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

被引：7

作者：

Seibold, Petra ^{[1
]}

Schmezer, Peter ^{[2
]}

Behrens, Sabine ^{[1
]}

Michailidou, Kyriaki ^{[3
]}

Bolla, Manjeet K. ^{[3
]}

Wang, Qin ^{[3
]}

Flesch-Janys, Dieter ^{[4
,5
,6
]}

Nevanlinna, Heli ^{[7
,8
]}

Fagerholm, Rainer ^{[7
,8
]}

Aittomaki, Kristiina ^{[8
,9
]}

Blomqvist, Carl ^{[9
,10
]}

Margolin, Sara ^{[11
]}

Mannermaa, Arto ^{[12
,13
,14
]}

Kataja, Vesa ^{[12
,15
]}

Kosma, Veli-Matti ^{[12
,13
,14
]}

Hartikainen, Jaana M. ^{[12
,13
,14
]}

Lambrechts, Diether ^{[16
,17
]}

Wildiers, Hans ^{[18
]}

Kristensen, Vessela ^{[19
,20
,21
]}

Alnaes, Grethe Grenaker ^{[19
]}

Nord, Silje ^{[19
]}

Borresen-Dale, Anne-Lise ^{[19
,20
]}

Hooning, Maartje J. ^{[22
]}

Hollestelle, Antoinette ^{[22
]}

Jager, Agnes ^{[22
]}

Seynaeve, Caroline ^{[22
]}

Li, Jingmei ^{[23
]}

Liu, Jianjun ^{[23
]}

Humphreys, Keith ^{[24
]}

Dunning, Alison M. ^{[25
]}

Rhenius, Valerie ^{[25
]}

Shah, Mitul ^{[25
]}

Kabisch, Maria ^{[26
]}

Torres, Diana ^{[26
,27
]}

Ulmer, Hans-Ulrich ^{[28
]}

Hamann, Ute ^{[26
]}

Schildkraut, Joellen M. ^{[29
]}

Purrington, Kristen S. ^{[30
,31
]}

Couch, Fergus J. ^{[32
]}

Hall, Per

Pharoah, Paul ^{[25
]}

Easton, Doug F. ^{[3
]}

Schmidt, Marjanka K. ^{[33
]}

Chang-Claude, Jenny ^{[1
]}

Popanda, Odilia ^{[2
]}

机构：

[1] German Canc Res Ctr, Div Canc Epidemiol, D-69124 Heidelberg, Germany

[2] German Canc Res Ctr, Div Epigen & Canc Risk Factors, D-69124 Heidelberg, Germany

[3] Univ Cambridge, Ctr Canc Genet Epidemiol, Dept Publ Hlth & Primary Care, Cambridge, England

[4] Univ Canc Ctr Hamburg UCCH, Dept Canc Epidemiol Clin Canc Registry, Hamburg, Germany

[5] Univ Med Ctr Hamburg Eppendorf, Dept Med Biometr & Epidemiol, Hamburg, Germany

[6] Univ Med Ctr Hamburg Eppendorf, Dept Med Biometr & Epidemiol, Hamburg, Germany

[7] Univ Helsinki, Dept Obstet & Gynecol, Helsinki, Finland

[8] Helsinki Univ Cent Hosp, Helsinki, Finland

[9] Univ Helsinki, Dept Clin Genet, Helsinki, Finland

[10] Univ Helsinki, Dept Oncol, Helsinki, Finland

[11] Karolinska Inst, Dept Oncol Pathol, Stockholm, Sweden

[12] Univ Eastern Finland, Inst Clin Med Pathol & Forens Med, Sch Med, Kuopio, Finland

[13] Univ Eastern Finland, Canc Ctr Eastern Finland, Kuopio, Finland

[14] Kuopio Univ Hosp, Dept Clin Pathol, Imaging Ctr, SF-70210 Kuopio, Finland

[15] Jyvaskyla Cent Hosp, Cent Finland Hlth Care Dist, Jyvaskyla, Finland

[16] VIB, VRC, Leuven, Belgium

[17] Univ Leuven, Lab Translat Genet, Dept Oncol, Leuven, Belgium

[18] Univ Hosp Leuven, Multidisciplinary Breast Ctr, Dept Gen Med Oncol, Leuven, Belgium

[19] Oslo Univ Hosp, Radiumhosp, Inst Canc Res, Dept Canc Genet, N-0450 Oslo, Norway

[20] Univ Oslo UiO, Fac Med, KG Jebsen Ctr Breast Canc Res, Inst Clin Med, Oslo, Norway

[21] Univ Oslo UiO, Aker Univ Hosp, Dept Clin Mol Biol EpiGen, Oslo, Norway

[22] Erasmus MC Canc Inst, Dept Med Oncol, Rotterdam, Netherlands

[23] Genome Inst Singapore, Div Human Genet, Singapore, Singapore

[24] Karolinska Inst, Dept Med Epidemiol & Biostat, Stockholm, Sweden

[25] Univ Cambridge, Ctr Canc Genet Epidemiol, Dept Oncol Public Hlth & Primary Care, Cambridge, England

[26] German Canc Res Ctr, Mol Genet Breast Canc, Heidelberg, Germany

[27] Pontificia Univ Javeriana, Inst Human Genet, Bogota, Colombia

[28] Frauenklin Stadtklin Baden Baden, Baden Baden, Germany

[29] Duke Univ, Med Ctr, Dept Community & Family Med, Durham, NC 27710 USA

[30] Wayne State Univ, Sch Med, Dept Oncol, Detroit, MI USA

[31] Karmanos Canc Inst, Detroit, MI USA

[32] Mayo Clin, Dept Lab Med & Pathol, Rochester, MI USA

[33] Antoni van Leeuwenhoek Hosp, Netherlands Canc Inst, Amsterdam, Netherlands

来源：

BMC CANCER | 2015年 / 15卷

基金：

加拿大健康研究院; 芬兰科学院; 美国国家卫生研究院;

关键词：

Survival; Genetic variation; Chemotherapy; Radiotherapy; Anthracyclines; STRESS-RELATED GENES; POLY(ADP-RIBOSE) POLYMERASES; DOXORUBICIN; EXPRESSION; RISK; IMPACT; DAMAGE; XRCC1;

D O I：

10.1186/s12885-015-1957-7

中图分类号：

R73 [肿瘤学];

学科分类号：

100214 ;

摘要：

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.

引用

页数：11

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