Department of Clinical Laboratory, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China.
Research Center for Tissue Engineering and Regenerative Medicine, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China.
PLoS Genet. 2023 Feb 22;19(2):e1010514. doi: 10.1371/journal.pgen.1010514. eCollection 2023 Feb.
Structural variations (SVs) are a key type of cancer genomic alterations, contributing to oncogenesis and progression of many cancers, including colorectal cancer (CRC). However, SVs in CRC remain difficult to be reliably detected due to limited SV-detection capacity of the commonly used short-read sequencing. This study investigated the somatic SVs in 21 pairs of CRC samples by Nanopore whole-genome long-read sequencing. 5200 novel somatic SVs from 21 CRC patients (494 SVs / patient) were identified. A 4.9-Mbp long inversion that silences APC expression (confirmed by RNA-seq) and an 11.2-kbp inversion that structurally alters CFTR were identified. Two novel gene fusions that might functionally impact the oncogene RNF38 and the tumor-suppressor SMAD3 were detected. RNF38 fusion possesses metastasis-promoting ability confirmed by in vitro migration and invasion assay, and in vivo metastasis experiments. This work highlighted the various applications of long-read sequencing in cancer genome analysis, and shed new light on how somatic SVs structurally alter critical genes in CRC. The investigation on somatic SVs via nanopore sequencing revealed the potential of this genomic approach in facilitating precise diagnosis and personalized treatment of CRC.
结构变异 (SVs) 是癌症基因组改变的主要类型之一，导致许多癌症的发生和进展，包括结直肠癌 (CRC)。然而，由于常用的短读测序对 SV 的检测能力有限，CRC 中的 SV 仍然难以可靠地检测到。本研究通过纳米孔全基因组长读测序对 21 对 CRC 样本中的体细胞 SV 进行了研究。从 21 名 CRC 患者中鉴定出 5200 个新的体细胞 SV（每个患者 494 个 SV）。鉴定出一个长 4.9-Mbp 的倒位，沉默 APC 的表达（通过 RNA-seq 证实），以及一个长 11.2-kbp 的倒位，改变 CFTR 的结构。检测到两个可能对致癌基因 RNF38 和肿瘤抑制基因 SMAD3 产生功能影响的新基因融合。RNF38 融合具有促进转移的能力，通过体外迁移和侵袭实验以及体内转移实验得到证实。这项工作突出了长读测序在癌症基因组分析中的各种应用，并揭示了体细胞 SV 如何在 CRC 中改变关键基因的结构。通过纳米孔测序对体细胞 SV 的研究揭示了这种基因组方法在促进 CRC 精确诊断和个体化治疗中的潜力。
