Mutations in TP53, but not FGFR3, in urothelial cell carcinoma of the bladder are influenced by smoking:: contribution of exogenous versus endogenous carcinogens
Mutations in TP53, but not FGFR3, in urothelial cell carcinoma of the bladder are influenced by smoking:: contribution of exogenous versus endogenous carcinogens
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DOI：
10.1093/carcin/bgh275
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发表时间：
2005-01-01
期刊：
影响因子：
4.7
通讯作者：
Chopin, DK
中科院分区：
文献类型：
--
作者：
Wallerand, H;Bakkar, AA;Chopin, DK
吸烟是膀胱尿路上皮细胞癌（UCC）的主要危险因素。 FGFR3 和 TP53 基因的突变已被证明分别定义了浅表乳头状和侵袭性 UCC 疾病的两种不同途径。我们通过变性高效液相色谱和对 110 个膀胱原发性 UCC 进行测序，研究了吸烟与这些突变之间的关系。这项研究包括 48 名当前吸烟者、31 名戒烟者和 31 名不吸烟者。其中 35 个肿瘤为 pTa 期，40 个为 pT1 期，35 个肿瘤为大于或等于 topT2 期。其中 14 例肿瘤为 1 级，37 例为 2 级，59 例为 3 级。吸烟与高分期 (P = 0.03) 和高级别肿瘤 (P = 0.006) 相关。研究的 110 个肿瘤中有 22 个含有 TP53 突变 (20%)，43 个含有 FGFR3 突变 (39%)。当前吸烟者中 TP53 突变的比值比 (OR) 较高 [OR, 2.25； 95% 置信区间 (95% CI), 0.65-7.75] 和戒烟者 (OR, 1.62; 95% CI, 0.41-6.42) 比不吸烟者高。双重 TP53 突变和 A:T-->G:C TP53 突变模式仅在当前吸烟者中发现。以包年为单位衡量，FGFR3（野生型）/TP53（突变型）基因型患者的烟草消费水平显着较高（P = 0.01）。吸烟既不影响 FGFR3 突变的频率，也不影响 FGFR3 突变的模式。我们的结果表明，吸烟与最初出现的侵袭性和高级别 UCC 相关，并影响 TP53 或由这些突变定义的分子途径。相比之下，FGFR3 突变不受吸烟影响，可能是内源性改变造成的。这些数据对临床管理和预防策略具有潜在影响。
Smoking is a major risk factor for urothelial cell carcinoma of the bladder (UCC). Mutations in the FGFR3 and TP53 genes have been shown to define two distinct pathways in superficial papillary and invasive UCC disease, respectively. We investigated the relationship between smoking and these mutations by means of denaturing high performance liquid chromatography and sequencing for 110 primary UCC of the bladder. This study included 48 current smokers, 31 ex-smokers and 31 non-smokers. Thirty-five of the tumors were stage pTa, 40 pT1 and 35 greater than or equal topT2. Fourteen of the tumors were grade 1, 37 were grade 2 and 59 grade 3. Smoking was associated with high stage (P = 0.03) and high grade tumors (P = 0.006). Twenty-two of the 110 tumors studied harbored TP53 mutations (20%) and 43 harbored FGFR3 mutations (39%). Odds ratios (OR) were higher for TP53 mutations in current smokers [OR, 2.25; 95% confidence interval (95% CI), 0.65-7.75] and ex-smokers (OR, 1.62; 95% CI, 0.41-6.42) than in non-smokers. Double TP53 mutations and the A:T-->G:C TP53 mutation pattern was found only in current smokers. Patients with the FGFR3(wild-type)/TP53(mutated) genotype had significantly higher levels of tobacco consumption, as measured in pack-years (P = 0.01). Smoking influenced neither the frequency nor the pattern of FGFR3 mutations. Our results suggest that smoking is associated with invasive and high grade UCCs, at initial presentation, and influenced TP53 or the molecular pathway defined by these mutations. In contrast, FGFR3 mutations are not affected by smoking and probably result from endogenous alterations. These data have potential implications for clinical management and prevention strategies.