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Review
. 2015 Sep 30;5(4):2464-76.
doi: 10.3390/biom5042464.

Molecular Process Producing Oncogene Fusion in Lung Cancer Cells by Illegitimate Repair of DNA Double-Strand Breaks

Affiliations
Review

Molecular Process Producing Oncogene Fusion in Lung Cancer Cells by Illegitimate Repair of DNA Double-Strand Breaks

Yoshitaka Seki et al. Biomolecules. .

Abstract

Constitutive activation of oncogenes by fusion to partner genes, caused by chromosome translocation and inversion, is a critical genetic event driving lung carcinogenesis. Fusions of the tyrosine kinase genes ALK (anaplastic lymphoma kinase), ROS1 (c-ros oncogene 1), or RET (rearranged during transfection) occur in 1%-5% of lung adenocarcinomas (LADCs) and their products constitute therapeutic targets for kinase inhibitory drugs. Interestingly, ALK, RET, and ROS1 fusions occur preferentially in LADCs of never- and light-smokers, suggesting that the molecular mechanisms that cause these rearrangements are smoking-independent. In this study, using previously reported next generation LADC genome sequencing data of the breakpoint junction structures of chromosome rearrangements that cause oncogenic fusions in human cancer cells, we employed the structures of breakpoint junctions of ALK, RET, and ROS1 fusions in 41 LADC cases as "traces" to deduce the molecular processes of chromosome rearrangements caused by DNA double-strand breaks (DSBs) and illegitimate joining. We found that gene fusion was produced by illegitimate repair of DSBs at unspecified sites in genomic regions of a few kb through DNA synthesis-dependent or -independent end-joining pathways, according to DSB type. This information will assist in the understanding of how oncogene fusions are generated and which etiological factors trigger them.

Keywords: fusion; lung cancer; non-homologous end-joining; oncogene; synthesis-dependent end-joining.

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Figures

Figure 1
Figure 1
Mutually exclusive occurrence of oncogene aberrations in lung adenocarcinomas (LADC). Data on patients in Japan (A) and of European descent (B) were generated by summarizing the results of previous reports. Molecular target drugs for each oncogene aberrations are shown in blue (approved for lung cancer) or black (in clinical or preclinical studies). Anaplastic lymphoma kinase (ALK), c-ros oncogene 1 (ROS1), and rearranged during transfection (RET) oncogene fusions are present in a subset of LADCs in both populations.
Figure 2
Figure 2
Cluster of breakpoints in oncogenes and partner genes. (A) Chromosome inversion and translocation producing oncogene fusions. (B–D) Distribution of breakpoints in ALK and its major partner gene EML4 (B), ROS1 and its major partner gene CD74 (C), and RET and its major partner gene KIF5B (D). Yellow arrowheads indicate the locations of breakpoints for fusions in 41 Japanese LADC cases. All these cases were identified in a Japanese LADC cohort of 608 cases [8]. Breakpoints for chromosome rearrangements were identified by next-generation sequencing and/or genomic PCR analyses of tumor DNAs as previously described [9]. Breakpoint cluster regions are gray-hatched for partner genes and orange-hatched for oncogenes. Breakpoints in tumors of smokers are marked by asterisks.
Figure 3
Figure 3
Deduction of joining repair pathways based on the structure of breakpoint junctions. (A) A representative case in which reciprocal fusion was determined to be caused by non-homologous end joining (NHEJ). Overlapping and deleted nucleotides at breakpoint junctions are indicated; (B) A representative case in which reciprocal fusion occurred with duplication of a genomic segment (indicated by black rectangle); (C) Molecular processes causing gene fusions in LADC. Illegitimate DSB repair by synthesis-dependent end-joining (SDEJ) and NHEJ produces oncogene fusion. The pathway used might depend on the type of DSB, i.e., replication-associated or not; (D) Deduced process of reciprocal EML4-ALK fusion by SDEJ causing duplication of an ALK genome segment at breakpoint junctions, as in the case of AD09-055T (Figure 3B).
Figure 3
Figure 3
Deduction of joining repair pathways based on the structure of breakpoint junctions. (A) A representative case in which reciprocal fusion was determined to be caused by non-homologous end joining (NHEJ). Overlapping and deleted nucleotides at breakpoint junctions are indicated; (B) A representative case in which reciprocal fusion occurred with duplication of a genomic segment (indicated by black rectangle); (C) Molecular processes causing gene fusions in LADC. Illegitimate DSB repair by synthesis-dependent end-joining (SDEJ) and NHEJ produces oncogene fusion. The pathway used might depend on the type of DSB, i.e., replication-associated or not; (D) Deduced process of reciprocal EML4-ALK fusion by SDEJ causing duplication of an ALK genome segment at breakpoint junctions, as in the case of AD09-055T (Figure 3B).
Figure 4
Figure 4
Deduction of non-homologous end joining (NHEJ) modes based on the structures of breakpoint junctions. (A and B) Representative cases in which reciprocal fusion was deduced to be caused by canonical NHEJ. Joining was performed without (A) and with (B) nucleotide insertions. (C) Representative cases in which reciprocal fusion was deduced to be caused by alt-EJ. Joining was deduced to involve microhomologies of three or four base pairs. C, NHEJ causing gene fusions in LADC. Canonical NHEJ is a major NHEJ mode used for DNA end-joining.

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