Peng Yizhou, Yuan Chongze, Tao Xiaoting, Zhao Yue, Yao Xingxin, Zhuge Lingdun, Huang Jianwei, Zheng Qiang, Zhang Yue, Hong Hui, Chen Haiquan, Sun Yihua
Department of Thoracic Surgery, Fudan University Shanghai Cancer Center, Shanghai 200032, China.
Department of Oncology, Shanghai Medical College, Fudan University, Shanghai 200032, China.
Transl Lung Cancer Res. 2020 Jun;9(3):670-681. doi: 10.21037/tlcr-19-401.
Intratumoral heterogeneity is a crucial factor to the outcome of patients and resistance to therapies, in which structural variants play an indispensable but undiscovered role.
We performed an integrated analysis of optical mapping and whole-genome sequencing on a primary tumor (PT) and matched metastases including lymph node metastasis (LNM) and tumor thrombus in the pulmonary vein (TPV). Single nucleotide variants, indels and structural variants were analyzed to reveal intratumoral genetic heterogeneity among tumor cells in different sites.
Our results demonstrated there were less nonsynonymous somatic variants shared with PT in LNM than in TPV, while there were more structural variants shared with PT in LNM than in TPV. More private variants and its affected genes associated with tumorigenesis and progression were identified in TPV than in LNM. It should be noticed that optical mapping detected an average of 77.1% (74.5-78.5%) large structural variants (>5,000 bp) not detected by whole-genome sequencing and identified several structural variants private to metastases.
Our study does demonstrate structural variants, especially large structural variants play a crucial role in intratumoral genetic heterogeneity and optical mapping could make up for the deficiency of whole-genome sequencing to identify structural variants.
肿瘤内异质性是影响患者预后和治疗耐药性的关键因素，其中结构变异发挥着不可或缺但尚未被发现的作用。
我们对原发性肿瘤（PT）以及匹配的转移灶进行了光学图谱和全基因组测序的综合分析，转移灶包括肺静脉中的淋巴结转移（LNM）和肿瘤血栓（TPV）。分析单核苷酸变异、插入缺失和结构变异，以揭示不同部位肿瘤细胞之间的肿瘤内基因异质性。
我们的结果表明，与原发性肿瘤相比，LNM中与PT共享的非同义体细胞变异比TPV中少，而LNM中与PT共享的结构变异比TPV中多。与LNM相比，TPV中鉴定出更多与肿瘤发生和进展相关的私有变异及其受影响的基因。值得注意的是，光学图谱检测到平均77.1%（74.5 - 78.5%）的大结构变异（>5,000 bp）未被全基因组测序检测到，并鉴定出几个转移灶特有的结构变异。
我们的研究确实表明结构变异，尤其是大结构变异在肿瘤内基因异质性中起关键作用，并且光学图谱可以弥补全基因组测序在识别结构变异方面的不足。
