Small-Cell Carcinomas of the Bladder and Lung Are Characterized by a Convergent but Distinct Pathogenesis.
Small-Cell Carcinomas of the Bladder and Lung Are Characterized by a Convergent but Distinct Pathogenesis.
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DOI：
10.1158/1078-0432.ccr-17-2655
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发表时间：
2018-04-15
期刊：
影响因子：
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通讯作者：
Taylor BS
中科院分区：
文献类型：
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作者：
Chang MT;Penson A;Desai NB;Socci ND;Shen R;Seshan VE;Kundra R;Abeshouse A;Viale A;Cha EK;Hao X;Reuter VE;Rudin CM;Bochner BH;Rosenberg JE;Bajorin DF;Schultz N;Berger MF;Iyer G;Solit DB;Al-Ahmadie HA;Taylor BS
膀胱小细胞癌（SCCB）是一种罕见的侵袭性神经内分泌肿瘤，预后不佳，治疗方案有限。由于SCCB在组织学上与小细胞肺癌难以区分，因此提出了共同的发病机制和细胞起源。本研究的目的是确定sccb是由先前存在的尿路上皮癌引起的，还是与小细胞肺癌有共同的分子发病机制。我们对61例SCCB肿瘤进行了综合分析，以确定组织学和器官特异性的异同。SCCB具有很高的体细胞突变负担，主要由apobecc介导的突变过程驱动。几乎所有样本中都存在TP53、RB1和TERT启动子突变。虽然这些事件似乎在所有受影响的肿瘤中早期出现，并且可能反映了一个可能驱动小细胞谱系分化的进化分支点，但它们不太可能是创始转化事件，因为它们之前通常是多种多样且不太常见的驱动突变，其中许多在膀胱尿路上皮癌中常见，但在小细胞肺肿瘤中并不常见。大多数肿瘤患者（72%）也经历了基因组加倍（GD）。虽然在疾病进化的不同时间点出现，GD通常在TP53双等位基因突变之前，保留了两个完整的拷贝。我们的研究结果表明，膀胱癌和肺癌的小细胞癌具有趋同但不同的发病机制，sccb起源于与尿路上皮性膀胱癌相同的细胞。
Small cell carcinoma of the bladder (SCCB) is a rare and aggressive neuroendocrine tumor with a dismal prognosis and limited treatment options. As SCCB is histologically indistinguishable from small cell lung cancer, a shared pathogenesis and cell of origin has been proposed. The aim of this study is to determine whether SCCBs arise from a pre-existent urothelial carcinoma or share a molecular pathogenesis in common with small cell lung cancer. We performed an integrative analysis of 61 SCCB tumors to identify histology- and organ-specific similarities and differences. SCCB has a high somatic mutational burden driven predominantly by an APOBEC-mediated mutational process. TP53, RB1, and TERT promoter mutations were present in nearly all samples. While these events appeared to arise early in all affected tumors and likely reflect an evolutionary branch point that may have driven small cell lineage differentiation, they were unlikely the founding transforming event, as they were often preceded by diverse and less common driver mutations, many of which are common in bladder urothelial cancers but not small cell lung tumors. Most patient tumors (72%) also underwent genome doubling (GD). While arising at different chronological points in the evolution of the disease, GD was often preceded by biallelic mutations in TP53 with retention of two intact copies. Our findings indicate that small cell cancers of the bladder and lung have a convergent but distinct pathogenesis with SCCBs arising from a cell of origin shared with urothelial bladder cancer.