title: Specific TP53 Mutants Overrepresented in Ovarian Cancer Impact CNV, TP53 Activity, Responses to Nutlin-3a, and Cell Survival.
abstract: Evolutionary Action analyses of The Cancer Gene Atlas data sets show that many specific p53 missense and gain-of-function mutations are selectively overrepresented and functional in high-grade serous ovarian cancer (HGSC). As homozygous alleles, p53 mutants are differentially associated with specific loss of heterozygosity (R273; chromosome 17); copy number variation (R175H; chromosome 9); and up-stream, cancer-related regulatory pathways. The expression of immune-related cytokines was selectively related to p53 status, showing for the first time that specific p53 mutants impact, and are related to, the immune subtype of ovarian cancer. Although the majority (31%) of HGSCs exhibit loss of heterozygosity, a significant number (24%) maintain a wild-type (WT) allele and represent another HGSC subtype that is not well defined. Using human and mouse cell lines, we show that specific p53 mutants differentially alter endogenous WT p53 activity; target gene expression; and responses to nutlin-3a, a small molecular that activates WT p53 leading to apoptosis, providing "proof of principle" that ovarian cancer cells expressing WT and mutant alleles represent a distinct ovarian cancer subtype. We also show that siRNA knock down of endogenous p53 in cells expressing homozygous mutant alleles causes apoptosis, whereas cells expressing WT p53 (or are heterozygous for WT and mutant p53 alleles) are highly resistant. Therefore, despite different gene regulatory pathways associated with specific p53 mutants, silencing mutant p53 might be a suitable, powerful, global strategy for blocking ovarian cancer growth in those tumors that rely on mutant p53 functions for survival. Knowing p53 mutational status in HGSC should permit new strategies tailored to control this disease.
authors.affiliation: Department of Molecular and Cellular Biology, Baylor College of Medicine, One Baylor Plaza, Houston, TX 77030, USA.
authors.forename: Lisa K
authors.initials: LK
authors.lastname: Mullany
authors.affiliation: Department of Gynecologic Oncology, The University of Texas MD Anderson Cancer Center, 1515 Holcombe Blvd, Houston TX 77030, USA.
authors.forename: Kwong-Kwok
authors.initials: KK
authors.lastname: Wong
authors.affiliation: Department of Molecular and Human Genetics, Baylor College of Medicine, One Baylor Plaza, Houston, TX 77030, USA.
authors.forename: David C
authors.initials: DC
authors.lastname: Marciano
authors.affiliation: Department of Molecular and Human Genetics, Baylor College of Medicine, One Baylor Plaza, Houston, TX 77030, USA.
authors.forename: Panagiotis
authors.initials: P
authors.lastname: Katsonis
authors.affiliation: Department of Gynecologic Oncology, The University of Texas MD Anderson Cancer Center, 1515 Holcombe Blvd, Houston TX 77030, USA.
authors.forename: Erin R
authors.initials: ER
authors.lastname: King-Crane
authors.affiliation: Department of Molecular and Cellular Biology, Baylor College of Medicine, One Baylor Plaza, Houston, TX 77030, USA.
authors.forename: Yi Athena
authors.initials: YA
authors.lastname: Ren
authors.affiliation: Department of Molecular and Human Genetics, Baylor College of Medicine, One Baylor Plaza, Houston, TX 77030, USA.
authors.forename: Olivier
authors.initials: O
authors.lastname: Lichtarge
authors.affiliation: Department of Molecular and Cellular Biology, Baylor College of Medicine, One Baylor Plaza, Houston, TX 77030, USA. Electronic address: joanner@bcm.edu.
authors.forename: JoAnne S
authors.initials: JS
authors.lastname: Richards
mesh_terms: D000818:Animals; D017209:Apoptosis; D002470:Cell Survival; D056915:DNA Copy Number Variations; D005260:Female; D006801:Humans; D007093:Imidazoles / Q000378:metabolism*; D051379:Mice; D009154:Mutation / Q000235:genetics*; D010051:Ovarian Neoplasms / Q000235:genetics* / Q000378:metabolism / Q000473:pathology*; D010879:Piperazines / Q000378:metabolism*; D034741:RNA, Small Interfering / Q000235:genetics; D014407:Tumor Cells, Cultured; D016159:Tumor Suppressor Protein p53 / Q000037:antagonists & inhibitors / Q000235:genetics*
chemical_list: D007093:Imidazoles; D010879:Piperazines; D034741:RNA, Small Interfering; C495901:TP53 protein, human; D016159:Tumor Suppressor Protein p53; C482205:nutlin 3