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BMC Cancer
Published in: BMC Cancer 1/2015

Open Access 01-12-2015 | Research article

A polymorphism in the base excision repair gene PARP2 is associated with differential prognosis by chemotherapy among postmenopausal breast cancer patients

Authors: Petra Seibold, Peter Schmezer, Sabine Behrens, Kyriaki Michailidou, Manjeet K. Bolla, Qin Wang, Dieter Flesch-Janys, Heli Nevanlinna, Rainer Fagerholm, Kristiina Aittomäki, Carl Blomqvist, Sara Margolin, Arto Mannermaa, Vesa Kataja, Veli-Matti Kosma, Jaana M. Hartikainen, Diether Lambrechts, Hans Wildiers, Vessela Kristensen, Grethe Grenaker Alnæs, Silje Nord, Anne-Lise Borresen-Dale, Maartje J. Hooning, Antoinette Hollestelle, Agnes Jager, Caroline Seynaeve, Jingmei Li, Jianjun Liu, Keith Humphreys, Alison M. Dunning, Valerie Rhenius, Mitul Shah, Maria Kabisch, Diana Torres, Hans-Ulrich Ulmer, Ute Hamann, Joellen M. Schildkraut, Kristen S. Purrington, Fergus J. Couch, Per Hall, Paul Pharoah, Doug F. Easton, Marjanka K. Schmidt, Jenny Chang-Claude, Odilia Popanda

Published in: BMC Cancer | Issue 1/2015

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Abstract

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.
Appendix
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Metadata
Title
A polymorphism in the base excision repair gene PARP2 is associated with differential prognosis by chemotherapy among postmenopausal breast cancer patients
Authors
Petra Seibold
Peter Schmezer
Sabine Behrens
Kyriaki Michailidou
Manjeet K. Bolla
Qin Wang
Dieter Flesch-Janys
Heli Nevanlinna
Rainer Fagerholm
Kristiina Aittomäki
Carl Blomqvist
Sara Margolin
Arto Mannermaa
Vesa Kataja
Veli-Matti Kosma
Jaana M. Hartikainen
Diether Lambrechts
Hans Wildiers
Vessela Kristensen
Grethe Grenaker Alnæs
Silje Nord
Anne-Lise Borresen-Dale
Maartje J. Hooning
Antoinette Hollestelle
Agnes Jager
Caroline Seynaeve
Jingmei Li
Jianjun Liu
Keith Humphreys
Alison M. Dunning
Valerie Rhenius
Mitul Shah
Maria Kabisch
Diana Torres
Hans-Ulrich Ulmer
Ute Hamann
Joellen M. Schildkraut
Kristen S. Purrington
Fergus J. Couch
Per Hall
Paul Pharoah
Doug F. Easton
Marjanka K. Schmidt
Jenny Chang-Claude
Odilia Popanda
Publication date
01-12-2015
Publisher
BioMed Central
Published in
BMC Cancer / Issue 1/2015
Electronic ISSN: 1471-2407
DOI
https://doi.org/10.1186/s12885-015-1957-7

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