Whole-genome approach implicates CD44 in cellular resistance to carboplatin.

摘要: Carboplatin is a chemotherapeutic agent used in the management of many cancers, yet treatment limited by resistance and toxicities. To achieve better understanding genetic contribution to carboplatin or toxicities, lymphoblastoid cell lines from 34 large Centre d'Etude du Polymorphisme Humain pedigrees were utilised evaluate interindividual variation cytotoxicity. Significant heritability, ranging 0.17-0.36 (p = 1 × 10-7 9 10-4), was found for growth inhibition following 72-hour at each concentration (10, 20, 40 80 μM) IC50 (concentration 50 per cent inhibition). Linkage analysis revealed 11 regions with logarithm odds (LOD) scores greater than 1.5. The highest LOD score on chromosome (LOD 3.36, p 4.2 10-5) encompasses 65 genes within confidence interval IC50. We further analysed phenotype linkage-directed association using 71 unrelated HapMap Perlegen identified 18 single nucleotide polymorphisms eight that significantly associated < 3.6 10-5; false discovery rate 5 cent). Next, we performed linear regression baseline expression values genes, which most significant correlation between CD44 (r2 0.20; 6 10-4). quantitative real-time polymerase chain reaction confirmed statistically difference levels carboplatin-resistant -sensitive 5.9 10-3). Knockdown through small interfering RNA resulted increased cellular sensitivity 0.01). Our whole-genome approach molecular experiments as being important conferring carboplatin.