Document Detail


Germline variation in TP53 regulatory network genes associates with breast cancer survival and treatment outcome.
MedLine Citation:
PMID:  23034890     Owner:  NLM     Status:  MEDLINE    
Abstract/OtherAbstract:
Germline variation in the TP53 network genes PRKAG2, PPP2R2B, CCNG1, PIAS1 and YWHAQ was previously suggested to have an impact on drug response in vitro. Here, we investigated the effect on breast cancer survival of germline variation in these genes in 925 Finnish breast cancer patients and further analyzed five single nucleotide polymorphisms (SNPs) in PRKAG2 (rs1029946, rs4726050, rs6464153, rs7789699) and PPP2R2B (rs10477313) for 10-year survival in breast cancer patients, interaction with TP53 R72P and MDM2-SNP309, outcome after specific adjuvant therapy and correlation to tumor characteristics in 4,701 invasive cases from four data sets. We found evidence for carriers of PRKAG2-rs1029946 and PRKAG2-rs4726050 having improved survival in the pooled data (HR 0.53, 95% CI 0.3-0.9; p = 0.023 for homozygous carriers of the rare G-allele and HR 0.85, 95% CI 0.7-0.9; p = 0.049 for carriers of the rare G allele, respectively). PRKAG2-rs4726050 showed a significant interaction with MDM2-SNP309, with PRKAG2-rs4726050 rare G-allele having a dose-dependent effect for better breast cancer survival confined only to MDM2 SNP309 rare G-allele carriers (HR 0.45, 95% CI 0.2-0.7; p = 0.001). This interaction also emerged as an independent predictor of better survival (p = 0.047). PPP2R2B-rs10477313 rare A-allele was found to predict better survival (HR 0.82, 95% CI 0.6-0.9; p = 0.018), especially after hormonal therapy (HR 0.66, 95% CI 0.5-0.9; p = 0.048). These findings warrant further studies and suggest that genetic markers in TP53 network genes such as PRKAG2 and PPP2R2B might affect prognosis and treatment outcome in breast cancer patients.
Authors:
Maral Jamshidi; Marjanka K Schmidt; Thilo Dörk; Montserrat Garcia-Closas; Tuomas Heikkinen; Sten Cornelissen; Alexandra J van den Broek; Peter Schürmann; Andreas Meyer; Tjoung-Won Park-Simon; Jonine Figueroa; Mark Sherman; Jolanta Lissowska; Garrett Teoh Hor Keong; Astrid Irwanto; Marko Laakso; Sampsa Hautaniemi; Kristiina Aittomäki; Carl Blomqvist; Jianjun Liu; Heli Nevanlinna
Publication Detail:
Type:  Journal Article; Research Support, Non-U.S. Gov't     Date:  2012-10-25
Journal Detail:
Title:  International journal of cancer. Journal international du cancer     Volume:  132     ISSN:  1097-0215     ISO Abbreviation:  Int. J. Cancer     Publication Date:  2013 May 
Date Detail:
Created Date:  2013-02-19     Completed Date:  2013-05-07     Revised Date:  2014-10-14    
Medline Journal Info:
Nlm Unique ID:  0042124     Medline TA:  Int J Cancer     Country:  United States    
Other Details:
Languages:  eng     Pagination:  2044-55     Citation Subset:  IM    
Copyright Information:
Copyright © 2012 UICC.
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MeSH Terms
Descriptor/Qualifier:
AMP-Activated Protein Kinases / genetics
Adult
Antineoplastic Agents, Hormonal / therapeutic use*
Breast Neoplasms / drug therapy,  genetics*,  mortality
Carcinoma, Ductal, Breast / drug therapy,  genetics*,  mortality
Carcinoma, Lobular / drug therapy,  genetics*,  mortality
Female
Gene Regulatory Networks / genetics*
Genotype
Germ-Line Mutation / genetics*
Humans
Middle Aged
Neoplasm Grading
Neoplasm Invasiveness
Neoplasm Metastasis
Nerve Tissue Proteins / genetics
Polymorphism, Single Nucleotide / genetics
Prognosis
Protein Phosphatase 2 / genetics
Proto-Oncogene Proteins c-mdm2 / genetics
RNA, Messenger / genetics
RNA, Neoplasm / genetics
Real-Time Polymerase Chain Reaction
Reverse Transcriptase Polymerase Chain Reaction
Survival Rate
Tumor Suppressor Protein p53 / genetics*
Grant Support
ID/Acronym/Agency:
ZIA CP010126-14/CP/NCI NIH HHS
Chemical
Reg. No./Substance:
0/Antineoplastic Agents, Hormonal; 0/Nerve Tissue Proteins; 0/RNA, Messenger; 0/RNA, Neoplasm; 0/TP53 protein, human; 0/Tumor Suppressor Protein p53; EC 2.7.11.1/AMP-Activated Protein Kinases; EC 2.7.11.1/PRKAG2 protein, human; EC 3.1.3.16/PPP2R2B protein, human; EC 3.1.3.16/Protein Phosphatase 2; EC 6.3.2.19/MDM2 protein, human; EC 6.3.2.19/Proto-Oncogene Proteins c-mdm2
Comments/Corrections

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