title: KRAS gene amplification and overexpression but not mutation associates with aggressive and metastatic endometrial cancer.
abstract: BACKGROUND
  Three quarter of endometrial carcinomas are treated at early stage. Still, 15 to 20% of these patients experience recurrence, with little effect from systemic therapies. Homo sapiens v-Ki-ras2 Kirsten rat sarcoma viral oncogenes homologue (KRAS) mutations have been reported to have an important role in tumorigenesis for human cancers, but there is limited knowledge regarding clinical relevance of KRAS status in endometrial carcinomas.
  
  
  METHODS
  We have performed a comprehensive and integrated characterisation of genome-wide expression related to KRAS mutations and copy-number alterations in primary- and metastatic endometrial carcinoma lesions in relation to clinical and histopathological data. A primary investigation set and clinical validation set was applied, consisting of 414 primary tumours and 61 metastatic lesions totally.
  
  
  RESULTS
  Amplification and gain of KRAS present in 3% of the primary lesions and 18% of metastatic lesions correlated significantly with poor outcome, high International Federation of Gynaecology and Obstetrics stage, non-endometrioid subtype, high grade, aneuploidy, receptor loss and high KRAS mRNA levels, also found to be associated with aggressive phenotype. In contrast, KRAS mutations were present in 14.7% of primary lesions with no increase in metastatic lesions, and did not influence outcome, but was significantly associated with endometrioid subtype, low grade and obesity.
  
  
  CONCLUSIONS
  These results support that KRAS amplification and KRAS mRNA expression, both increasing from primary to metastatic lesions, are relevant for endometrial carcinoma disease progression.
authors.affiliation: Department of Obstetrics and Gynaecology, Haukeland University Hospital, Bergen 5021, Norway.
authors.forename: E
authors.initials: E
authors.lastname: Birkeland
authors.forename: E
authors.initials: E
authors.lastname: Wik
authors.forename: S
authors.initials: S
authors.lastname: Mjøs
authors.forename: E A
authors.initials: EA
authors.lastname: Hoivik
authors.forename: J
authors.initials: J
authors.lastname: Trovik
authors.forename: H M J
authors.initials: HM
authors.lastname: Werner
authors.forename: K
authors.initials: K
authors.lastname: Kusonmano
authors.forename: K
authors.initials: K
authors.lastname: Petersen
authors.forename: M B
authors.initials: MB
authors.lastname: Raeder
authors.forename: F
authors.initials: F
authors.lastname: Holst
authors.forename: A M
authors.initials: AM
authors.lastname: Øyan
authors.forename: K-H
authors.initials: KH
authors.lastname: Kalland
authors.forename: L A
authors.initials: LA
authors.lastname: Akslen
authors.forename: R
authors.initials: R
authors.lastname: Simon
authors.forename: C
authors.initials: C
authors.lastname: Krakstad
authors.forename: H B
authors.initials: HB
authors.lastname: Salvesen
mesh_terms: D000328:Adult; D000368:Aged; D016889:Endometrial Neoplasms / Q000235:genetics* / Q000378:metabolism / Q000401:mortality / Q000473:pathology*; D005260:Female; D005784:Gene Amplification; D018628:Gene Dosage; D015972:Gene Expression Regulation, Neoplastic; D011905:Genes, ras / Q000235:genetics*; D006801:Humans; D007150:Immunohistochemistry; D008207:Lymphatic Metastasis; D008875:Middle Aged; D009154:Mutation; D060787:Neoplasm Grading; D020411:Oligonucleotide Array Sequence Analysis; D010641:Phenotype; D016133:Polymerase Chain Reaction; D011237:Predictive Value of Tests; D011379:Prognosis; D011518:Proto-Oncogene Proteins / Q000235:genetics*; D016283:Proto-Oncogene Proteins p21(ras); D017422:Sequence Analysis, DNA; D046888:Tissue Array Analysis; D015854:Up-Regulation; D018631:ras Proteins / Q000235:genetics*
chemical_list: C117307:KRAS protein, human; D011518:Proto-Oncogene Proteins; D016283:Proto-Oncogene Proteins p21(ras); D018631:ras Proteins