Frey Ulrich H, Nückel Holger, Sellmann Ludger, Siemer Dörte, Küppers Ralf, Dürig Jan, Dührsen Ulrich, Siffert Winfried
Institut für Pharmakogenetik, Universitätsklinikum Essen, Hufelandstrasse 55, D-45122 Essen, Germany.
Clin Cancer Res. 2006 Oct 1;12(19):5686-92. doi: 10.1158/1078-0432.CCR-06-0288.
B-cell chronic lymphocytic leukemia (B-CLL) is characterized by the accumulation of monoclonal mature B cells. The G protein Galphas subunit has been linked to proapoptotic processes in cancer cell lines. The TT genotype of the GNAS1 T393C polymorphism is associated with increased Galphas transcript levels and a more favorable clinical course in different solid cancers.
We retrospectively genotyped 144 patients with B-CLL to examine a potential association between T393C genotypes with progression-free survival (time from diagnosis to initiation of chemotherapy) and overall survival.
The C-allele frequency in the patient group was 0.57 and not significantly different from that of healthy blood donors. Median progression-free survival was significantly different between genotypes (TT 130 months; TC 100 months; CC 31 months; P = 0.0066). Multivariable analysis showed that besides of ZAP-70 (P = 0.005) and Binet stage (P < 0.001), the T393C polymorphism was an independent prognostic factor for progression-free survival [hazard ratio (HR) CC versus TT 2.7; P = 0.010]. In Binet A stages, ZAP-70-positive patients with CC genotypes had a HR of 4.4 to receive first therapy compared with ZAP-70-negative patients with T-alleles (P = 0.0001). Regarding overall survival, CC genotypes (median overall survival, 197 months) were at highest risk for death compared with T-alleles (median overall survival, 310 months) in both univariate (HR, 4.8; P < 0.0001) and multivariable analysis (HR, 5.6; P = 0.002).
Here, we show that the GNAS1 T393C status is a novel independent prognostic marker in patients with B-CLL. These results could help to define patients who could benefit from an early individualized therapy.
B 细胞慢性淋巴细胞白血病（B-CLL）的特征是单克隆成熟 B 细胞的积累。G 蛋白α亚基已与癌细胞系中的促凋亡过程相关联。GNAS1 T393C 多态性的 TT 基因型与不同实体癌中α亚基转录水平升高及更有利的临床病程相关。
我们对 144 例 B-CLL 患者进行回顾性基因分型，以研究 T393C 基因型与无进展生存期（从诊断到开始化疗的时间）和总生存期之间的潜在关联。
患者组中 C 等位基因频率为 0.57，与健康献血者无显著差异。不同基因型的无进展生存期中位数有显著差异（TT 为 130 个月；TC 为 100 个月；CC 为 31 个月；P = 0.0066）。多变量分析显示，除 ZAP-70（P = 0.005）和 Binet 分期（P < 0.001）外，T393C 多态性是无进展生存期的独立预后因素[CC 与 TT 的风险比（HR）为 2.7；P = 0.010]。在 Binet A 期，CC 基因型的 ZAP-70 阳性患者接受首次治疗的 HR 为 4.4，而 T 等位基因的 ZAP-70 阴性患者为（P = 0.0001）。关于总生存期，在单变量（HR，4.8；P < 0.0001）和多变量分析（HR，5.6；P = 0.002）中，CC 基因型（总生存期中位数为 197 个月）与 T 等位基因（总生存期中位数为 310 个月）相比，死亡风险最高。
在此，我们表明 GNAS1 T393C 状态是 B-CLL 患者的一种新的独立预后标志物。这些结果有助于确定可能从早期个体化治疗中获益的患者。
