title: ras gene activation and infrequent mutation in papillary serous carcinoma of the peritoneum.
abstract: OBJECTIVE
  The ras genes are a well-studied family of proto-oncogenes whose involvement in many cancers has been delineated. However, K-ras mutations have not previously been examined in papillary serous carcinoma of the peritoneum (PSCP), a tumor which resembles serous epithelial ovarian carcinoma (SEOC) both in histology and epidemiology. In this study we examine the role of the K-ras oncogene in PSCP compared to SEOC.
  
  
  METHODS
  Using single-strand conformational polymorphism analysis and cycle sequencing protocols, we evaluated our collection of 51 cases of PSCP for K-ras mutations and compared these findings with the experience in SEOC. We then examined 5 cases of PSCP for activation of ras proteins and MAP kinase to evaluate the potential involvement of the ras pathway in PSCP tumorigenesis.
  
  
  RESULTS
  We found only one K-ras mutation in our 51 cases (2%) of PSCP compared to three mutations in 46 cases (6.5%) of high-grade, late-stage SEOC. This was not significantly different (P > 0.10). In the single PSCP case with a K-ras mutation, the mutation was found in only one of five tumor sites tested. All four mutations involved a single nucleotide alteration in codon 12 (GGT to GTT, Gly to Val). To evaluate the ras pathway in PSCP, we used the known activated ras binding domain on Raf-1 to perform an assay to test for activated ras. We identified ras activation in 4 of 5 PSCP cases tested and, to confirm that the activation was functional, we tested and found similar activation of MAP kinase, a downstream mediator for K-ras expression.
  
  
  CONCLUSIONS
  K-ras mutations occur at low rates in both PSCP and high-grade, late-stage SEOC, and therefore K-ras mutations are not involved in the development of these two diseases. Finding the mutation in only one of multiple tumor sites in the PSCP case supports growing evidence for a multifocal origin of PSCP. Our findings of ras activation in four of five cases of PSCP suggest that ras activation by mechanisms other than genetic mutation is important for PSCP tumorigenesis.
authors.affiliation: Laboratory and Division of Gynecologic Oncology, Department of Obstetrics and Gynecology and Reproductive Biology, Harvard Medical School, Boston, Massachusetts 02115, USA.
authors.forename: A P
authors.initials: AP
authors.lastname: Garrett
authors.forename: S W
authors.initials: SW
authors.lastname: Ng
authors.forename: M G
authors.initials: MG
authors.lastname: Muto
authors.forename: W R
authors.initials: WR
authors.lastname: Welch
authors.forename: D A
authors.initials: DA
authors.lastname: Bell
authors.forename: R S
authors.initials: RS
authors.lastname: Berkowitz
authors.forename: S C
authors.initials: SC
authors.lastname: Mok
mesh_terms: D018283:Cystadenocarcinoma, Papillary / Q000235:genetics* / Q000378:metabolism; D004252:DNA Mutational Analysis; D004273:DNA, Neoplasm / Q000032:analysis; D005260:Female; D011905:Genes, ras / Q000235:genetics*; D006801:Humans; D020928:Mitogen-Activated Protein Kinases / Q000378:metabolism; D010051:Ovarian Neoplasms / Q000235:genetics / Q000378:metabolism; D010534:Peritoneal Neoplasms / Q000235:genetics* / Q000378:metabolism; D017354:Point Mutation; D016133:Polymerase Chain Reaction; D018807:Polymorphism, Single-Stranded Conformational; D016283:Proto-Oncogene Proteins p21(ras) / Q000378:metabolism; D015533:Transcriptional Activation
chemical_list: D004273:DNA, Neoplasm; D020928:Mitogen-Activated Protein Kinases; C501009:HRAS protein, human; D016283:Proto-Oncogene Proteins p21(ras)