RESUMEN
OBJECTIVE: To examine germline single nucleotide polymorphisms (SNPs) as markers of response to gemcitabine platinum (GP) combination chemotherapy in urothelial carcinoma (UC). METHODS: Saliva or blood was prospectively collected from 216 patients treated with GP for UC of the bladder between 1991 and 2011. Based on reported associations with gemcitabine and cisplatin response or putative mechanisms of gemcitabine or cisplatin/carboplatin activity, we selected SNPs of interest and were able to genotype 59 SNPs (using the SequenomMass ARRAYiPLEX platform) in 261 patients randomly split 2/3 into a training set (n = 174) and 1/3 into a test set (n = 87). Logistic regression was used to test the association between response to GP and SNPs. RESULTS: The median age at diagnosis was 64 years (range: 28 - 85) for the discovery set and 67 years (range: 30 - 84) for the validation set. Males composed 76% and 69%, and white non-Hispanics composed 88% and 91% of the training and test validation sets, respectively. Three SNPs on GALNTL4 (rs7937567, rs12278731, and rs9988868) and one intergenic SNP (rs1321391) were significantly associated with response to GP in the training set and were used to build a SNP score. However, when assessed in the test set, the SNP score was not significantly associated with response. CONCLUSION: Multiple SNPs selected from previous studies failed to predict response to GP in this cohort. Larger studies capable of accounting for population-based allele frequency heterogeneity may be required for replication of genetic alterations important to pharmacogenomics.â©.
Asunto(s)
Protocolos de Quimioterapia Combinada Antineoplásica/farmacocinética , Carboplatino/farmacocinética , Carcinoma/tratamiento farmacológico , Cisplatino/farmacocinética , Desoxicitidina/análogos & derivados , N-Acetilgalactosaminiltransferasas/genética , Variantes Farmacogenómicas , Polimorfismo de Nucleótido Simple , Neoplasias de la Vejiga Urinaria/tratamiento farmacológico , Urotelio/efectos de los fármacos , Adulto , Anciano , Anciano de 80 o más Años , Protocolos de Quimioterapia Combinada Antineoplásica/administración & dosificación , Protocolos de Quimioterapia Combinada Antineoplásica/efectos adversos , Protocolos de Quimioterapia Combinada Antineoplásica/sangre , Carboplatino/administración & dosificación , Carboplatino/efectos adversos , Carcinoma/genética , Carcinoma/patología , Cisplatino/administración & dosificación , Cisplatino/efectos adversos , Cisplatino/sangre , Desoxicitidina/administración & dosificación , Desoxicitidina/efectos adversos , Desoxicitidina/sangre , Desoxicitidina/farmacocinética , Femenino , Genotipo , Humanos , Intrones , Modelos Logísticos , Masculino , Persona de Mediana Edad , Modelos Genéticos , N-Acetilgalactosaminiltransferasas/metabolismo , Farmacogenética , Fenotipo , Estudios Prospectivos , Resultado del Tratamiento , Neoplasias de la Vejiga Urinaria/genética , Neoplasias de la Vejiga Urinaria/patología , Urotelio/patología , Gemcitabina , Polipéptido N-AcetilgalactosaminiltransferasaRESUMEN
Somatic alterations of the lymphoid transcription factor gene PAX5 (also known as BSAP) are a hallmark of B cell precursor acute lymphoblastic leukemia (B-ALL), but inherited mutations of PAX5 have not previously been described. Here we report a new heterozygous germline variant, c.547G>A (p.Gly183Ser), affecting the octapeptide domain of PAX5 that was found to segregate with disease in two unrelated kindreds with autosomal dominant B-ALL. Leukemic cells from all affected individuals in both families exhibited 9p deletion, with loss of heterozygosity and retention of the mutant PAX5 allele at 9p13. Two additional sporadic ALL cases with 9p loss harbored somatic PAX5 substitutions affecting Gly183. Functional and gene expression analysis of the PAX5 mutation demonstrated that it had significantly reduced transcriptional activity. These data extend the role of PAX5 alterations in the pathogenesis of pre-B cell ALL and implicate PAX5 in a new syndrome of susceptibility to pre-B cell neoplasia.