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

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

doi:10.1186/s12885-015-1957-7

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

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 AlnæsSilje 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

Research output: Contribution to journal › Article

5 Scopus citations

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.

Original language	English (US)
Article number	978
Journal	BMC cancer
Volume	15
Issue number	1
DOIs	https://doi.org/10.1186/s12885-015-1957-7
State	Published - Dec 16 2015

Keywords

Anthracyclines
Chemotherapy
Genetic variation
Radiotherapy
Survival

ASJC Scopus subject areas

Genetics
Oncology
Cancer Research

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Seibold, P., Schmezer, P., Behrens, S., Michailidou, K., Bolla, M. K., Wang, Q., Flesch-Janys, D., Nevanlinna, H., Fagerholm, R., Aittomäki, K., Blomqvist, C., Margolin, S., Mannermaa, A., Kataja, V., Kosma, V. M., Hartikainen, J. M., Lambrechts, D., Wildiers, H., Kristensen, V., ... Popanda, O. (2015). A polymorphism in the base excision repair gene PARP2 is associated with differential prognosis by chemotherapy among postmenopausal breast cancer patients. BMC cancer, 15(1), [978]. https://doi.org/10.1186/s12885-015-1957-7

A polymorphism in the base excision repair gene PARP2 is associated with differential prognosis by chemotherapy among postmenopausal breast cancer patients. / Seibold, Petra; Schmezer, Peter; Behrens, Sabine; Michailidou, Kyriaki; Bolla, Manjeet K.; Wang, Qin; Flesch-Janys, Dieter; Nevanlinna, Heli; Fagerholm, Rainer; Aittomäki, Kristiina; Blomqvist, Carl; Margolin, Sara; Mannermaa, Arto; Kataja, Vesa; Kosma, Veli Matti; Hartikainen, Jaana M.; Lambrechts, Diether; Wildiers, Hans; Kristensen, Vessela; Alnæs, Grethe Grenaker; Nord, Silje; Borresen-Dale, Anne Lise; Hooning, Maartje J.; Hollestelle, Antoinette; Jager, Agnes; Seynaeve, Caroline; Li, Jingmei; Liu, Jianjun; Humphreys, Keith; Dunning, Alison M.; Rhenius, Valerie; Shah, Mitul; Kabisch, Maria; Torres, Diana; Ulmer, Hans Ulrich; Hamann, Ute; Schildkraut, Joellen M.; Purrington, Kristen S.; Couch, Fergus J.; Hall, Per; Pharoah, Paul; Easton, Doug F.; Schmidt, Marjanka K.; Chang-Claude, Jenny; Popanda, Odilia.

In: BMC cancer, Vol. 15, No. 1, 978, 16.12.2015.

Research output: Contribution to journal › Article

Seibold, P, Schmezer, P, Behrens, S, Michailidou, K, Bolla, MK, Wang, Q, Flesch-Janys, D, Nevanlinna, H, Fagerholm, R, Aittomäki, K, Blomqvist, C, Margolin, S, Mannermaa, A, Kataja, V, Kosma, VM, Hartikainen, JM, Lambrechts, D, Wildiers, H, Kristensen, V, Alnæs, GG, Nord, S, Borresen-Dale, AL, Hooning, MJ, Hollestelle, A, Jager, A, Seynaeve, C, Li, J, Liu, J, Humphreys, K, Dunning, AM, Rhenius, V, Shah, M, Kabisch, M, Torres, D, Ulmer, HU, Hamann, U, Schildkraut, JM, Purrington, KS, Couch, FJ, Hall, P, Pharoah, P, Easton, DF, Schmidt, MK, Chang-Claude, J & Popanda, O 2015, 'A polymorphism in the base excision repair gene PARP2 is associated with differential prognosis by chemotherapy among postmenopausal breast cancer patients', BMC cancer, vol. 15, no. 1, 978. https://doi.org/10.1186/s12885-015-1957-7

Seibold, Petra ; Schmezer, Peter ; Behrens, Sabine ; Michailidou, Kyriaki ; Bolla, Manjeet K. ; Wang, Qin ; Flesch-Janys, Dieter ; Nevanlinna, Heli ; Fagerholm, Rainer ; Aittomäki, Kristiina ; Blomqvist, Carl ; Margolin, Sara ; Mannermaa, Arto ; Kataja, Vesa ; Kosma, Veli Matti ; Hartikainen, Jaana M. ; Lambrechts, Diether ; Wildiers, Hans ; Kristensen, Vessela ; Alnæs, Grethe Grenaker ; Nord, Silje ; Borresen-Dale, Anne Lise ; Hooning, Maartje J. ; Hollestelle, Antoinette ; Jager, Agnes ; Seynaeve, Caroline ; Li, Jingmei ; Liu, Jianjun ; Humphreys, Keith ; Dunning, Alison M. ; Rhenius, Valerie ; Shah, Mitul ; Kabisch, Maria ; Torres, Diana ; Ulmer, Hans Ulrich ; Hamann, Ute ; Schildkraut, Joellen M. ; Purrington, Kristen S. ; Couch, Fergus J. ; Hall, Per ; Pharoah, Paul ; Easton, Doug F. ; Schmidt, Marjanka K. ; Chang-Claude, Jenny ; Popanda, Odilia. / A polymorphism in the base excision repair gene PARP2 is associated with differential prognosis by chemotherapy among postmenopausal breast cancer patients. In: BMC cancer. 2015 ; Vol. 15, No. 1.

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

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.",

keywords = "Anthracyclines, Chemotherapy, Genetic variation, Radiotherapy, Survival",

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

year = "2015",

month = dec,

day = "16",

doi = "10.1186/s12885-015-1957-7",

language = "English (US)",

volume = "15",

journal = "BMC Cancer",

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number = "1",

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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

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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