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

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 E. Sherman, Jolanta Lissowska, Garrett Teoh Hor Keong, Astrid Irwanto, Marko Laakso, Sampsa Hautaniemi, Kristiina Aittomäki, Carl Blomqvist, Jianjun LiuHeli Nevanlinna

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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. What's new? Single nucleotide polymorphisms (SNPs) that influence breast cancer survival could play a valuable role in assessing disease prognosis. Here, in an analysis of invasive breast cancer, improved survival was associated with either of two germ-line variations in PRKAG2 (rs4726050 and rs1029946). One of the variations was further associated with a SNP in MDM2, a negative regulator of the tumor promoter protein p53 (TP53). A variant in the gene PPP2R2B was found to be predictive of better survival after hormonal therapy.

Original languageEnglish (US)
Pages (from-to)2044-2055
Number of pages12
JournalInternational Journal of Cancer
Volume132
Issue number9
DOIs
StatePublished - May 1 2013

Fingerprint

p53 Genes
Breast Neoplasms
Survival
Alleles
Single Nucleotide Polymorphism
Tumor Suppressor Protein p53
Genetic Markers
Germ Cells
Carcinogens
Genes
Therapeutics

Keywords

  • breast cancer
  • hormonal therapy
  • MDM2
  • PPP2R2B
  • PRKAG2
  • TP53

ASJC Scopus subject areas

  • Medicine(all)
  • Oncology
  • Cancer Research

Cite this

Jamshidi, M., Schmidt, M. K., Dörk, T., Garcia-Closas, M., Heikkinen, T., Cornelissen, S., ... Nevanlinna, H. (2013). Germline variation in TP53 regulatory network genes associates with breast cancer survival and treatment outcome. International Journal of Cancer, 132(9), 2044-2055. https://doi.org/10.1002/ijc.27884

Germline variation in TP53 regulatory network genes associates with breast cancer survival and treatment outcome. / 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 E.; Lissowska, Jolanta; Keong, Garrett Teoh Hor; Irwanto, Astrid; Laakso, Marko; Hautaniemi, Sampsa; Aittomäki, Kristiina; Blomqvist, Carl; Liu, Jianjun; Nevanlinna, Heli.

In: International Journal of Cancer, Vol. 132, No. 9, 01.05.2013, p. 2044-2055.

Research output: Contribution to journalArticle

Jamshidi, M, Schmidt, MK, Dörk, T, Garcia-Closas, M, Heikkinen, T, Cornelissen, S, Van Den Broek, AJ, Schürmann, P, Meyer, A, Park-Simon, TW, Figueroa, J, Sherman, ME, Lissowska, J, Keong, GTH, Irwanto, A, Laakso, M, Hautaniemi, S, Aittomäki, K, Blomqvist, C, Liu, J & Nevanlinna, H 2013, 'Germline variation in TP53 regulatory network genes associates with breast cancer survival and treatment outcome', International Journal of Cancer, vol. 132, no. 9, pp. 2044-2055. https://doi.org/10.1002/ijc.27884
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 E. ; 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. In: International Journal of Cancer. 2013 ; Vol. 132, No. 9. pp. 2044-2055.
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AU - Jamshidi, Maral

AU - Schmidt, Marjanka K.

AU - Dörk, Thilo

AU - Garcia-Closas, Montserrat

AU - Heikkinen, Tuomas

AU - Cornelissen, Sten

AU - Van Den Broek, Alexandra J.

AU - Schürmann, Peter

AU - Meyer, Andreas

AU - Park-Simon, Tjoung Won

AU - Figueroa, Jonine

AU - Sherman, Mark E.

AU - Lissowska, Jolanta

AU - Keong, Garrett Teoh Hor

AU - Irwanto, Astrid

AU - Laakso, Marko

AU - Hautaniemi, Sampsa

AU - Aittomäki, Kristiina

AU - Blomqvist, Carl

AU - Liu, Jianjun

AU - Nevanlinna, Heli

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N2 - 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. What's new? Single nucleotide polymorphisms (SNPs) that influence breast cancer survival could play a valuable role in assessing disease prognosis. Here, in an analysis of invasive breast cancer, improved survival was associated with either of two germ-line variations in PRKAG2 (rs4726050 and rs1029946). One of the variations was further associated with a SNP in MDM2, a negative regulator of the tumor promoter protein p53 (TP53). A variant in the gene PPP2R2B was found to be predictive of better survival after hormonal therapy.

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