*Division of Genome Biology, National Cancer Center Research Institute, Tokyo, Japan; †Department of Radiation Oncology, Gunma University Graduate School of Medicine, Gunma, Japan; ‡Division of Pathology and Clinical Laboratories, National Cancer Center Hospital, Tokyo, Japan; §Division of Genetics, National Cancer Center Research Institute, Tokyo, Japan; and ¶Division of Cancer Genomics, National Cancer Center Research Institute, Tokyo, Japan.
J Thorac Oncol. 2014 May;9(5):622-30. doi: 10.1097/JTO.0000000000000135.
Oncogenic RET fusion, caused by an inversion in chromosome 10, was recently identified as a driver mutation for the development of lung adenocarcinoma (LADC). Nevertheless, the molecular mechanism(s) underlying the rearrangement of the RET locus during lung carcinogenesis are unknown.
Genomic segments containing breakpoint junctions for RET fusions were cloned and analyzed by genomic polymerase chain reaction and genome capture sequencing using a next-generation sequencer to identify the mechanisms involved in DNA strand breaks and illegitimate joining of DNA ends. Of the 18 cases studied, 16 were identified by screening 671 LADC cases and two were previously published.
Almost all (17 of 18, 94%) of the breakpoints in RET were located within a 2.0-kb region spanning exon 11 to intron 11 and no breakpoint occurred within 4 bp of any other. This suggested that as in papillary thyroid carcinoma, DNA strand breaks formed at nonspecific sites within this region trigger RET fusion. Just over half of the RET fusions in LADC (10 of 18, 56%) were caused by simple reciprocal inversion, and two DNA-repair mechanisms, namely nonhomologous end joining and break-induced replication, were deduced to have contributed to the illegitimate joining of the DNA ends.
Oncogenic RET fusion in LADC occurs through multiple pathways and involves the illegitimate repair of DNA strand breaks through mechanisms different from those identified in papillary thyroid carcinoma, where RET fusion also functions as a driver mutation.
致癌 RET 融合是由 10 号染色体倒位引起的，最近被确定为肺腺癌（LADC）发展的驱动突变。然而，在肺癌发生过程中 RET 基因座重排的分子机制尚不清楚。
通过基因组聚合酶链反应和使用下一代测序仪的基因组捕获测序，克隆和分析包含 RET 融合断点连接的基因组片段，以鉴定涉及 DNA 链断裂和 DNA 末端非合法连接的机制。在研究的 18 个病例中，通过筛选 671 个 LADC 病例鉴定出 16 个，另外 2 个先前已发表。
几乎所有（18 个中的 17 个，94%）RET 的断点都位于跨越外显子 11 到内含子 11 的 2.0kb 区域内，并且没有任何其他的断点发生在 4bp 内。这表明，与甲状腺乳头状癌一样，DNA 链断裂在该区域的非特异性位点形成，触发 RET 融合。LADC 中超过一半的 RET 融合（18 个中的 10 个，56%）是由简单的相互倒位引起的，并且推断两种 DNA 修复机制，即非同源末端连接和断裂诱导复制，促成了 DNA 末端的非合法连接。
LADC 中的致癌 RET 融合是通过多种途径发生的，涉及通过与在甲状腺乳头状癌中鉴定的不同机制来修复 DNA 链断裂，在甲状腺乳头状癌中，RET 融合也是驱动突变。
