RSPO fusion transcripts in colorectal cancer in Japanese population.
R-spondin (RSPO) gene fusions have recently been discovered in a subset of human colorectal cancer (CRC) in the U.S. population; however, whether the fusion is recurrent in CRC arising in patients from the other demographic areas and whether it is specific for CRC remain uncertain. In this study, we examined 75 primary CRCs and 121 primary lung cancers in the Japanese population for EIF3E-RSPO2 and PTPRK-RSPO3 fusion transcripts using RT-PCR and subsequent sequencing analyses. Although the expression of EIF3E-RSPO2 and PTPRK-RSPO3 was not detected in any of the lung carcinomas, RSPO fusions were detected in three (4%) of the 75 CRCs. Two CRCs contained EIF3E-RSPO2 fusion transcripts, and another CRC contained PTPRK-RSPO3 fusion transcripts. Interestingly, in one of the two EIF3E-RSPO2 fusion-positive CRCs, a novel fusion variant form of EIF3E-RSPO2 was identified: exon 1 of EIF3E was connected to exon 2 of RSPO2 by a 351-bp insertion. A quantitative RT-PCR analysis revealed that RSPO mRNA expression was upregulated in the three CRCs containing RSPO fusion transcripts, while it was downregulated in nearly all of the other CRCs. An immunohistochemical analysis and a mutational analysis revealed that the RSPO fusion-containing CRC had a CDX2 cell lineage, was positive for mismatch repair protein expression, and had the wild-type APC allele. Finally, the forced expression of RSPO fusion proteins were shown to endow colorectal cells with an increased growth ability. These results suggest that the expression of RSPO fusion transcripts is related to a subset of CRCs arising in the Japanese population.
Department of Tumor Pathology, Hamamatsu University School of Medicine, 1-20-1 Handayama, Higashi Ward, Hamamatsu, 431-3192, Japan, kzshinmu@hama-med.ac.jp.
Kazuya
K
Shinmura
Tomoaki
T
Kahyo
Hisami
H
Kato
Hisaki
H
Igarashi
Shun
S
Matsuura
Satoki
S
Nakamura
Kiyotaka
K
Kurachi
Toshio
T
Nakamura
Hiroshi
H
Ogawa
Kazuhito
K
Funai
Masayuki
M
Tanahashi
Hiroshi
H
Niwa
Haruhiko
H
Sugimura
D000368:Aged; D044466:Asian People / Q000235:genetics*; D045744:Cell Line, Tumor; D049109:Cell Proliferation; D015179:Colorectal Neoplasms / Q000235:genetics*; D053843:DNA Mismatch Repair; D004252:DNA Mutational Analysis; D005091:Exons; D005260:Female; D050939:Gene Fusion; D006801:Humans; D036341:Intercellular Signaling Peptides and Proteins / Q000235:genetics* / Q000378:metabolism; D008175:Lung Neoplasms / Q000235:genetics; D008297:Male; D008875:Middle Aged; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D020133:Reverse Transcriptase Polymerase Chain Reaction; D019699:Thrombospondins / Q000235:genetics* / Q000378:metabolism; D000098907:R-Spondins
D036341:Intercellular Signaling Peptides and Proteins; D012333:RNA, Messenger; D019699:Thrombospondins; C475438:RSPO3 protein, human; D000098907:R-Spondins; C557408:Rspo2 protein, human