title: TP53 mutations are common in all subtypes of epithelial ovarian cancer and occur concomitantly with KRAS mutations in the mucinous type.
abstract: OBJECTIVE
  Epithelial ovarian cancer (EOC) can be classified into four major types (serous, endometrioid, clear cell, mucinous). The prevalence of driver gene mutations in the different subtypes is controversial. High-grade serous carcinomas show frequent TP53 mutations, whereas KRAS and BRAF mutations are less common. In non-serous EOC, the relevance of these gene mutations remains to be elucidated.
  
  
  METHODS
  We investigated 142 formalin-fixed, paraffin-embedded EOC, including serous (n=63), endometrioid (n=29), clear cell (n=25), mucinous (n=14), and others (n=11) for mutations in TP53 exons 5-8, KRAS exons 2 and 3, and BRAF exon 15 by pyro-sequencing using the GS Junior 454 platform. The mutational status was correlated with clinicopathological features and patient overall survival.
  
  
  RESULTS
  We identified mutations in the coding region of TP53 in 51.4% (73/142), and of KRAS in 9.9% (14/142) but not of BRAF. TP53 mutations occurred frequently not only in high-grade serous carcinomas (58.7%), but also in mucinous (57%) and clear cell EOC (52%). TP53 mutations were associated with high-grade carcinomas (p=0.014), advanced FIGO stage (p=0.001), intraoperative residual disease >1cm (p=0.004), as well as poor overall survival (p=0.002). KRAS mutations were mainly identified in mucinous EOC (57%) and were concomitantly with TP53 mutations in five mucinous carcinomas (36%).
  
  
  CONCLUSIONS
  TP53 gene driver mutations are a common feature of all advanced ovarian cancer subtypes, whereas BRAF mutations seem to be a rare event in EOC. KRAS mutations with synchronous TP53 mutations occur predominantly in low-grade mucinous carcinomas, suggesting a specific molecular background of this ovarian cancer type.
authors: Institute of Surgical Pathology, University Hospital Zurich, Switzerland.
authors: Markus
authors: M
authors: Rechsteiner
authors: Anne-Katrin
authors: AK
authors: Zimmermann
authors: Peter J
authors: PJ
authors: Wild
authors: Rosmarie
authors: R
authors: Caduff
authors: Adriana
authors: A
authors: von Teichman
authors: Daniel
authors: D
authors: Fink
authors: Holger
authors: H
authors: Moch
authors: Aurelia
authors: A
authors: Noske
mesh_terms: D018262:Adenocarcinoma, Clear Cell / Q000235:genetics / Q000473:pathology; D002288:Adenocarcinoma, Mucinous / Q000235:genetics* / Q000473:pathology; D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D018269:Carcinoma, Endometrioid / Q000235:genetics / Q000473:pathology; D000077216:Carcinoma, Ovarian Epithelial; D018284:Cystadenocarcinoma, Serous / Q000235:genetics / Q000473:pathology; D004252:DNA Mutational Analysis; D005260:Female; D006801:Humans; D008875:Middle Aged; D009154:Mutation; D060787:Neoplasm Grading; D009367:Neoplasm Staging; D009375:Neoplasms, Glandular and Epithelial / Q000235:genetics* / Q000473:pathology*; D010051:Ovarian Neoplasms / Q000235:genetics* / Q000473:pathology*; D011518:Proto-Oncogene Proteins / Q000235:genetics*; D016283:Proto-Oncogene Proteins p21(ras); D016159:Tumor Suppressor Protein p53 / Q000235:genetics*; D055815:Young Adult; D018631:ras Proteins / Q000235:genetics*
chemical_list: C117307:KRAS protein, human; D011518:Proto-Oncogene Proteins; C495901:TP53 protein, human; D016159:Tumor Suppressor Protein p53; D016283:Proto-Oncogene Proteins p21(ras); D018631:ras Proteins
keywords: BRAF; Deep-sequencing; Epithelial ovarian cancer; KRAS; TP53