PIK3CA mutations are an early genetic alteration associated with FGFR3 mutations in superficial papillary bladder tumors
PIK3CA mutations are an early genetic alteration associated with FGFR3 mutations in superficial papillary bladder tumors
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DOI：
10.1158/0008-5472.can-06-1182
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发表时间：
2006-08-01
期刊：
影响因子：
11.2
通讯作者：
Real, Francisco X.
中科院分区：
文献类型：
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作者：
Lopez-knowles, Elena;Hernandez, Silvia;Real, Francisco X.
膀胱肿瘤是一种异质性很强的疾病。浅表性肿瘤的特征在于FGFR 3突变和9号染色体改变的高患病率。高级别和肌肉浸润性肿瘤的特征在于Tp 53突变和非整倍体。我们分析了一组膀胱肿瘤中PIK 3CA的外显子9和20的序列，涵盖了整个疾病谱。用PCR扩增福尔马林固定、石蜡包埋的肿瘤切片的DNA，并对产物进行测序。在一组代表该疾病的肿瘤中，PIK 3CA突变的患病率为13%（87例中的11例）。突变主要发生在先前鉴定的热点（密码子542、545、1007和1047）。根据分期的分布如下：恶性潜能不确定的乳头状尿路上皮肿瘤（PUNLMP; 11/43，25.6%），T-a（9/57，16%），T-1（2/10，20%）和肌肉浸润性肿瘤（0/20，0%; P = 0.019）。突变与低级别肿瘤相关：1级（6/27，22.2%）、2级（3/23，13%）和3级（2/37，5.4%; P = 0.047）。总体而言，PIK 3CA突变与FGFR 3突变密切相关：69例（26%）FGFR 3（mut）肿瘤的IS为PIK 3CA（mut），而58例（6.9%）FGFR 3（wt）肿瘤中有4例为PIK 3CA（mut）（P = 0.005）。我们的研究结果表明，PIK 3CA突变是一种常见的事件，可以发生在膀胱癌发生的早期，并支持乳头状和肌肉浸润性肿瘤通过不同的分子途径产生的概念。PIK 3CA可能构成膀胱癌的一种新的诊断和预后工具，以及治疗靶点。
Bladder tumors constitute a very heterogeneous disease. Superficial tumors are characterized by a high prevalence of FGFR3 mutations and chromosome 9 alterations. High-grade and muscle-invasive tumors are characterized by Tp53 mutations and aneuploidy. We have analyzed the sequence of exons 9 and 20 of PIK3CA in a panel of bladder tumors covering the whole spectrum of the disease. DNA from formalin-flixed, paraffin-embedded tumor sections was amplified by PCR and products were sequenced. In an unselected panel of tumors representative of the disease, the PIK3CA mutation prevalence was 13% (11 of 87). Mutations occurred mainly at the previously identified hotspots (codons 542, 545, 1007, and 1047). The distribution according to stage was as follows: papillary urothelial neoplasms of uncertain malignant potential (PUNLMP; 11 of 43, 25.6%), T-a (9 of 57, 16%), T-1 (2 of 10, 20%), and muscle-invasive tumors (0 of 20, 0%; P = 0.019). Mutations were associated with low-grade tumors: grade 1 (6 of 27, 22.2%), grade 2 (3 of 23, 13%), and grade 3 (2 of 37, 5.4%; P = 0.047). Overall, PIK3CA mutations were strongly associated with FGFR3 mutations: IS of 69 (26%) FGFR3(mut) tumors were PIK3CA(mut), versus 4 of 58 (6.9%) FGFR3(wt) tumors (P = 0.005). Our findings indicate that PIK3CA mutations are a common event that can occur early in bladder carcinogenesis and support the notion that papillary and muscle-invasive tumors arise through different molecular pathways. PIK3CA may constitute a novel diagnostic and prognostic tool, as well as a therapeutic target, in bladder cancer.