title: Multiple mutations in the Kras gene in colorectal cancer: review of the literature with two case reports.
abstract: OBJECTIVE
  Kras mutations are negative predictors of anti-EGFR therapy, occurring in 40% of colorectal carcinomas (CRCs). Point substitutions in codon 12 or 13 are the most frequent mutations in Kras, but multiple mutations (MMs) in other codons can also develop. Few data exist on MMs with regard to their frequency and the codons and amino acids that are affected. We report two cases of Kras double mutations in codons 12 and 13 and review Kras MMs in primary CRC in PubMed databases.
  
  
  METHODS
  A 53-year-old woman and a 70-year-old man presented with deep, invasive, moderately differentiated CRC at an advanced clinical stage. The former had regional lymph node involvement and vaginal wall neoplastic implantation, and the latter had liver metastasis. Primary tumors were examined for Kras mutations by pyrosequencing, which were confirmed by direct sequencing. Both tumors had a mutation in codons 12 and 13, wherein codon 12 was mutated to GAT, and codon 13 became GAC.
  
  
  CONCLUSIONS
  We identified 69 reported cases of Kras MMs and reported two other cases, representing 2.1% of all mutated tumors; the incidence of such mutations is 1.0% in CRC patients. In most cases (59%), MMs develop in a single codon, usually codon 12. Codons 12 and 13 are affected simultaneously in only 27% of cases. These findings add information about the impact of specific amino acid changes in the Kras gene.
authors: Department of Pathology, Hospital A.C. Camargo, São Paulo, Brazil. maripetaccia@hotmail.com
authors: Mariana Petaccia
authors: MP
authors: Macedo
authors: Louise De Brot
authors: Lde B
authors: Andrade
authors: Renata
authors: R
authors: Coudry
authors: Rodrigo
authors: R
authors: Crespo
authors: Marina
authors: M
authors: Gomes
authors: Bianca Cristina Garcia
authors: BC
authors: Lisboa
authors: Samuel
authors: S
authors: Aguiar
authors: Fernando Augusto
authors: FA
authors: Soares
authors: Dirce Maria
authors: DM
authors: Carraro
authors: Isabela Werneck
authors: IW
authors: Cunha
references: Cancer Chemother Pharmacol. 2010 Aug;66(3):605-9
references: 20361188
references: Gut. 2009 Sep;58(9):1234-41
references: 19474002
references: Carcinogenesis. 2000 Feb;21(2):307-9
references: 10657973
references: J Clin Oncol. 2008 Apr 1;26(10):1626-34
references: 18316791
references: J Cell Mol Med. 2010 Aug;14(8):2122-31
references: 19453520
references: Saudi J Gastroenterol. 2009 Oct-Dec;15(4):244-52
references: 19794270
references: Am J Surg. 1998 Mar;175(3):198-202
references: 9560119
references: BMC Clin Pathol. 2009 Oct 15;9:8
references: 19832985
references: Ann Surg Oncol. 2010 May;17(5):1429-34
references: 20049644
references: Virchows Arch. 2008 Nov;453(5):417-31
references: 18802721
references: Ann Oncol. 2005 Feb;16(2):189-94
references: 15668269
references: J Clin Oncol. 2010 Mar 1;28(7):1254-61
references: 20100961
references: Lancet Oncol. 2010 Aug;11(8):753-62
references: 20619739
references: N Engl J Med. 2008 Oct 23;359(17):1757-65
references: 18946061
references: Genes Chromosomes Cancer. 2000 Dec;29(4):309-14
references: 11066074
references: Br J Cancer. 1994 Feb;69(2):367-71
references: 8297737
references: BMC Cancer. 2008 May 21;8:142
references: 18495026
references: J Int Med Res. 2007 Jul-Aug;35(4):450-7
references: 17697521
references: Br J Cancer. 2001 Sep 1;85(5):692-6
references: 11531254
references: Carcinogenesis. 2003 Apr;24(4):703-10
references: 12727799
references: Genes Chromosomes Cancer. 2011 May;50(5):307-12
references: 21305640
references: Environ Health Perspect. 1991 Jun;93:125-31
references: 1685441
references: J Clin Pathol. 2009 Oct;62(10):886-91
references: 19783717
references: J Natl Cancer Inst. 1998 May 6;90(9):675-84
references: 9586664
references: Int J Cancer. 1993 May 8;54(2):249-54
references: 8486427
references: JAMA. 2010 Oct 27;304(16):1812-20
references: 20978259
references: Adv Anat Pathol. 2010 Jan;17(1):23-32
references: 20032635
references: Cancer Epidemiol Biomarkers Prev. 2000 Nov;9(11):1193-7
references: 11097226
references: Ann Oncol. 2008 Mar;19(3):508-15
references: 17998284
references: Oncogene. 2010 May 27;29(21):3033-43
references: 20383189
references: Int J Cancer. 2009 Dec 1;125(11):2744-5
references: 19521964
references: Cancer Res. 1994 Jul 1;54(13):3376-8
references: 8012953
references: Pathol Res Pract. 2009;205(12):858-62
references: 19679400
references: Adv Anat Pathol. 2009 Jul;16(4):196-203
references: 19546608
references: BMC Med Genet. 2010 Feb 26;11:34
references: 20184776