TY - JOUR
T1 - A polymorphism in the base excision repair gene PARP2 is associated with differential prognosis by chemotherapy among postmenopausal breast cancer patients
AU - Seibold, Petra
AU - Schmezer, Peter
AU - Behrens, Sabine
AU - Michailidou, Kyriaki
AU - Bolla, Manjeet K.
AU - Wang, Qin
AU - Flesch-Janys, Dieter
AU - Nevanlinna, Heli
AU - Fagerholm, Rainer
AU - Aittomäki, Kristiina
AU - Blomqvist, Carl
AU - Margolin, Sara
AU - Mannermaa, Arto
AU - Kataja, Vesa
AU - Kosma, Veli Matti
AU - Hartikainen, Jaana M.
AU - Lambrechts, Diether
AU - Wildiers, Hans
AU - Kristensen, Vessela
AU - Alnæs, Grethe Grenaker
AU - Nord, Silje
AU - Borresen-Dale, Anne Lise
AU - Hooning, Maartje J.
AU - Hollestelle, Antoinette
AU - Jager, Agnes
AU - Seynaeve, Caroline
AU - Li, Jingmei
AU - Liu, Jianjun
AU - Humphreys, Keith
AU - Dunning, Alison M.
AU - Rhenius, Valerie
AU - Shah, Mitul
AU - Kabisch, Maria
AU - Torres, Diana
AU - Ulmer, Hans Ulrich
AU - Hamann, Ute
AU - Schildkraut, Joellen M.
AU - Purrington, Kristen S.
AU - Couch, Fergus J.
AU - Hall, Per
AU - Pharoah, Paul
AU - Easton, Doug F.
AU - Schmidt, Marjanka K.
AU - Chang-Claude, Jenny
AU - Popanda, Odilia
N1 - Funding Information:
We thank all the individuals who took part in these studies and all the researchers, clinicians, technicians and administrative staff who have enabled this work to be carried out. In particular, we thank Ursula Eilber, Christina Krieg and Muhabbet Celik for excellent technical assistance in the MARIE study and M. Schick and R. Fischer from the DKFZ Genomics and Proteomics Core Facilities for their support during Illumina genotyping. This study would not have been possible without the contributions of the following: Joe Dennis, Alison M. Dunning, Andrew Lee, and Ed Dicks, Craig Luccarini and the staff of the Centre for Genetic Epidemiology Laboratory, Javier Benitez, Anna Gonzalez-Neira and the staff of the CNIO genotyp-ing unit, Jacques Simard and Daniel C. Tessier, Francois Bacot, Daniel Vincent, Sylvie LaBoissière and Frederic Robidoux and the staff of the McGill University and Génome Québec Innovation Centre, Stig E. Bojesen, Sune F. Nielsen, Borge G. Nordestgaard, and the staff of the Copenhagen DNA laboratory, and Julie M. Cunningham, Sharon A. Windebank, Christopher A. Hilker, Jeffrey Meyer and the staff of Mayo Clinic Genotyping Core Facility. RBCS thank Petra Bos, Jannet Blom, Ellen Crepin, Anja Nieuwlaat, Annette Heemskerk, the Erasmus MC Family Cancer Clinic. The MARIE study was supported by the Deutsche Krebshilfe e.V. (70-2892-BR I, 106332, 108253, 108419), the Hamburg Cancer Society, the German Cancer Research Center, the Federal Ministry of Education and Research (BMBF) Germany (01KH0402) and the Dietmar Hopp Stiftung (23017006). Funding for the iCOGS infrastructure came from: the European Community’s Seventh Framework Programme under grant agreement n° 223175 (HEALTH-F2-2009-223175) (COGS), Cancer Research UK (C1287/A10118, C1287/A10710, C490/ A10119, C490/A16561), the National Institutes of Health (CA128978, CA076016) and Post-Cancer GWAS initiative (No. 1 U19 CA148537 - the GAME-ON initiative), the Department of Defence (W81XWH-10-1-0341), the Canadian Institutes of Health Research (CIHR) for the CIHR Team in Familial Risks of Breast Cancer, Komen Foundation for the Cure, the Breast Cancer Research Foundation, and the Ovarian Cancer Research Fund. The HEBCS study was funded by the Helsinki University Central Hospital Research Fund, the Academy of Finland (132473), the Sigrid Juselius Foundation, the Finnish Cancer Society and the Nordic Cancer Union. Financial support for KARBAC was provided through the regional agreement on medical training and clinical research (ALF) between Stockholm County Council and Karolinska Institutet, the Swedish Cancer Society, The Gustav V Jubilee foundation and Bert von Kantzows foundation. The KBCP was financially supported by the special Government Funding (EVO) of Kuopio University Hospital grants, Cancer Fund of North Savo, the Finnish Cancer Organizations, the Academy of Finland and by the strategic funding of the University of Eastern Finland. LMBC is supported by the ‘Stichting tegen Kanker’ (232–2008 and 196–2010). Diether Lambrechts is supported by the FWO and the KULPFV/10/016-SymBioSysII. The NBCS was supported by the K.G. Jebsen Centre for Breast Cancer Research; the Research Council of Norway grant 193387/V50 (to A-L Børresen-Dale and V.N. Kristensen) and grant 193387/H10 (to A-L Børresen-Dale and V.N. Kristensen), South Eastern Norway Health Authority (grant 39346 to A-L Børresen-Dale) and the Norwegian Cancer Society (to A-L Børresen-Dale and V.N. Kristensen). The RBCS was funded by the Dutch Cancer Society (DDHK 2004–3124, DDHK 2009–4318). The SASBAC study was supported by funding from the Agency for Science, Technology and Research of Singapore (A*STAR), the US National Institute of Health (NIH) and the Susan G. Komen Breast Cancer Foundation. SEARCH is funded Cancer Research UK and Breast Cancer Campaign (C490/A10124, 2009MayPR42) and supported by the UK National Institute for Health Research Biomedical Research Centre at the University of Cambridge. SKKDKFZS is supported by the German Cancer Research Center (DKFZ).
Publisher Copyright:
© 2015 Seibold et al.
PY - 2015/12/16
Y1 - 2015/12/16
N2 - Background: Personalized therapy considering clinical and genetic patient characteristics will further improve breast cancer survival. Two widely used treatments, chemotherapy and radiotherapy, can induce oxidative DNA damage and, if not repaired, cell death. Since base excision repair (BER) activity is specific for oxidative DNA damage, we hypothesized that germline genetic variation in this pathway will affect breast cancer-specific survival depending on treatment. Methods: We assessed in 1,408 postmenopausal breast cancer patients from the German MARIE study whether cancer specific survival after adjuvant chemotherapy, anthracycline chemotherapy, and radiotherapy is modulated by 127 Single Nucleotide Polymorphisms (SNPs) in 21 BER genes. For SNPs with interaction terms showing p<0.1 (likelihood ratio test) using multivariable Cox proportional hazard analyses, replication in 6,392 patients from nine studies of the Breast Cancer Association Consortium (BCAC) was performed. Results: rs878156 in PARP2 showed a differential effect by chemotherapy (p=0.093) and was replicated in BCAC studies (p=0.009; combined analysis p=0.002). Compared to non-carriers, carriers of the variant G allele (minor allele frequency=0.07) showed better survival after chemotherapy (combined allelic hazard ratio (HR)=0.75, 95 % 0.53-1.07) and poorer survival when not treated with chemotherapy (HR=1.42, 95 % 1.08-1.85). A similar effect modification by rs878156 was observed for anthracycline-based chemotherapy in both MARIE and BCAC, with improved survival in carriers (combined allelic HR=0.73, 95 % CI 0.40-1.32). None of the SNPs showed significant differential effects by radiotherapy. Conclusions: Our data suggest for the first time that a SNP in PARP2, rs878156, may together with other genetic variants modulate cancer specific survival in breast cancer patients depending on chemotherapy. These germline SNPs could contribute towards the design of predictive tests for breast cancer patients.
AB - Background: Personalized therapy considering clinical and genetic patient characteristics will further improve breast cancer survival. Two widely used treatments, chemotherapy and radiotherapy, can induce oxidative DNA damage and, if not repaired, cell death. Since base excision repair (BER) activity is specific for oxidative DNA damage, we hypothesized that germline genetic variation in this pathway will affect breast cancer-specific survival depending on treatment. Methods: We assessed in 1,408 postmenopausal breast cancer patients from the German MARIE study whether cancer specific survival after adjuvant chemotherapy, anthracycline chemotherapy, and radiotherapy is modulated by 127 Single Nucleotide Polymorphisms (SNPs) in 21 BER genes. For SNPs with interaction terms showing p<0.1 (likelihood ratio test) using multivariable Cox proportional hazard analyses, replication in 6,392 patients from nine studies of the Breast Cancer Association Consortium (BCAC) was performed. Results: rs878156 in PARP2 showed a differential effect by chemotherapy (p=0.093) and was replicated in BCAC studies (p=0.009; combined analysis p=0.002). Compared to non-carriers, carriers of the variant G allele (minor allele frequency=0.07) showed better survival after chemotherapy (combined allelic hazard ratio (HR)=0.75, 95 % 0.53-1.07) and poorer survival when not treated with chemotherapy (HR=1.42, 95 % 1.08-1.85). A similar effect modification by rs878156 was observed for anthracycline-based chemotherapy in both MARIE and BCAC, with improved survival in carriers (combined allelic HR=0.73, 95 % CI 0.40-1.32). None of the SNPs showed significant differential effects by radiotherapy. Conclusions: Our data suggest for the first time that a SNP in PARP2, rs878156, may together with other genetic variants modulate cancer specific survival in breast cancer patients depending on chemotherapy. These germline SNPs could contribute towards the design of predictive tests for breast cancer patients.
KW - Anthracyclines
KW - Chemotherapy
KW - Genetic variation
KW - Radiotherapy
KW - Survival
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U2 - 10.1186/s12885-015-1957-7
DO - 10.1186/s12885-015-1957-7
M3 - Article
C2 - 26674097
AN - SCOPUS:84959139071
VL - 15
JO - BMC Cancer
JF - BMC Cancer
SN - 1471-2407
IS - 1
M1 - 978
ER -