Characterizing Genetic Transitions of Copy Number Alterations and Allelic Imbalances in Oral Tongue Carcinoma Metastasis
Characterizing Genetic Transitions of Copy Number Alterations and Allelic Imbalances in Oral Tongue Carcinoma Metastasis
复制标题
DOI：
10.1002/gcc.22395
复制
发表时间：
2016-12-01
影响因子：
3.7
通讯作者：
Harada, Kiyoshi
中科院分区：
文献类型：
--
作者：
Morita, Takuma;Uzawa, Narikazu;Harada, Kiyoshi
原发肿瘤(PT)的异质性可以显著影响转移部位克隆的遗传特征。为了了解转移的机制，我们比较了来自口腔舌鳞状细胞癌(OTSCC)患者的成对PT和转移淋巴结(MLN)样本的遗传特征。使用高密度单核苷酸多态性微阵列对来自10名OTSCC患者的PT-MLN样本进行了大规模的遗传图谱分析。我们比较了PT和MLN OTSCC样本的遗传图谱，以确定常见和特定的拷贝数改变和拷贝中性杂合性丢失(CN-LOH)。非监督等级聚类分析表明，10对PT-MLN样本中有8对形成了聚类，这表明原发和转移肿瘤由主要遗传相似的肿瘤细胞组成。在10对中的6对中，PT和MLN均检测到8q11.21、8q12.2-3和8q21.3的增益和22q11.23的丢失。此外，在10对中有9对检测到16p11.2 CN-LOH。相反，20q11.2扩增仅在10对样本中的5对MLN中观察到，提示该染色体区域的基因可能在OTSCC的淋巴转移中起重要作用。为了证实这一点，我们调查了两个候选20q11.2基因在一个单独的患者队列中的表达。其中一种基因E2F1在肿瘤转移过程中表达明显增强。这项研究表明，额外的遗传变化，如编码E2F1基因的20q11.2获得，可以通过克隆进化获得，可能是转移过程所必需的。(C)2016威利期刊公司。
Primary tumor (PT) heterogeneity can significantly affect the genetic profile of clones at metastatic sites. To understand the mechanisms underlying metastasis, we compared the genetic profile of paired PT and metastatic lymph node (MLN) samples obtained from patients with oral tongue squamous cell carcinoma (OTSCC). Large-scale genetic profiling was performed on paired PT-MLN samples obtained from 10 OTSCC patients using high-density single-nucleotide polymorphism microarrays. We compared the genetic profile of PT and MLN OTSCC samples to identify common and specific copy number alterations and copy-neutral loss-of-heterozygosity (CN-LOH). Unsupervised hierarchical clustering analysis indicated that 8 of the 10 PT-MLN sample pairs formed clusters, indicating that the primary and metastatic tumors were composed of predominantly genetically similar tumor cells. In 6 of the 10 pairs, 8q11.21, 8q12.2-3, and 8q21.3 gains, and 22q11.23 loss were detected in both the PT and MLN. In addition, 16p11.2 CN-LOH was identified in 9 of the 10 pairs. Conversely, 20q11.2 gain was only observed in the MLNs of 5 of the 10 sample pairs, indicating that genes in this chromosomal region may play a significant role in OTSCC lymph node metastasis. To confirm this, we investigated the expression of two candidate 20q11.2 genes in a separate patient cohort. The expression of one of these genes, E2F1, was significantly increased during the process of metastasis. This study indicates that additional genetic changes, such as 20q11.2 gain, which encodes the E2F1 gene, can be acquired through clonal evolution, and may be required for the metastatic process. (C) 2016 Wiley Periodicals, Inc.