Intratumoral morphologic and molecular heterogeneity of rhabdoid renal cell carcinoma: challenges for personalized therapy.
Intratumoral morphologic and molecular heterogeneity of rhabdoid renal cell carcinoma: challenges for personalized therapy.
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DOI：
10.1038/modpathol.2015.68
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发表时间：
2015-09
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影响因子：
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通讯作者：
Sircar K
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作者：
Singh RR;Murugan P;Patel LR;Voicu H;Yoo SY;Majewski T;Mehrotra M;Wani K;Tannir N;Karam JA;Jonasch E;Wood CG;Creighton CJ;Medeiros LJ;Broaddus RR;Tamboli P;Baggerly KA;Aldape KD;Czerniak B;Luthra R;Sircar K
肾透明细胞癌的横纹肌样组织学与预后不良有关。肾透明细胞癌患者的预后也可能受到分子改变的影响。本研究的目的是评估横纹肌样透明细胞癌的组织学特征与显著的分子改变之间的关系。我们对12例横纹肌样透明细胞癌的横纹肌样和透明细胞上皮样成分进行了大体解剖。我们使用临床下一代外显子组测序平台评估了8例癌症相关突变。用RNA-SEQ和基因表达芯片检测横纹肌样透明细胞癌(n=8)和非横纹肌样透明细胞癌(n=37)的转录组。VHL(63%)在同一肿瘤的所有区域显示相同的突变。BAP1(38%)和PBRM1(13%)突变存在于横纹肌样成分，而不存在于上皮样成分，且分别有3/3例和1例相互排斥。SETD2(63%)突变在2/5的组织学区域不一致，仅在上皮样成分和横纹肌样成分中发现突变。横纹肌样透明细胞癌的转录组与晚期和高级别透明细胞癌不同。然而，横纹肌样透明细胞癌的不同组织成分显示出相似的转录程序，包括相似的预后基因表达特征。横纹肌样透明细胞肾细胞癌在转录水平上是不同的，表现为SETD2和BAP1的高突变率以及PBRM1的低突变率。肾透明细胞癌的驱动突变在不同的形态区域通常是不一致的，而基因表达程序是相对稳定的。通过评估基因表达和从不同组织学区域采集肿瘤灶，透明细胞肾癌的分子图谱可能会得到改善。
Rhabdoid histology in clear cell renal cell carcinoma is associated with a poor prognosis. The prognosis of patients with clear cell renal cell carcinoma may also be influenced by molecular alterations. The aim of this study was to evaluate the association between histologic features and salient molecular changes in rhabdoid clear cell renal cell carcinoma. We macrodissected the rhabdoid and clear cell epithelioid components from 12 cases of rhabdoid clear cell renal cell carcinoma. We assessed cancer related mutations from 8 cases using a clinical next generation exome sequencing platform. The transcriptome of rhabdoid clear cell renal cell carcinoma (n=8) and non-rhabdoid clear cell renal cell carcinoma (n=37) was assessed by RNA-seq and gene expression microarray. VHL (63%) showed identical mutations in all regions from the same tumor. BAP1 (38%) and PBRM1 (13%) mutations were identified in the rhabdoid but not the epithelioid component and were mutually exclusive in 3/3 cases and 1 case, respectively. SETD2 (63%) mutations were discordant between different histologic regions in 2/5 cases, with mutations called only in the epithelioid and rhabdoid components, respectively. The transcriptome of rhabdoid clear cell renal cell carcinoma was distinct from advanced stage and high grade clear cell renal cell carcinoma. The diverse histologic components of rhabdoid clear cell renal cell carcinoma, however, showed a similar transcriptomic program, including a similar prognostic gene expression signature. Rhabdoid clear cell renal cell carcinoma is transcriptomically distinct and shows a high rate of SETD2 and BAP1 mutations and a low rate of PBRM1 mutations. Driver mutations in clear cell renal cell carcinoma are often discordant across different morphologic regions whereas the gene expression program is relatively stable. Molecular profiling of clear cell renal cell carcinoma may improve by assessing for gene expression and sampling tumor foci from different histologic regions.