PDF(Pubmed)
Abstract：
Background: Small bowel carcinoids are insidious tumors that are often metastatic when diagnosed. Limited mutation landscape studies of carcinoids indicate that these tumors have a relatively low mutational burden. The development of targeted therapies will depend upon the identification of mutations that drive the pathogenesis and metastasis of carcinoid tumors. Methods: Whole exome and RNA sequencing of 5 matched sets of normal tissue, primary small intestine carcinoid tumors, and liver metastases were investigated. Germline and somatic variants included: single nucleotide variants (SNVs), insertions/deletions (indels), structural variants, and copy number alterations (CNAs). The functional impact of mutations was predicted using Ensembl Variant Effect Predictor. Results: Large-scale CNAs were observed including the loss of chromosome 18 in all 5 metastases and 3/5 primary tumors. Certain somatic SNVs were metastasis-specific; including mutations in ATRX, CDKN1B, MXRA5 (leading to the activation of a cryptic splice site and loss of mRNA), SMARCA2, and the loss of UBE4B. Additional mutations in ATRX, and splice site loss of PYGL, leading to intron retention observed in primary and metastatic tumors. Conclusions: We observed novel mutations in primary/metastatic carcinoid tumor pairs, and some have been observed in other types of neuroendocrine tumors. We confirmed a previously observed loss of chromosome 18 and CDKN1B. Transcriptome sequencing added relevant information that would not have been appreciated with DNA sequencing alone. The detection of several splicing mutations on the DNA level and their consequences at the RNA level suggests that RNA splicing aberrations may be an important mechanism underlying carcinoid tumors.
摘要：
背景：小肠类癌是隐匿的肿瘤，在诊断时通常是转移性的。类癌的有限突变景观研究表明，这些肿瘤具有相对较低的突变负担。靶向治疗的发展将取决于驱动类癌的发病机理和转移的突变的鉴定。方法:对5组匹配的正常组织进行全外显子组和RNA测序,原发性小肠类癌，和肝转移进行了调查。种系和体细胞变体包括：单核苷酸变体（SNV），插入/删除(indel)，结构变体，和拷贝数更改（CNAs）。使用Ensembl变体效应预测器来预测突变的功能影响。结果：在所有5个转移和3/5个原发性肿瘤中观察到大规模的CNAs，包括18号染色体的丢失。某些体细胞SNV具有转移特异性；包括ATRX中的突变，CDKN1B,MXRA5（导致隐蔽剪接位点的激活和mRNA的丢失），SMARCA2和UBE4B的损失。ATRX中的其他突变，和PYGL的拼接位点丢失，导致在原发性和转移性肿瘤中观察到内含子保留。结论：我们在原发性/转移性类癌对中观察到新的突变，在其他类型的神经内分泌肿瘤中也观察到了一些。我们证实了先前观察到的18号染色体和CDKN1B的丢失。转录组测序增加了相关信息，这些信息单独使用DNA测序是无法理解的。在DNA水平上检测到几种剪接突变及其在RNA水平上的后果表明，RNA剪接异常可能是类癌肿瘤的重要机制。
