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Jamshidi, Maral; Schmidt, Marjanka K.; Dörk, Thilo; Garcia‐Closas, Montserrat; Heikkinen, Tuomas; Cornelissen, Sten; van den Broek, Alexandra J.; Schürmann, Peter; Meyer, Andreas; Park‐Simon, Tjoung‐Won; Figueroa, Jonine; Sherman, Mark; Lissowska, Jolanta; Keong, Garrett Teoh Hor; Irwanto, Astrid; Laakso, Marko; Hautaniemi, Sampsa; Aittomäki, Kristiina; Blomqvist, Carl; Liu, Jianjun; Nevanlinna, Heli

Germline variation in TP53 regulatory network genes associates with breast cancer survival and treatment outcome

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  • Media type: E-Article
  • Title: Germline variation in TP53 regulatory network genes associates with breast cancer survival and treatment outcome
  • Contributor: Jamshidi, Maral; Schmidt, Marjanka K.; Dörk, Thilo; Garcia‐Closas, Montserrat; Heikkinen, Tuomas; Cornelissen, Sten; van den Broek, Alexandra J.; Schürmann, Peter; Meyer, Andreas; Park‐Simon, Tjoung‐Won; Figueroa, Jonine; Sherman, Mark; Lissowska, Jolanta; Keong, Garrett Teoh Hor; Irwanto, Astrid; Laakso, Marko; Hautaniemi, Sampsa; Aittomäki, Kristiina; Blomqvist, Carl; Liu, Jianjun; Nevanlinna, Heli
  • Published: Wiley, 2013
  • Published in: International Journal of Cancer, 132 (2013) 9, Seite 2044-2055
  • Language: English
  • DOI: 10.1002/ijc.27884
  • ISSN: 0020-7136; 1097-0215
  • Keywords: Cancer Research ; Oncology
  • Origination:
  • Footnote:
  • Description: <jats:title>Abstract</jats:title><jats:p>Germline variation in the TP53 network genes <jats:italic>PRKAG2, PPP2R2B, CCNG1, PIAS1</jats:italic> and <jats:italic>YWHAQ</jats:italic> was previously suggested to have an impact on drug response <jats:italic>in vitro</jats:italic>. 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 <jats:italic>PRKAG2</jats:italic> (rs1029946, rs4726050, rs6464153, rs7789699) and <jats:italic>PPP2R2B</jats:italic> (rs10477313) for 10‐year survival in breast cancer patients, interaction with <jats:italic>TP53</jats:italic> R72P and <jats:italic>MDM2</jats:italic>‐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 <jats:italic>PRKAG2</jats:italic>‐rs1029946 and <jats:italic>PRKAG2‐</jats:italic>rs4726050 having improved survival in the pooled data (HR 0.53, 95% CI 0.3–0.9; <jats:italic>p =</jats:italic> 0.023 for homozygous carriers of the rare G‐allele and HR 0.85, 95% CI 0.7–0.9; <jats:italic>p =</jats:italic> 0.049 for carriers of the rare G allele, respectively). <jats:italic>PRKAG2‐</jats:italic>rs4726050 showed a significant interaction with <jats:italic>MDM2</jats:italic>‐SNP309, with <jats:italic>PRKAG2‐</jats:italic>rs4726050 rare G‐allele having a dose‐dependent effect for better breast cancer survival confined only to <jats:italic>MDM2</jats:italic> SNP309 rare G‐allele carriers (HR 0.45, 95% CI 0.2–0.7; <jats:italic>p =</jats:italic> 0.001). This interaction also emerged as an independent predictor of better survival (<jats:italic>p =</jats:italic> 0.047). <jats:italic>PPP2R2B‐</jats:italic>rs10477313 rare A‐allele was found to predict better survival (HR 0.82, 95% CI 0.6–0.9; <jats:italic>p =</jats:italic> 0.018), especially after hormonal therapy (HR 0.66, 95% CI 0.5–0.9; <jats:italic>p =</jats:italic> 0.048). These findings warrant further studies and suggest that genetic markers in TP53 network genes such as <jats:italic>PRKAG2</jats:italic> and <jats:italic>PPP2R2B</jats:italic> might affect prognosis and treatment outcome in breast cancer patients.</jats:p>
  • Access State: Open Access