TY - JOUR
T1 - Molecular mechanisms underlying oncogenic RET fusion in lung adenocarcinoma
AU - Mizukami, Tatsuji
AU - Shiraishi, Kouya
AU - Shimada, Yoko
AU - Ogiwara, Hideaki
AU - Tsuta, Koji
AU - Ichikawa, Hitoshi
AU - Sakamoto, Hiromi
AU - Kato, Mamoru
AU - Shibata, Tatsuhiro
AU - Nakano, Takashi
AU - Kohno, Takashi
PY - 2014/5
Y1 - 2014/5
N2 - BACKGROUND:: 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. METHODS:: 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. RESULTS:: 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. CONCLUSIONS:: 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.
AB - BACKGROUND:: 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. METHODS:: 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. RESULTS:: 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. CONCLUSIONS:: 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.
KW - DNA strand break
KW - Gene fusion
KW - Lung adenocarcinoma
KW - Molecular target therapy
KW - Personalized medicine
KW - RET
UR - http://www.scopus.com/inward/record.url?scp=84899472081&partnerID=8YFLogxK
U2 - 10.1097/JTO.0000000000000135
DO - 10.1097/JTO.0000000000000135
M3 - 学術論文
C2 - 24722152
AN - SCOPUS:84899472081
SN - 1556-0864
VL - 9
SP - 622
EP - 630
JO - Journal of Thoracic Oncology
JF - Journal of Thoracic Oncology
IS - 5
ER -