Molecular characterization of metastatic pancreatic neuroendocrine tumors (PNETs) using whole-genome and transcriptome sequencing.
Molecular characterization of metastatic pancreatic neuroendocrine tumors (PNETs) using whole-genome and transcriptome sequencing.
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DOI：
10.1101/mcs.a002329
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发表时间：
2018-03
影响因子：
1.8
通讯作者：
Renouf DJ
中科院分区：
文献类型：
--
作者：
Wong HL;Yang KC;Shen Y;Zhao EY;Loree JM;Kennecke HF;Kalloger SE;Karasinska JM;Lim HJ;Mungall AJ;Feng X;Davies JM;Schrader K;Zhou C;Karsan A;Jones SJM;Laskin J;Marra MA;Schaeffer DF;Gorski SM;Renouf DJ
胰腺神经内分泌肿瘤是一组基因组和临床异质性胰腺肿瘤，常诊断为远处转移。PNET患者的复发性体细胞突变、染色体畸变和基因表达特征已被描述，但这些分子变化的临床意义仍知之甚少，PNET患者的临床结局仍高度可变。为了帮助确定有助于PNET进展和转移的分子因素，并作为BC癌症机构正在进行的临床试验的一部分（clinicaltrials.gov ID：NCT 02155621），分析了5名患者（4名PNET和1名神经内分泌癌）肝转移的基因组和转录组学特征。在5例中的4例中，我们发现MEN1和DAXX的双等位基因丢失以及杂合性丢失的复发区域。观察到几个新的发现，包括在一个具有野生型MEN1和DAXX的样品中MYCN的局灶性扩增伴随APC和TP53的丢失。转录组分析显示该样本中MYCN靶基因上调，证实了MYCN驱动的基因表达特征。我们还在一个样品中鉴定了一个生殖系NTHL 1融合事件，该事件导致了先前在PNTR中未报道的惊人的C>T突变特征谱。这些不同的分子改变表明不同的细胞途径可能有助于PNET进展，与这种疾病的异质性临床性质一致。此外，基因组图谱似乎与治疗反应密切相关，支持前瞻性基因分型工作在指导PNIPs治疗中的作用。
Pancreatic neuroendocrine tumors (PNETs) are a genomically and clinically heterogeneous group of pancreatic neoplasms often diagnosed with distant metastases. Recurrent somatic mutations, chromosomal aberrations, and gene expression signatures in PNETs have been described, but the clinical significance of these molecular changes is still poorly understood, and the clinical outcomes of PNET patients remain highly variable. To help identify the molecular factors that contribute to PNET progression and metastasis, and as part of an ongoing clinical trial at the BC Cancer Agency (clinicaltrials.gov ID: NCT02155621), the genomic and transcriptomic profiles of liver metastases from five patients (four PNETs and one neuroendocrine carcinoma) were analyzed. In four of the five cases, we identified biallelic loss of MEN1 and DAXX as well as recurrent regions with loss of heterozygosity. Several novel findings were observed, including focal amplification of MYCN concomitant with loss of APC and TP53 in one sample with wild-type MEN1 and DAXX. Transcriptome analyses revealed up-regulation of MYCN target genes in this sample, confirming a MYCN-driven gene expression signature. We also identified a germline NTHL1 fusion event in one sample that resulted in a striking C>T mutation signature profile not previously reported in PNETs. These varying molecular alterations suggest different cellular pathways may contribute to PNET progression, consistent with the heterogeneous clinical nature of this disease. Furthermore, genomic profiles appeared to correlate well with treatment response, lending support to the role of prospective genotyping efforts to guide therapy in PNETs.