title: KEAP1 Genetic Polymorphisms Associate with Breast Cancer Risk and Survival Outcomes.
abstract: OBJECTIVE
  Defective oxidative stress response may increase cancer susceptibility. In tumors, these rescue mechanisms may cause chemo- and radioresistance impacting patient outcome. We previously showed that genetic variation in the nuclear factor erythroid 2-related factor 2 (NFE2L2) is associated with breast cancer risk and prognosis. Here we further studied this pathway by investigating Kelch-like ECH-associated protein 1 (KEAP1).
  
  
  METHODS
  Five tagging SNPs in the KEAP1 gene were genotyped in 996 breast cancer cases and 880 controls from two Finnish case-control sets. KEAP1 protein expression was studied in 373 invasive breast cancer tumors.
  
  
  RESULTS
  rs34197572 genotype TT was associated with increased risk of breast cancer in the KBCP samples [P = 1.8×10(-4); OR, 7.314; confidence interval (CI), 2.185-24.478]. rs11085735 allele A was associated with lower KEAP1 protein expression (P = 0.040; OR,= 3.545) and high nuclear NRF2 expression (P = 0.009; OR, 2.445) and worse survival in all invasive cases (P = 0.023; HR, 1.634). When including treatment data, rs11085735 was associated with recurrence-free survival (RFS; P = 0.020; HR, 1.545) and breast cancer-specific survival (P = 0.016; HR, 1.683) and rs34197572 with overall survival (P = 0.045; HR, 1.304). rs11085735 associated with RFS also among tamoxifen-treated cases (P = 0.003; HR, 3.517). Among radiotherapy-treated cases, overall survival was associated with rs34197572 (P = 0.018; HR, 1.486) and rs8113472 (P = 0.025; HR, 1.455). RFS was associated with rs9676881 (P = 0.024; HR, 1.452) and rs1048290 (P = 0.020; HR, 1.468) among all invasive cases and among estrogen receptor (ER)-positive tamoxifen-treated cases (P = 0.018; HR, 2.407 and P = 0.015; HR, 2.476, respectively).
  
  
  CONCLUSIONS
  The present findings suggest that the investigated SNPs have effects related to oxidative stress induced by cancer treatment, supporting involvement of the NRF2/KEAP1 pathway in breast cancer susceptibility and patient outcome.
authors.affiliation: School of Medicine, Institute of Clinical Medicine, Pathology and Forensic Medicine, and Cancer Center of Eastern Finland, University of Eastern Finland, Kuopio, Finland. jaana.hartikainen@uef.fi.
authors.forename: Jaana M
authors.initials: JM
authors.lastname: Hartikainen
authors.affiliation: School of Medicine, Institute of Clinical Medicine, Oncology, University of Eastern Finland, Kuopio, Finland. Cancer Center, Kuopio University Hospital, Kuopio, Finland.
authors.forename: Maria
authors.initials: M
authors.lastname: Tengström
authors.affiliation: Laboratory of Cancer Genetics and Tumor Biology, Department of Clinical Chemistry and Biocenter Oulu, University of Oulu, Oulu, Finland. Laboratory of Cancer Genetics and Tumor Biology, Northern Finland Laboratory Centre NordLab, Oulu, Finland.
authors.forename: Robert
authors.initials: R
authors.lastname: Winqvist
authors.affiliation: Department of Oncology, University of Oulu, Oulu University Hospital, University of Oulu, Oulu, Finland.
authors.forename: Arja
authors.initials: A
authors.lastname: Jukkola-Vuorinen
authors.affiliation: Laboratory of Cancer Genetics and Tumor Biology, Department of Clinical Chemistry and Biocenter Oulu, University of Oulu, Oulu, Finland. Laboratory of Cancer Genetics and Tumor Biology, Northern Finland Laboratory Centre NordLab, Oulu, Finland.
authors.forename: Katri
authors.initials: K
authors.lastname: Pylkäs
authors.affiliation: School of Medicine, Institute of Clinical Medicine, Pathology and Forensic Medicine, and Cancer Center of Eastern Finland, University of Eastern Finland, Kuopio, Finland. Imaging Center, Clinical Pathology, Kuopio University Hospital, Kuopio, Finland.
authors.forename: Veli-Matti
authors.initials: VM
authors.lastname: Kosma
authors.affiliation: School of Medicine, Institute of Clinical Medicine, Pathology and Forensic Medicine, and Cancer Center of Eastern Finland, University of Eastern Finland, Kuopio, Finland. Imaging Center, Clinical Pathology, Kuopio University Hospital, Kuopio, Finland.
authors.forename: Ylermi
authors.initials: Y
authors.lastname: Soini
authors.affiliation: School of Medicine, Institute of Clinical Medicine, Pathology and Forensic Medicine, and Cancer Center of Eastern Finland, University of Eastern Finland, Kuopio, Finland. Imaging Center, Clinical Pathology, Kuopio University Hospital, Kuopio, Finland.
authors.forename: Arto
authors.initials: A
authors.lastname: Mannermaa
mesh_terms: D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D001943:Breast Neoplasms / Q000235:genetics* / Q000401:mortality / Q000628:therapy; D016022:Case-Control Studies; D002648:Child; D005260:Female; D020022:Genetic Predisposition to Disease / Q000235:genetics*; D005838:Genotype; D006801:Humans; D007150:Immunohistochemistry; D047908:Intracellular Signaling Peptides and Proteins / Q000235:genetics*; D053208:Kaplan-Meier Estimate; D000072019:Kelch-Like ECH-Associated Protein 1; D008875:Middle Aged; D020411:Oligonucleotide Array Sequence Analysis; D018384:Oxidative Stress / Q000235:genetics*; D020641:Polymorphism, Single Nucleotide; D011878:Radiotherapy; D012307:Risk Factors; D020845:Selective Estrogen Receptor Modulators / Q000627:therapeutic use; D013629:Tamoxifen / Q000627:therapeutic use
chemical_list: D047908:Intracellular Signaling Peptides and Proteins; C431364:KEAP1 protein, human; D000072019:Kelch-Like ECH-Associated Protein 1; D020845:Selective Estrogen Receptor Modulators; D013629:Tamoxifen