title: Germline variation in TP53 regulatory network genes associates with breast cancer survival and treatment outcome.
abstract: 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.affiliation: Department of Obstetrics and Gynecology, Biomedicum Helsinki, University of Helsinki and Helsinki University Central Hospital, 00029 Helsinki, Finland.
authors.forename: Maral
authors.initials: M
authors.lastname: Jamshidi
authors.forename: Marjanka K
authors.initials: MK
authors.lastname: Schmidt
authors.forename: Thilo
authors.initials: T
authors.lastname: Dörk
authors.forename: Montserrat
authors.initials: M
authors.lastname: Garcia-Closas
authors.forename: Tuomas
authors.initials: T
authors.lastname: Heikkinen
authors.forename: Sten
authors.initials: S
authors.lastname: Cornelissen
authors.forename: Alexandra J
authors.initials: AJ
authors.lastname: van den Broek
authors.forename: Peter
authors.initials: P
authors.lastname: Schürmann
authors.forename: Andreas
authors.initials: A
authors.lastname: Meyer
authors.forename: Tjoung-Won
authors.initials: TW
authors.lastname: Park-Simon
authors.forename: Jonine
authors.initials: J
authors.lastname: Figueroa
authors.forename: Mark
authors.initials: M
authors.lastname: Sherman
authors.forename: Jolanta
authors.initials: J
authors.lastname: Lissowska
authors.forename: Garrett Teoh Hor
authors.initials: GT
authors.lastname: Keong
authors.forename: Astrid
authors.initials: A
authors.lastname: Irwanto
authors.forename: Marko
authors.initials: M
authors.lastname: Laakso
authors.forename: Sampsa
authors.initials: S
authors.lastname: Hautaniemi
authors.forename: Kristiina
authors.initials: K
authors.lastname: Aittomäki
authors.forename: Carl
authors.initials: C
authors.lastname: Blomqvist
authors.forename: Jianjun
authors.initials: J
authors.lastname: Liu
authors.forename: Heli
authors.initials: H
authors.lastname: Nevanlinna
mesh_terms: D055372:AMP-Activated Protein Kinases / Q000235:genetics; D000328:Adult; D018931:Antineoplastic Agents, Hormonal / Q000627:therapeutic use*; D001943:Breast Neoplasms / Q000188:drug therapy / Q000235:genetics* / Q000401:mortality; D018270:Carcinoma, Ductal, Breast / Q000188:drug therapy / Q000235:genetics* / Q000401:mortality; D018275:Carcinoma, Lobular / Q000188:drug therapy / Q000235:genetics* / Q000401:mortality; D005260:Female; D053263:Gene Regulatory Networks / Q000235:genetics*; D005838:Genotype; D018095:Germ-Line Mutation / Q000235:genetics*; D006801:Humans; D008875:Middle Aged; D060787:Neoplasm Grading; D009361:Neoplasm Invasiveness; D009362:Neoplasm Metastasis; D009419:Nerve Tissue Proteins / Q000235:genetics; D020641:Polymorphism, Single Nucleotide / Q000235:genetics; D011379:Prognosis; D054648:Protein Phosphatase 2 / Q000235:genetics; D051736:Proto-Oncogene Proteins c-mdm2 / Q000235:genetics; D012333:RNA, Messenger / Q000235:genetics; D012334:RNA, Neoplasm / Q000235:genetics; D060888:Real-Time Polymerase Chain Reaction; D020133:Reverse Transcriptase Polymerase Chain Reaction; D015996:Survival Rate; D016159:Tumor Suppressor Protein p53 / Q000235:genetics*
chemical_list: D018931:Antineoplastic Agents, Hormonal; D009419:Nerve Tissue Proteins; D012333:RNA, Messenger; D012334:RNA, Neoplasm; C495901:TP53 protein, human; D016159:Tumor Suppressor Protein p53; C497206:MDM2 protein, human; D051736:Proto-Oncogene Proteins c-mdm2; C526223:PRKAG2 protein, human; D055372:AMP-Activated Protein Kinases; C505936:PPP2R2B protein, human; D054648:Protein Phosphatase 2