title: Clinical relevance of gain-of-function mutations of p53 in high-grade serous ovarian carcinoma.
abstract: OBJECTIVE
  Inactivation of TP53, which occurs predominantly by missense mutations in exons 4-9, is a major genetic alteration in a subset of human cancer. In spite of growing evidence that gain-of-function (GOF) mutations of p53 also have oncogenic activity, little is known about the clinical relevance of these mutations.
  
  
  METHODS
  The clinicopathological features of high-grade serous ovarian carcinoma (HGS-OvCa) patients with GOF p53 mutations were evaluated according to a comprehensive somatic mutation profile comprised of whole exome sequencing, mRNA expression, and protein expression profiles obtained from the Cancer Genome Atlas (TCGA).
  
  
  RESULTS
  Patients with a mutant p53 protein (mutp53) with a GOF mutation showed higher p53 mRNA and protein expression levels than patients with p53 mutation with no evidence of GOF (NE-GOF). GOF mutations were more likely to occur within mutational hotspots, and at CpG sites, and resulted in mutp53 with higher functional severity (FS) scores. Clinically, patients with GOF mutations showed a higher frequency of platinum resistance (22/58, 37.9%) than patients with NE-GOF mutations (12/56, 21.4%) (p=0.054). Furthermore, patients with GOF mutations were more likely to develop distant metastasis (36/55, 65.5%) than local recurrence (19/55, 34.5%), whereas patients with NE-GOF mutations showed a higher frequency of locoregional recurrence (26/47, 55.3%) than distant metastasis (21/47, 44.7%) (p=0.035). There were no differences in overall or progression-free survival between patients with GOF or NE-GOF mutp53.
  
  
  CONCLUSIONS
  This study demonstrates that patient with GOF mutp53 is characterized by a greater likelihood of platinum treatment resistance and distant metastatic properties in HGS-OvCa.
authors: Department of Pathology, Asan Medical Center, University of Ulsan College of Medicine, Seoul, Korea.
authors: Hyo Jeong
authors: HJ
authors: Kang
authors: Sung-Min
authors: SM
authors: Chun
authors: Kyu-Rae
authors: KR
authors: Kim
authors: Insuk
authors: I
authors: Sohn
authors: Chang Ohk
authors: CO
authors: Sung
mesh_terms: D000328:Adult; D000368:Aged; D001482:Base Composition; D002277:Carcinoma / Q000235:genetics* / Q000401:mortality / Q000473:pathology*; D018899:CpG Islands; D019008:Drug Resistance, Neoplasm / Q000235:genetics; D059472:Exome; D005260:Female; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D008875:Middle Aged; D009154:Mutation; D060787:Neoplasm Grading; D009367:Neoplasm Staging; D010051:Ovarian Neoplasms / Q000235:genetics* / Q000401:mortality / Q000473:pathology*; D016159:Tumor Suppressor Protein p53 / Q000235:genetics* / Q000378:metabolism
chemical_list: D016159:Tumor Suppressor Protein p53
references: Proc Natl Acad Sci U S A. 2000 Apr 11;97(8):4174-9
references: 10760284
references: Int J Cancer. 2008 Apr 15;122(8):1701-9
references: 18092324
references: Genes Cancer. 2011 Apr;2(4):466-74
references: 21779514
references: J Cell Biol. 2011 Jan 24;192(2):209-18
references: 21263025
references: Cell Death Differ. 2011 Feb;18(2):271-81
references: 20689556
references: FEBS J. 2009 Aug;276(15):4142-55
references: 19558493
references: Proc Natl Acad Sci U S A. 2010 Jan 5;107(1):246-51
references: 20018721
references: Nat Cell Biol. 2013 Jan;15(1):2-8
references: 23263379
references: Nat Rev Cancer. 2010 Nov;10(11):803-8
references: 20944665
references: Science. 1994 Jul 15;265(5170):346-55
references: 8023157
references: PLoS One. 2012;7(9):e45484
references: 23029043
references: Hum Mutat. 2007 Jun;28(6):622-9
references: 17311302
references: Cold Spring Harb Perspect Biol. 2010 Jan;2(1):a001008
references: 20182602
references: Cancer Inform. 2007 Feb 04;3:11-7
references: 19455231
references: J Clin Oncol. 2003 May 15;21(10 Suppl):149s-167s
references: 17633784
references: J Pathol. 2010 Oct;222(2):129-37
references: 20662002
references: Cancer Res. 2010 Sep 1;70(17):6913-24
references: 20663910
references: Cancer Res. 2008 Mar 15;68(6):1723-31
references: 18339852
references: Gynecol Oncol. 2012 Jul;126(1):103-8
references: 22484402
references: J Clin Oncol. 2009 Jun 1;27(16):2686-91
references: 19332726
references: J Pathol. 2010 May;221(1):49-56
references: 20229506
references: Oncogene. 1999 Jan 14;18(2):477-85
references: 9927204
references: Crit Rev Oncol Hematol. 2009 Nov;72(2):98-109
references: 19249225
references: Cold Spring Harb Perspect Biol. 2010 Feb;2(2):a001107
references: 20182618
references: Nat Cell Biol. 2009 Jun;11(6):694-704
references: 19448627
references: J Cell Biol. 2001 Jun 11;153(6):1161-74
references: 11402061
references: PLoS One. 2013;8(1):e54089
references: 23326577
references: Proc Natl Acad Sci U S A. 2001 Apr 24;98(9):5116-21
references: 11309499
references: Cell. 2004 Dec 17;119(6):861-72
references: 15607981
references: Mol Cancer Ther. 2006 Oct;5(10):2512-21
references: 17041095
references: Cell. 2009 Apr 3;137(1):87-98
references: 19345189