Genetic susceptibility to distinct bladder cancer subphenotypes.
Genetic susceptibility to distinct bladder cancer subphenotypes.
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DOI：
10.1016/j.eururo.2009.08.001
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发表时间：
2010-02
期刊：
影响因子：
23.4
通讯作者：
Malats, Nuria
中科院分区：
文献类型：
--
作者：
Guey, Lin T.;Garcia-Closas, Montserrat;Murta-Nascimento, Cristiane;Lloreta, Josep;Palencia, Laia;Kogevinas, Manolis;Rothman, Nathaniel;Vellalta, Gemma;Luz Calle, M.;Marenne, Gaelle;Tardon, Adonina;Carrato, Alfredo;Garcia-Closas, Reina;Serra, Consol;Silverman, Debra T.;Chanock, Stephen;Real, Francisco X.;Malats, Nuria
关键词：
临床、病理和分子证据表明，膀胱癌具有异质性，其病理/分子特征定义了不同肿瘤的不同亚表型。可以想象，特定的遗传易感性模式与特定的亚表型有关。检查生殖系遗传变异对膀胱癌异质性的贡献的证据。西班牙膀胱癌/EPICURO研究是一项基于西班牙五个地区18家医院的病例对照研究。病例为1998年至2001年间新诊断并经组织学证实的膀胱尿路上皮细胞癌患者。病例诊断由病理学家按照世界卫生组织/国际泌尿病理学会1999年标准进行审查和统一分类。对照组为医院匹配的患者（n = 1149）。共分析了423个候选基因中的1526个候选变异。根据分期和分级定义了三种不同的亚表型：低度非肌肉浸润性（n = 586），高度非肌肉浸润性（n = 219）和肌肉浸润性（n = 246）。通过调整潜在混杂因素的多分类风险模型评估每个变异体和亚表型之间的关联。还测试了亚表型之间遗传易感性的异质性。两种已建立的膀胱癌易感基因型，NAT 2慢乙酰化和GSTM 1-null，在亚表型之间表现出类似的关联，正如我们之前研究中发现的VEGF-rs 25648。其他变体赋予特定肿瘤亚表型的风险，如PMS 2-rs6463524和CD 4-rs3213427（异质性p值分别为0.006和0.004），与肌肉浸润性肿瘤相关（每个等位基因的比值比[95%置信区间]分别为0.56 [0.41-0.77]和0.71 [0.57-0.88]），但与非肌肉浸润性肿瘤无关。根据其错误发现率，在多次测试中异源检验值并不稳健。这些探索性分析表明，遗传易感基因位点可能与膀胱癌的分子/病理多样性。需要通过大规模的复制研究以及对其他基因和单核苷酸多态性的研究进行验证。
Clinical, pathologic, and molecular evidence indicate that bladder cancer is heterogeneous with pathologic/molecular features that define distinct subphenotypes with different prognoses. It is conceivable that specific patterns of genetic susceptibility are associated with particular subphenotypes. To examine evidence for the contribution of germline genetic variation to bladder cancer heterogeneity. The Spanish Bladder Cancer/EPICURO Study is a case-control study based in 18 hospitals located in five areas in Spain. Cases were patients with a newly diagnosed, histologically confirmed, urothelial cell carcinoma of the bladder from 1998 to 2001. Case diagnoses were reviewed and uniformly classified by pathologists following the World Health Organisation/International Society of Urological Pathology 1999 criteria. Controls were hospital-matched patients (n = 1149). A total of 1526 candidate variants in 423 candidate genes were analysed. Three distinct subphenotypes were defined according to stage and grade: low-grade nonmuscle invasive (n = 586), high-grade nonmuscle invasive (n = 219), and muscle invasive (n = 246). The association between each variant and subphenotype was assessed by polytomous risk models adjusting for potential confounders. Heterogeneity in genetic susceptibility among subphenotypes was also tested. Two established bladder cancer susceptibility genotypes, NAT2 slow-acetylation and GSTM1-null, exhibited similar associations among the subphenotypes, as did VEGF-rs25648, which was previously identified in our study. Other variants conferred risks for specific tumour subphenotypes such as PMS2-rs6463524 and CD4-rs3213427 (respective heterogeneity p values of 0.006 and 0.004), which were associated with muscle-invasive tumours (per-allele odds ratios [95% confidence interval] of 0.56 [0.41–0.77] and 0.71 [0.57–0.88], respectively) but not with non–muscle-invasive tumours. Heterogeneity p values were not robust in multiple testing according to their false-discovery rate. These exploratory analyses suggest that genetic susceptibility loci might be related to the molecular/pathologic diversity of bladder cancer. Validation through large-scale replication studies and the study of additional genes and single nucleotide polymorphisms are required.
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影响因子：
30.8
作者：
Kiemeney LA;Thorlacius S;Sulem P;Geller F;Aben KK;Stacey SN;Gudmundsson J;Jakobsdottir M;Bergthorsson JT;Sigurdsson A;Blondal T;Witjes JA;Vermeulen SH;Hulsbergen-van de Kaa CA;Swinkels DW;Ploeg M;Cornel EB;Vergunst H;Thorgeirsson TE;Gudbjartsson D;Gudjonsson SA;Thorleifsson G;Kristinsson KT;Mouy M;Snorradottir S;Placidi D;Campagna M;Arici C;Koppova K;Gurzau E;Rudnai P;Kellen E;Polidoro S;Guarrera S;Sacerdote C;Sanchez M;Saez B;Valdivia G;Ryk C;de Verdier P;Lindblom A;Golka K;Bishop DT;Knowles MA;Nikulasson S;Petursdottir V;Jonsson E;Geirsson G;Kristjansson B;Mayordomo JI;Steineck G;Porru S;Buntinx F;Zeegers MP;Fletcher T;Kumar R;Matullo G;Vineis P;Kiltie AE;Gulcher JR;Thorsteinsdottir U;Kong A;Rafnar T;Stefansson K
通讯作者：
Stefansson K
影响因子：
6.4
作者：
Baccarelli, Andrea;Hou, Lifang;Chow, Wong-Ho
通讯作者：
Chow, Wong-Ho
影响因子：
4.5
作者：
Hull, Jeremy;Campino, Susana;Kwiatkowski, Dominic
通讯作者：
Kwiatkowski, Dominic
影响因子：
3.4
作者：
Lotan, Yair;Svatek, Robert S.;Malats, Nuria
通讯作者：
Malats, Nuria
影响因子：
11.2
作者：
Lopez-knowles, Elena;Hernandez, Silvia;Real, Francisco X.
通讯作者：
Real, Francisco X.