, Siegel R, Ward E, Murray T, Xu J, Thun MJ: Cancer statistics, 2007. CA Cancer J Clin. 2007, 57: 43-66. 10.3322/canjclin.57.1.43.PubMedCrossRef
3.
Russo A, Rizzo S, Bronte G, Silvestris N, Colucci G, Gebbia N, Bazan V, Fulfaro F: The long and winding road to useful predictive factors for anti-EGFR therapy in metastatic colorectal carcinoma: the KRAS/BRAF pathway. Oncology. 2009, 77 (Suppl 1): 57-68. 10.1159/000258497.PubMedCrossRef
4.
Vogelstein B, Fearon ER, Hamilton SR, Kem SE, Preisinger AC, Leppert M, Nakamura Y, White R, Smits AM, Bos JL: Genetic alterations during colorectal tumor development. Engl J Med. 1998, 319 (9): 525-532. 10.1056/NEJM198809013190901.CrossRef
5.
Porebska I, Harlozińska A, Bojarowski T: Expression of the tyrosine kinase activity growth factor receptors (EGFR, ERB B2, ERB B3) in colorectal adenocarcinomas and adenomas. Tumour Biol. 2000, 21 (2): 105-115. 10.1159/000030116.PubMedCrossRef
6.
Reynolds NA, Wagstaff AJ: Cetuximab: in the treatment of metastatic colorectal cancer. Drugs. 2004, 64 (1): 109-118. 10.2165/00003495-200464010-00007.PubMedCrossRef
7.
Benvenuti S, Sartore-Bianchi A, Di Nicolantonio F, Zanon C, Moroni M, Veronese S, Siena S, Bardelli A: Oncogenic activation of the RAS/RAF signaling pathway impairs theresponse of metastatic colorectal cancers to anti-epidermal growth factor receptor antibody therapies. Cancer Res. 2007, 67 (6): 2643-2648. 10.1158/0008-5472.CAN-06-4158.PubMedCrossRef
8.
Rajagopalan H, Bardelli A, Lengauer C, Kinzler KW, Vogelstein B, Velculescu VE: Tumorigenesis: RAF/RAS oncogenes and mismatch-repair status. Nature. 2002, 418 (6901): 934-10.1038/418934a.PubMedCrossRef
9.
Davies H, Bignell GR, Cox C, Stephens P, Edkins S, Clegg S, Teague J, Woffendin H, Garnett MJ, Bottomley W, Davis N, Dicks E, Ewing R, Floyd Y, Gray K, Hall S, Hawes R, Hughes J, Kosmidou V, Menzies A, Mould C, Parker A, Stevens C, Watt S, Hooper S, Wilson R, Jayatilake H, Gusterson BA, Cooper C, Shipley J, et al.: Mutations of the BRAF gene in human cancer. Nature. 2002, 417 (6892): 949-954. 10.1038/nature00766.PubMedCrossRef
10.
Douillard JY, Oliner KS, Siena S, Tabernero J, Burkes R, Barugel M, Humblet Y, Bodoky G, Cunningham D, Jassem J, Rivera F, Kocákova I, Ruff P, Błasińska-Morawiec M, Šmakal M, Canon JL, Rother M, Williams R, Rong A, Wiezorek J, Sidhu R, Patterson SD: Panitumumab-FOLFOX4 treatment and RAS mutations in colorectal cancer. N Engl J Med. 2013, 369 (11): 1023-1034. 10.1056/NEJMoa1305275.PubMedCrossRef
11.
Russo A, Bazan V, Agnese V, Rodolico V, Gebbia N: Prognostic and predictive factors in colorectal cancer: Kirsten Ras in CRC (RASCAL) and TP53CRC collaborative studies. Ann Oncol. 2005, 16 (Suppl 4): iv44-iv49.PubMed
12.
Edkins S, O'Meara S, Parker A, Stevens C, Reis M, Jones S, Greenman C, Davies H, Dalgliesh G, Forbes S, Hunter C, Smith R, Stephens P, Goldstraw P, Nicholson A, Chan TL, Velculescu VE, Yuen ST, Leung SY, Stratton MR, Futreal PA: Recurrent KRAS codon 146 mutations in human colorectalcancer. Cancer Biol Ther. 2006, 5 (8): 928-932. 10.4161/cbt.5.8.3251.PubMedPubMedCentralCrossRef
13.
Oliveira C, Westra JL, Arango D, Ollikainen M, Domingo E, Ferreira A, Velho S, Niessen R, Lagerstedt K, Alhopuro P, Laiho P, Veiga I, Teixeira MR, Ligtenberg M, Kleibeuker JH, Sijmons RH, Plukker JT, Imai K, Lage P, Hamelin R, Albuquerque C, Schwartz S, Lindblom A, Peltomaki P, Yamamoto H, Aaltonen LA, Seruca R, Hofstra RM: Distinct patterns of KRAS mutations incolorectal carcinomas according to germline mismatch repair defects and hMLH1 methylation status. Hum Mol Genet. 2004, 13 (19): 2303-2311. 10.1093/hmg/ddh238.PubMedCrossRef
14.
Imamura Y, Lochhead P, Yamauchi M, Kuchiba A, Qian ZR, Liao X, Nishihara R, Jung S, Wu K, Nosho K, Wang YE, Peng S, Bass AJ, Haigis KM, Meyerhardt JA, Chan AT, Fuchs CS, Ogino S: Analyses of clinicopathological, molecular, and prognostic associations of KRAS codon 61 and codon 146 mutations in colorectal cancer: cohort study and literature review. Mol Cancer. 2014, 13: 135-10.1186/1476-4598-13-135.PubMedPubMedCentralCrossRef
15.
Siena S, Sartore-Bianchi A, Di Nicolantonio F, Balfour J, Bardelli A: Biomarkers predicting clinical outcome of epidermal growth factor receptor-targeted therapy in metastatic colorectal cancer. J Natl Cancer Inst. 2009, 101 (19): 1308-1324. 10.1093/jnci/djp280.PubMedPubMedCentralCrossRef
16.
Jones S, Chen WD, Parmigiani G, Diehl F, Beerenwinkel N, Antal T, Traulsen A, Nowak MA, Siegel C, Velculescu VE, Kinzler KW, Vogelstein B, Willis J, Markowitz SD: Comparative lesion sequencing provides insights into tumor evolution. Proc Natl Acad Sci U S A. 2008, 105 (11): 4283-4288. 10.1073/pnas.0712345105.PubMedPubMedCentralCrossRef
17.
Risio M, Malacarne D, Giaretti W: KRAS transitions and villous growth in colorectal adenomas. Cell Oncol. 2005, 27 (5-6): 363-366.PubMed
18.
Karapetis CS, Khambata-Ford S, Jonker DJ, O°Callaghan CJ, Tu D, Tebbutt NC, Simes RJ, Chalchal H, Shapiro JD, Robitaille S, Price TJ, Shepherd L, Au HJ, Langer C, Moore MJ, Zalcberg JR: K-ras mutations and benefit from cetuximab in advanced colorectal cancer. N Engl J Med. 2008, 359 (17): 1757-1765. 10.1056/NEJMoa0804385.PubMedCrossRef
19.
Di Nicolantonio F1, Martini M, Molinari F, Sartore-Bianchi A, Arena S, Saletti P, De Dosso S, Mazzucchelli L, Frattini M, Siena S, Bardelli A: Wild Type BRAF is required for response to panitumumab or cetuximab in metastatic colorectal cancer. J Clin Oncol. 2008, 26 (35): 5705-5712. 10.1200/JCO.2008.18.0786.PubMedCrossRef
20.
Peyssonnaux C, Eychene A: The Raf/MEK//ERK pathway: new concepts of activation. Biol Cell. 2001, 93 (1-2): 53-62. 10.1016/S0248-4900(01)01125-X.PubMedCrossRef
21.
Harari PM, Allen GW, Bonner JA: Biology of interactions: anti-epidermal growth factor receptor agents. J Clin Oncol. 2007, 25 (26): 4057-4065. 10.1200/JCO.2007.11.8984.PubMedCrossRef
22.
Hemming AW, Davis NL, Kluftinger A, Robinson B, Quenville NF, Liseman B, LeRiche J: Prognostic markers of colorectal cancer: an evaluation of DNA content, epidermal growth factor receptor, and ki-67. J Surg Oncol. 1992, 51 (3): 147-152. 10.1002/jso.2930510304.PubMedCrossRef
23.
Bonomi PD, Buckingham L, Coon J: Selecting patients for treatment with epidermal growth factor tyrosine kinase inhibitors. Clin Cancer Res. 2007, 13 (15Pt2): s4606-s4612. 10.1158/1078-0432.CCR-07-0332.PubMedCrossRef
24.
Dassonville O, Bozec A, Fischel JL, Milano G: EGFR targeting therapies: monoclonal antibodies versus tyrosine kinase inhibitors. Similarities and differences. Crit Rev Oncol Hematol. 2007, 62 (1): 53-61. 10.1016/j.critrevonc.2006.12.008.PubMedCrossRef
25.
Amado RG, Wolf M, Peeters M, Van Cutsem E, Siena S, Freeman DJ, Juan T, Sikorski R, Suggs S, Radinsky R, Patterson SD, Chang DD: Wild-type KRAS is required for panitumumab efficacy in patients with metastatic colorectal cancer. J Clin Oncol. 2008, 26 (10): 1626-1634. 10.1200/JCO.2007.14.7116.PubMedCrossRef
26.
De Roock W, Piessevaux H, De Schutter J, Janssens M, De Hertogh G, Personeni N, Biesmans B, Van Laethem JL, Peeters M, Humblet Y, Van Cutsem E, Tejpar S: KRAS wild-type state predicts survival and is associated to early radiological response in metastatic colorectal cancer treated with cetuximab. Ann Oncol. 2008, 19 (3): 508-515. 10.1093/annonc/mdm496.PubMedCrossRef
27.
Zenker M, Lehmann K, Schulz AL: Expansion of the genotypic and phenotypic spectrum in patients with KRAS germline mutations. J Med Genet. 2007, 44 (2): 131-135. 10.1136/jmg.2006.046300.PubMedPubMedCentralCrossRef
28.
Van Krieken JH, Jung A, Kirchner T, Carneiro F, Seruca R, Bosman FT, Quirke P, Fléjou JF, Plato Hansen T, de Hertogh G, Jares P, Langner C, Hoefler G, Ligtenberg M, Tiniakos D, Tejpar S, Bevilacqua G, Ensari A: KRAS mutation testing for predicting response to anti-EGFR therapy for colorectal carcinoma proposal for an European quality assurance program. Virchows Arch. 2008, 453 (5): 417-431. 10.1007/s00428-008-0665-y.PubMedCrossRef
29.
Linardou H1, Dahabreh IJ, Kanaloupiti D, Siannis F, Bafaloukos D, Kosmidis P, Papadimitriou CA, Murray S: Assessment of somatic k-RAS 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): 962-972. 10.1016/S1470-2045(08)70206-7.PubMedCrossRef
30.
Sala E, Mologni L, Truffa S, Gaetano C, Bollag GE, Gambacorti-Passerini C: BRAF silencing by short hairpin RNA or chemical blockade by PLX4032 leads to different responses in melanoma and thyroid carcinoma cells. Mol Cancer Res. 2008, 6 (5): 751-759. 10.1158/1541-7786.MCR-07-2001.PubMedCrossRef
31.
Kumar R, Angelini S, Czene K, Sauroja I, Hahka-Kemppinen M, Pyrhönen S, Hemminki K: BRAF mutations in metastatic melanoma: a possible association with clinical outcome. Clin Cancer Res. 2003, 9 (9): 3362-3368.PubMed
32.
Loupakis F, Ruzzo A, Cremolini C, Vincenzi B, Salvatore L, Santini D, Masi G, Stasi I, Canestrari E, Rulli E, Floriani I, Bencardino K, Galluccio N, Catalano V, Tonini G, Magnani M, Fontanini G, Basolo F, Falcone A, Graziano F: KRAS codon 61, 146 and BRAF mutations predict resistance to cetuximab plus irinotecan in KRAS codon 12 and 13 wild-type metastatic colorectal cancer. Br J Cancer. 2009, 101 (4): 715-721. 10.1038/sj.bjc.6605177.PubMedPubMedCentralCrossRef
33.
Laurent-Puig P, Cayre A, Manceau G: Analysis of PTEN, BRAF, and EGFR status in determining benefit from cetuximab therapy in wild-type KRAS metastatic colon cancer. J Clin Oncol. 2009, 27 (35): 5924-5930. 10.1200/JCO.2008.21.6796.PubMedCrossRef
34.
Ozen F, Ozdemir S, Zemheri E, Hacimuto G, Silan F, Ozdemir O: The protoncogene KRAS and BRAF profiles and some clinical charateristics in colonrectal cancer in the Turkish population. Genet Test Mol Biomarkers. 2013, 17 (2): 135-139. 10.1089/gtmb.2012.0290.PubMedCrossRef
35.
Rako I, J. Jakic-Razumovic J, Katalinic D, Sertic J, Plestina S: Mutation pattern of KRAS and BRAF oncogenes in colorectal cancer patients. Neoplasma. 2012, 59 (4): 376-383. 10.4149/neo_2012_049.PubMedCrossRef
36.
Bozzao C, Varvara D, Piglionica M, Bagnulo R, Forte G, Patruno M, Russo S, Piscitelli D, Stella A, Resta N: Survey of KRAS, BRAF and PIK3CA mutational status in 209 consecutive Italian colorectal cancer patients. Int J Biol Markers. 2012, 27 (4): e366-e374. 10.5301/JBM.2012.9765.PubMedCrossRef
37.
Vaughn CP, Zobell SD, Furtado LV, Baker CL, Samowitz WS: Frequency of KRAS, BRAF, and NRAS mutations in colorectal cancer. Genes Chromosomes Cancer. 2011, 50 (5): 307-312. 10.1002/gcc.20854.PubMedCrossRef
38.
Topal MD: DNA repair, oncogenes and carcinogenesis. Carcinogenesis. 1998, 9 (5): 691-696. 10.1093/carcin/9.5.691.CrossRef
39.
Zarbl H, Sukumar S, Arthur AV, Martin-Zanca D, Barbacid M: Direct mutagenesis of Ha-ras-1 oncogenes by N-nitroso-N- methylurea during initiation of mammary carcinogenesis in rats. Nature. 1985, 315 (6018): 382-385. 10.1038/315382a0.PubMedCrossRef
40.
Adams R, Meade A, Wasan H, Griffiths G, Maughan T: Cetuximab therapy in first-line metastatic colorectal cancer and intermittent palliative chemotherapy: review of the COIN trial. Expert Rev Anticancer Ther. 2008, 8: 1237-1245. 10.1586/14737140.8.8.1237.PubMedCrossRef
41.
Andreyev HJ, Norman AR, Cunningham D, Oates JR, Clarke PA: Kirsten ras mutations in patients with colorectal cancer: the multicenter "RASCAL" study. J Natl Cancer Inst. 1998, 90 (9): 675-684. 10.1093/jnci/90.9.675.PubMedCrossRef
42.
Barault LI, Veyrie N, Jooste V, Lecorre D, Chapusot C, Ferraz JM, Lièvre A, Cortet M, Bouvier AM, Rat P, Roignot P, Faivre J, Laurent-Puig P, Piard F: Mutations in the RAS-MAPK, PI(3)K (phosphatidylinositol-3-OH kinase) signaling network correlate with poor survival in a population-based series of colon cancers. Int J Cancer. 2008, 122 (10): 2255-2259. 10.1002/ijc.23388.PubMedCrossRef
43.
Cerottini JP, Caplin S, Saraga E, Givel JC, Benhattar J: The type of K-ras mutation determines prognosis in colorectal cancer. Am J Surg. 1998, 175 (3): 198-202. 10.1016/S0002-9610(97)00283-3.PubMedCrossRef
44.
Di Fiore F, Blanchard F, Charbonnier F, Le Pessot F, Lamy A, Galais MP, Bastit L, Killian A, Sesboüé R, Tuech JJ, Queuniet AM, Paillot B, Sabourin JC, Michot F, Michel P, Frebourg T: Clinical relevance of KRAS mutation detection in metastatic colorectal cancer treated by Cetuximab plus chemotherapy. Br J Cancer. 2007, 96 (8): 1166-1169. 10.1038/sj.bjc.6603685.PubMedPubMedCentralCrossRef
45.
Kressner UI, Bjørheim J, Westring S, Wahlberg SS, Påhlman L, Glimelius B, Lindmark G, Lindblom A, Børresen-Dale AL: Ki-ras mutations and prognosis in colorectal cancer. Eur J Cancer. 1998, 34 (4): 518-521. 10.1016/S0959-8049(97)10111-3.PubMedCrossRef
46.
Moerkerk P, Arends JW, Van Driel M, De Bruine A, De Goeij A, Ten Kate J: Type and number of Ki-ras point mutations relate to stage of human colorectal cancer. Cancer Res. 1994, 54 (13): 3376-3378.PubMed
47.
Span M, Moerkerk PT, De Goeij AF, Arends JW: A detailed analysis of K-ras point mutations in relation to tumor progression and survival in colorectal cancer patients. Int J Cancer. 1996, 69 (3): 241-245. 10.1002/(SICI)1097-0215(19960621)69:3<241::AID-IJC15>3.0.CO;2-A.PubMedCrossRef
48.
Urosevic N, Krtolica K, Skaro-Milic A, Knezevic-Usaj S, Dujic A: Prevalence of G-to-T transversions among K-ras oncogene mutations in human colorectal tumors in Yugoslavia. Int J Cancer. 1993, 54 (2): 249-254. 10.1002/ijc.2910540215.PubMedCrossRef
49.
Yuen ST, Davies H, Chan TL, Ho JW, Bignell GR, Cox C, Stephens P, Edkins S, Tsui WW, Chan AS, Futreal PA, Stratton MR, Wooster R, Leung SY: Similarity of the phenotypic patterns associated with BRAF and KRAS mutations in colorectal neoplasia. Cancer Res. 2002, 62 (22): 6451-6455.PubMed
Metadata
Title
KRAS and BRAF mutational status in colon cancer from Albanian patients
Authors
Daniela Martinetti
Rosario Costanzo
Shahin Kadare
Mehdiu Alimehmeti
Cristina Colarossi
Vincenzo Canzonieri
Massimiliano Berretta
Lorenzo Memeo
Publication date
01-12-2014
Publisher
BioMed Central
Published in
Diagnostic Pathology / Issue 1/2014
Electronic ISSN: 1746-1596
DOI
https://doi.org/10.1186/s13000-014-0187-7

Other articles of this Issue 1/2014

Diagnostic Pathology 1/2014 Go to the issue

Research

Overexpression of both platelet-derived growth factor-BB and vascular endothelial growth factor-C and its association with lymphangiogenesis in primary human non-small cell lung cancer

Research

Meta-analysis of postoperative efficacy in patients receiving chemoradiotherapy followed by surgery for resectable esophageal carcinoma

Case Report

Case report: intraductal tubulopapillary neoplasm of the pancreas with unique clear cell phenotype

Research

Prognostic value of miR-96 in patients with acute myeloid leukemia

Research

Genetic susceptibility to total hip arthroplasty failure: a case-control study on the influence of MMP 1 gene polymorphism

Research

NF-κB signaling and vesicle transport are correlated with the reactivation of the memory trace of morphine dependence