Tan Qiang, Cui Jian, Huang Jia, Ding Zhengping, Lin Hao, Niu Xiaomin, Li Zhiming, Wang Guan, Luo Qingquan, Lu Shun
Department of Shanghai Lung Tumor Clinic Center, Shanghai Chest Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai, People's Republic of China.
Cell Physiol Biochem. 2016;38(2):469-86. doi: 10.1159/000438644. Epub 2016 Feb 1.
BACKGROUND/AIMS: Recurrent gene mutation has been identified by the analysis of exonic DNA from lung adenocarcinoma, but its progression has not been extensively profiled. The investigation of the mutational landscape of tumors provides new insights into cancer genome evolution and further discovers the interplay of somatic mutation, adaptation of clones to their environment and natural selection. Cancer development involves cycles of genomic damage, epigenetic deregulation, and increased cellular proliferation that eventually culminate in the carcinoma phenotype.
Comparative whole exome sequencing of both primary and metastatic tumor tissues from four patients of stage IV lung adenocarcinoma patients with chest wall metastasis was performed. Both primary and metastatic tumors were diagnosed through biopsy followed by surgical resection. All tumor specimens were cut into several pieces to assess potential heterogenic clones within the tumor tissue. Adjacent normal lung tissue was also obtained to provide germline mutation background.
By modeling and analyzing progression of the cancer metastasis based on non-synonymous variants, we defined the extent of heterogeneity of cancer genomes and identified similar cancer evolution pattern in the four patients: metastasis was an early event occurring right after the primary cancer formation and evolution in the metastatic tumor was continuously and simultaneously in progression with that in the primary tumor. By characterizing the clonal hierarchy of genetic lesions, we further charted a pathway of oncogenic events along which genes may drive lung adenocarcinoma metastasis, such as TAS2R31 and UMODL1, involving in G-protein coupled receptor protein signaling pathway.
The candidate genes identified in this study may become targets for the treatment of lung adenocarcinoma metastasis.
背景/目的：通过对肺腺癌外显子DNA的分析已鉴定出复发性基因突变，但其进展尚未得到广泛描述。对肿瘤突变图谱的研究为癌症基因组进化提供了新见解，并进一步揭示了体细胞突变、克隆对环境的适应性和自然选择之间的相互作用。癌症发展涉及基因组损伤、表观遗传失调和细胞增殖增加的循环，最终导致癌表型。
对4例伴有胸壁转移的IV期肺腺癌患者的原发性和转移性肿瘤组织进行了比较全外显子测序。原发性和转移性肿瘤均通过活检后手术切除进行诊断。将所有肿瘤标本切成几块，以评估肿瘤组织内潜在的异质性克隆。还获取了相邻的正常肺组织以提供种系突变背景。
通过基于非同义变体对癌症转移进展进行建模和分析，我们定义了癌症基因组的异质性程度，并在4例患者中确定了相似的癌症进化模式：转移是在原发性癌症形成后立即发生的早期事件，转移性肿瘤的进化与原发性肿瘤的进化持续且同时进行。通过表征遗传损伤的克隆层次结构，我们进一步绘制了一条致癌事件途径，基因可能沿着该途径驱动肺腺癌转移，例如涉及G蛋白偶联受体蛋白信号通路的TAS2R31和UMODL1。
本研究中鉴定出的候选基因可能成为治疗肺腺癌转移的靶点。
