title: Prognostic relevance of caspase 8 -652 6N InsDel and Asp302His polymorphisms for breast cancer.
abstract: The minor allele of two caspase 8 polymorphisms, namely CASP8 -652 6N InsDel (rs3834129) and CASP8 Asp302His (rs1045485), were repeatedly associated with reduced breast cancer susceptibility. Contrarily, the presence of the -652 6N Del or the CASP8 302His variant was reported to be an unfavorable prognostic factor in colorectal cancer or neuroblastoma. However, prognostic relevance of these genetic variants for breast cancer is completely unknown and is therefore adressed by the current study.
  
  
  
  Genotyping was performed by pyrosequencing. Caspase 8 mRNA expression was quantified by comparative RT-qPCR.
  
  
  
  We observed an allele-dose dependent association between CASP8 -652 6N InsDel and caspase 8 mRNA expression in breast cancer tissue, with homozygous deletion carriers showing lowest relative caspase 8 expression (p = 0.0131). Intriguingly, the presence of the -652 6N Del or the 302His variant was shown to be a negative prognostic factor for breast cancer in terms of an allele-dose dependent influence on overall survival (OS, p = 0.0018, p = 0.0150, respectively). Moreover, both polymorphisms were independent predictors of OS after adjusting for co-variats (p = 0.007, p = 0.037, respectively). Prognostic relevance of both polymorphisms were confirmed to be independent from each other and combined analysis of diplotypes revealed an additive influence upon OS (p = 0.0002).
  
  
  
  This is the first report, showing negative and independent prognostic impact of the CASP8 -652 6N Del and the 302His variant for breast cancer. Our data provide rationale to further validate clinical utility of these polymorphisms for breast cancer and to extend this investigation to a broad scope of other malignancies.
authors: Department of Gynecology and Obstetrics, Medical Faculty and University Hospital Carl Gustav Carus, Technische Universität Dresden, Dresden, Germany.|German Cancer Consortium (DKTK), Dresden and German Cancer Research Center (DKFZ), Heidelberg, Germany.|National Center for Tumor Diseases, Partner Site Dresden, Dresden, Germany.
authors: J D
authors: JD
authors: Kuhlmann
authors: Institute of Pathology and Neuropathology, University Hospital Essen, University of Duisburg-Essen, Essen, Germany.
authors: A
authors: A
authors: Bankfalvi
authors: Institute of Pathology and Neuropathology, University Hospital Essen, University of Duisburg-Essen, Essen, Germany.
authors: K W
authors: KW
authors: Schmid
authors: German Cancer Consortium (DKTK), Dresden and German Cancer Research Center (DKFZ), Heidelberg, Germany.|Department of Gynecology and Obstetrics, West German Cancer Center, University of Duisburg-Essen, Essen, Germany.
authors: R
authors: R
authors: Callies
authors: German Cancer Consortium (DKTK), Dresden and German Cancer Research Center (DKFZ), Heidelberg, Germany.|Department of Gynecology and Obstetrics, West German Cancer Center, University of Duisburg-Essen, Essen, Germany.
authors: R
authors: R
authors: Kimmig
authors: Department of Gynecology and Obstetrics, Medical Faculty and University Hospital Carl Gustav Carus, Technische Universität Dresden, Dresden, Germany.|German Cancer Consortium (DKTK), Dresden and German Cancer Research Center (DKFZ), Heidelberg, Germany.|National Center for Tumor Diseases, Partner Site Dresden, Dresden, Germany.
authors: P
authors: P
authors: Wimberger
authors: Institute of Pharmacogenetics, University Hospital Essen, University of Duisburg-Essen, Hufelandstr. 55, 45147, Essen, Germany.
authors: W
authors: W
authors: Siffert
authors: Institute of Pharmacogenetics, University Hospital Essen, University of Duisburg-Essen, Hufelandstr. 55, 45147, Essen, Germany. hagen.bachmann@uk-essen.de.
authors: H S
authors: HS
authors: Bachmann
mesh_terms: D000328:Adult; D000368:Aged; D001943:Breast Neoplasms / Q000235:genetics* / Q000401:mortality; D016022:Case-Control Studies; D053181:Caspase 8 / Q000235:genetics*; D005260:Female; D020022:Genetic Predisposition to Disease / Q000235:genetics*; D005838:Genotype; D006801:Humans; D053208:Kaplan-Meier Estimate; D008875:Middle Aged; D020641:Polymorphism, Single Nucleotide; D011379:Prognosis; D016016:Proportional Hazards Models; D060888:Real-Time Polymerase Chain Reaction
chemical_list: C505530:CASP8 protein, human; D053181:Caspase 8
keywords: Breast cancer; CASP8 -652 InsDel; CASP8 Asp302His; Caspase 8; Polymorphism; Prognostic biomarker