title: Somatic Mosaic Mutations in PPM1D and TP53 in the Blood of Women With Ovarian Carcinoma.
abstract: OBJECTIVE
  Somatic mosaic mutations in PPM1D have been reported in patients with breast cancer, lung cancer, and ovarian cancer (OC), but cause or effect has not been established.
  
  
  METHODS
  To test the hypothesis that somatic mosaic mutations are associated with chemotherapy exposure, we used massively parallel sequencing to quantitate mutations in peripheral blood mononuclear cells (PBMCs) of 686 women with primary OC (n = 412) or relapsed OC (n = 274). The frequency of somatic mosaic PPM1D mutations in PBMCs was significantly associated with prior chemotherapy (P < .001), and, in patients exposed to chemotherapy, with older age at blood draw (recurrent OC odds ratio [OR], 17.24; 95% CI, 6.80-43.69; and primary OC postchemotherapy OR, 4.82; 95% CI, 1.43-16.18). In contrast, somatic mosaic mutations in TP53 were not significantly associated with chemotherapy or age. In sequential PBMC samples harvested from 13 patients with OC near diagnosis and after a median of 2 different chemotherapy regimens, somatic mosaic PPM1D mutations increased in 11 individuals (84.6%) and TP53 mutations appeared in 2 (15.4%).
  
  
  CONCLUSIONS
  Chemotherapy exposure and age influence the accumulation of PPM1D-mutated PBMC clones. Care should be taken to control for chemotherapy exposure and age at blood draw when testing the association of somatic mosaic mutations in PBMCs with cancer risk.
authors: Department of Obstetrics and Gynecology, University of Washington, Seattle.
authors: Elizabeth M
authors: EM
authors: Swisher
authors: Department of Obstetrics and Gynecology, University of Washington, Seattle.
authors: Maria I
authors: MI
authors: Harrell
authors: Department of Obstetrics and Gynecology, University of Washington, Seattle.
authors: Barbara M
authors: BM
authors: Norquist
authors: Department of Medicine, University of Washington, Seattle.
authors: Tom
authors: T
authors: Walsh
authors: Statistical Office, NRG Oncology, Buffalo, New York.
authors: Mark
authors: M
authors: Brady
authors: Department of Medicine, University of Washington, Seattle.
authors: Ming
authors: M
authors: Lee
authors: VentiRx Pharmaceuticals, Seattle, Washington.
authors: Robert
authors: R
authors: Hershberg
authors: Department of Oncology, Mayo Clinic, Rochester, Minnesota.
authors: Kimberly R
authors: KR
authors: Kalli
authors: Statistical Office, NRG Oncology, Buffalo, New York.
authors: Heather
authors: H
authors: Lankes
authors: Department of Laboratory Medicine, University of Washington, Seattle.
authors: Eric Q
authors: EQ
authors: Konnick
authors: Department of Laboratory Medicine, University of Washington, Seattle.
authors: Colin C
authors: CC
authors: Pritchard
authors: St Joseph's Hospital and Medical Center, Division of Gynecologic Oncology, Phoenix, Arizona.
authors: Bradley J
authors: BJ
authors: Monk
authors: Division of Gynecologic Oncology, California Pacific Medical Center, Palo Alto Sutter Health, San Francisco.
authors: John K
authors: JK
authors: Chan
authors: Department of Obstetrics and Gynecology, University of Pennsylvania, Philadelphia.
authors: Robert
authors: R
authors: Burger
authors: Department of Oncology, Mayo Clinic, Rochester, Minnesota.
authors: Scott H
authors: SH
authors: Kaufmann
authors: Department of Medicine, Massachusetts General Hospital, Boston.
authors: Michael J
authors: MJ
authors: Birrer
mesh_terms: D000367:Age Factors; D000368:Aged; D000970:Antineoplastic Agents / Q000009:adverse effects; D005260:Female; D020022:Genetic Predisposition to Disease; D006801:Humans; D007963:Leukocytes, Mononuclear / Q000502:physiology; D008875:Middle Aged; D009030:Mosaicism; D009154:Mutation; D059645:Mutation Rate; D010051:Ovarian Neoplasms / Q000188:drug therapy* / Q000235:genetics* / Q000473:pathology; D010749:Phosphoprotein Phosphatases / Q000235:genetics*; D000071636:Protein Phosphatase 2C; D016159:Tumor Suppressor Protein p53 / Q000235:genetics*
chemical_list: D000970:Antineoplastic Agents; C495901:TP53 protein, human; D016159:Tumor Suppressor Protein p53; C000607458:PPM1D protein, human; D010749:Phosphoprotein Phosphatases; D000071636:Protein Phosphatase 2C