title: Tissue-specific signatures of activating PIK3CA and RAS mutations in carcinosarcomas of gynecologic origin.
abstract: OBJECTIVE
  Gynecologic carcinosarcoma is an aggressive malignancy that requires more effective treatment approaches. However, therapeutic implications regarding the specific gynecologic site of origin and the admixture of carcinomatous and sarcomatous elements that define this tumor remain uncertain. Therefore, broad genotyping was performed to identify tissue-specific somatic mutational profiles that may help direct targeted therapies in this complex neoplasia.
  
  
  METHODS
  Genotyping was conducted on primary gynecologic carcinosarcomas arising from various disease sites (uterus, ovary, fallopian tube, vagina) and within isolated histological subcomponents. Nucleic acids extracted from diagnostic tissue were used in a genotyping platform that simultaneously queried >120 common mutations across 14 cancer genes. Mutational status was correlated with clinical variables using logistic regression and Kaplan-Meier survival estimates.
  
  
  RESULTS
  Cancer gene mutations were identified in 46% of the 52 patient cohort and include TP53 (23%), PIK3CA (19%), KRAS (15%), CTNNB1 (4%) and NRAS (2%). Mutation in a single gene was observed in 31% of patient samples, while synchronous mutations involving 2 and 3 genes were noted in 13% and 2% of samples, respectively. Comparative evaluation of the carcinomatous and sarcomatous elements within a tumor demonstrated a similar mutation signature. Mutations in PIK3CA, KRAS and NRAS were exclusive to tumors of uterine origin and age-adjusted Cox proportional hazards modeling associated advanced age, stage and TP53 mutations with decreased survival in the uterine subset.
  
  
  CONCLUSIONS
  While carcinosarcomas across gynecologic disease sites are histologically similar, therapeutically relevant mutations in the mitogen-activated protein kinase and phosphatidylinositol 3-kinase pathways predominated in carcinosarcomas arising in the uterus.
authors.affiliation: Vincent Center for Reproductive Biology, MGH/Vincent Department of Obstetrics and Gynecology, Massachusetts General Hospital, Boston, MA 02114, USA.
authors.forename: Whitfield B
authors.initials: WB
authors.lastname: Growdon
authors.forename: Breton N
authors.initials: BN
authors.lastname: Roussel
authors.forename: Vanessa L
authors.initials: VL
authors.lastname: Scialabba
authors.forename: Rosemary
authors.initials: R
authors.lastname: Foster
authors.forename: Dora
authors.initials: D
authors.lastname: Dias-Santagata
authors.forename: A John
authors.initials: AJ
authors.lastname: Iafrate
authors.forename: Leif W
authors.initials: LW
authors.lastname: Ellisen
authors.forename: Rosemary H
authors.initials: RH
authors.lastname: Tambouret
authors.forename: Bo R
authors.initials: BR
authors.lastname: Rueda
authors.forename: Darrell R
authors.initials: DR
authors.lastname: Borger
mesh_terms: D000368:Aged; D000369:Aged, 80 and over; D014408:Biomarkers, Tumor / Q000235:genetics / Q000378:metabolism; D002296:Carcinosarcoma / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D058534:Class I Phosphatidylinositol 3-Kinases; D015331:Cohort Studies; D005260:Female; D011905:Genes, ras; D005833:Genital Neoplasms, Female / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D005838:Genotype; D006801:Humans; D008875:Middle Aged; D009154:Mutation; D019869:Phosphatidylinositol 3-Kinases / Q000235:genetics* / Q000378:metabolism; D011518:Proto-Oncogene Proteins / Q000235:genetics* / Q000378:metabolism; D016283:Proto-Oncogene Proteins p21(ras); D051176:beta Catenin / Q000235:genetics / Q000378:metabolism; D018631:ras Proteins / Q000235:genetics* / Q000378:metabolism
chemical_list: D014408:Biomarkers, Tumor; C495270:CTNNB1 protein, human; C117307:KRAS protein, human; D011518:Proto-Oncogene Proteins; D051176:beta Catenin; D019869:Phosphatidylinositol 3-Kinases; D058534:Class I Phosphatidylinositol 3-Kinases; C484760:PIK3CA protein, human; D016283:Proto-Oncogene Proteins p21(ras); D018631:ras Proteins