title: Influence of survivin (BIRC5) and caspase-9 (CASP9) functional polymorphisms in renal cell carcinoma development: a study in a southern European population.
abstract: Renal cell carcinoma (RCC) is the most common cancer of the adult kidney and its incidence and mortality has increase in the last 20 years. The disruption of cellular death is one the mechanism involved in cancer development. This process is precise regulated by apoptotic and anti-apoptotic molecules. Survivin (BIRC5) is a member of the inhibitor of apoptosis protein family and has the ability to inhibit the activation of the pro-apoptotic caspase-9 (CASP9). Thus BIRC5 and CASP9 functional polymorphisms might modulate the apoptosis and consequently RCC development. Our purpose was to investigate the potential role of BIRC5-31G/C and CASP9+83C/T functional polymorphisms in the risk for the development of RCC and metastatic disease. We studied the BIRC5-31G/C and CASP9+83C/T functional polymorphisms by PCR-RFLP and allelic discrimination using the 7300 real-time polymerase chain reaction system, respectively, in 178 RCC patients and in 305 healthy individuals. Regarding the BIRC5-31G/C polymorphism, there is a trend to an overrepresentation of CC genotype in RCC group compared with normal controls (aOR, 1.94; P=0.053). We observed, after gender stratification and age-adjustment, that BIRC5-31CC and CASP9+83CT/TT genotypes were associated with an increased risk for RCC development in the female group of our southern European study population (aOR=3.85; P=0.019; aOR=2.98; P=0.028; respectively). Concerning the waiting time for onset of metastatic disease, we observed that BIRC5-31CC homozygous developed metastasis 8 years earlier than the G carriers using a Cox proportional hazard model with gender as covariate (HR=4.9, P=0.038, P bootstrap=0.009). The Cox regression proportional hazard model was validated using bootstrap statistic with 1,000 samples of the same number of patients as the original dataset. Our results suggest that individual differences influence the susceptibility to RCC and tumor behavior. This genetic profile may help to define higher risk groups that would benefit from individualized chemoprevention strategies and therapies.
authors: Grupo de Oncologia Molecular-CI, Edifício Laboratórios, Instituto Português de Oncologia do Porto Francisco Gentil, EPE, 4º piso, Rua Dr. António Bernardino de Almeida, 4200-072, Porto, Portugal.
authors: Inês
authors: I
authors: Marques
authors: Ana L
authors: AL
authors: Teixeira
authors: Marta
authors: M
authors: Ferreira
authors: Joana
authors: J
authors: Assis
authors: Francisco
authors: F
authors: Lobo
authors: Joaquina
authors: J
authors: Maurício
authors: Rui
authors: R
authors: Medeiros
mesh_terms: D000368:Aged; D017209:Apoptosis / Q000235:genetics*; D002292:Carcinoma, Renal Cell / Q000235:genetics*; D053453:Caspase 9 / Q000235:genetics*; D005260:Female; D020022:Genetic Predisposition to Disease / Q000235:genetics*; D005838:Genotype; D006801:Humans; D051034:Inhibitor of Apoptosis Proteins / Q000235:genetics*; D008297:Male; D008875:Middle Aged; D009362:Neoplasm Metastasis / Q000235:genetics*; D016017:Odds Ratio; D012150:Polymorphism, Restriction Fragment Length; D020641:Polymorphism, Single Nucleotide / Q000235:genetics; D011174:Portugal; D016016:Proportional Hazards Models; D060888:Real-Time Polymerase Chain Reaction; D000077022:Survivin
chemical_list: C107489:BIRC5 protein, human; D051034:Inhibitor of Apoptosis Proteins; D000077022:Survivin; C506433:CASP9 protein, human; D053453:Caspase 9
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