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 - 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 -