Department of Clinical Oncology, University of Hong Kong, Hong Kong, (SAR), PR China.
Department of Cancer Molecular Pathology, Griffith Medical School and Menzies Health Institute Queensland, Griffith University, Gold Coast, Australia.
J Pathol. 2017 Aug;242(4):500-510. doi: 10.1002/path.4925. Epub 2017 Jul 12.
Oesophageal squamous cell carcinoma (ESCC) is one of the most lethal cancers, owing to a high frequency of metastasis. However, little is known about the genomic landscape of metastatic ESCC. To identify the genetic alterations that underlie ESCC metastasis, whole-exome sequencing was performed for 41 primary tumours and 15 lymph nodes (LNs) with metastatic ESCCs. Eleven cases included matched primary tumours, synchronous LN metastases, and non-neoplastic mucosa. Approximately 50-76% of the mutations identified in primary tumours appeared in the synchronous LN metastases. Metastatic ESCCs harbour frequent mutations of TP53, KMT2D, ZNF750, and IRF5. Importantly, ZNF750 was recurrently mutated in metastatic ESCC. Combined analysis from current and previous genomic ESCC studies indicated more frequent ZNF750 mutation in diagnosed cases with LN metastasis than in those without metastasis (14% versus 3.4%, n = 629, P = 1.78 × 10 ). The Cancer Genome Atlas data further showed that ZNF750 genetic alterations were associated with early disease relapse. Previous ESCC studies have demonstrated that ZNF750 knockdown strongly promotes proliferation, migration, and invasion. Collectively, these results suggest a role for ZNF750 as a metastasis suppressor. TP53 is highly mutated in ESCC, and missense mutations are associated with poor overall survival, independently of pathological stage, suggesting that these missense mutations have important functional impacts on tumour progression, and are thus likely to be gain-of-function (GOF) mutations. Additionally, mutations of epigenetic regulators, including KMT2D, TET2, and KAT2A, and chromosomal 6p22 and 11q23 deletions of histone variants, which are important for nucleosome assembly, were detected in 80% of LN metastases. Our study highlights the important role of critical genetic events including ZNF750 mutations, TP53 putative GOF mutations and nucleosome disorganization caused by genetic lesions seen with ESCC metastasis. Copyright © 2017 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd.
食管鳞状细胞癌（ESCC）是最致命的癌症之一，其转移率很高。然而，对于转移性 ESCC 的基因组景观知之甚少。为了确定导致 ESCC 转移的遗传改变，对 41 个原发性肿瘤和 15 个具有转移性 ESCC 的淋巴结（LN）进行了全外显子组测序。11 例包括匹配的原发性肿瘤、同步 LN 转移和非肿瘤性粘膜。在原发性肿瘤中发现的突变约有 50-76%出现在同步 LN 转移中。转移性 ESCC 频繁发生 TP53、KMT2D、ZNF750 和 IRF5 的突变。重要的是，ZNF750 在转移性 ESCC 中经常发生突变。来自当前和以前的基因组 ESCC 研究的综合分析表明，在诊断为 LN 转移的病例中，ZNF750 突变的频率高于没有转移的病例（14%对 3.4%，n=629，P=1.78×10）。癌症基因组图谱数据进一步表明，ZNF750 遗传改变与早期疾病复发有关。以前的 ESCC 研究表明，ZNF750 敲低强烈促进增殖、迁移和侵袭。总之，这些结果表明 ZNF750 作为转移抑制因子的作用。TP53 在 ESCC 中高度突变，错义突变与总生存期不良相关，独立于病理分期，这表明这些错义突变对肿瘤进展有重要的功能影响，因此可能是获得性功能（GOF）突变。此外，在 80%的 LN 转移中检测到表观遗传调节剂的突变，包括 KMT2D、TET2 和 KAT2A，以及组蛋白变体的染色体 6p22 和 11q23 缺失，这些对于核小体组装很重要。我们的研究强调了包括 ZNF750 突变、TP53 假定的 GOF 突变和由 ESCC 转移引起的核小体紊乱等关键遗传事件的重要作用。版权所有©2017 英国和爱尔兰病理学会。由 John Wiley & Sons，Ltd. 出版
