ROS1 receptor tyrosine kinase, a druggable target, is frequently overexpressed in non-small cell lung carcinomas via genetic and epigenetic mechanisms.
BACKGROUND
Microarray analyses have revealed significantly elevated expression of the proto-oncogene ROS1 receptor tyrosine kinase in 20-30% of non-small cell lung carcinomas (NSCLC). Selective and potent ROS1 kinase inhibitors have recently been developed and oncogenic rearrangement of ROS1 in NSCLC identified.


METHODS
We performed immunohistochemical evaluation of expression of ROS1 kinase and its downstream molecules in 399 NSCLC cases. ROS1 expression in primary and recurring lesions of 92 recurrent NSCLC cases was additionally analyzed. To elucidate mechanism of expression, two ROS1-nonexpressing NSCLC cell lines (Calu6 and H358) and fresh frozen tissues from 28 consecutive NSCLC patients were examined for ROS1 promoter methylation status and ROS1 expression.


RESULTS
Overall expression rate of ROS1 was 22% (19% for adenocarcinomas and 25% for nonadenocarcinomas) in NSCLC. ROS1 expression was a worse prognostic factor for overall survival in adenocarcinomas of stage I NSCLC. In recurred NSCLC, ROS1 expression was significantly higher in recurring tumors (38%) than primary tumors (19%). Two NSCLC cell lines showed increased ROS1 expression after treatment with 5-aza-2'deoxycytidine and/or trichostatin A. Among the 14 adenocarcinomas examined, two (14%) showed more than twice the level of ROS1 expression in tumor tissue than was observed in matched normal tissue and statistically significant differences in the ROS1 promoter methylation level.


CONCLUSIONS
A subset of NSCLC revealed overexpression of ROS1 receptor tyrosine kinase, possibly in relation to epigenetic changes. ROS1 expression was an independent prognostic factor for overall survival in adenocarcinomas of stage I NSCLC. Further studies are needed to validate our results.
Department of Pathology, Seoul National University Bundang Hospital, Sungnam, Korea.
Hee Jin
HJ
Lee
Hyang Sook
HS
Seol
Joo Young
JY
Kim
Sung-Min
SM
Chun
Young-Ah
YA
Suh
Young-Soo
YS
Park
Sang-we
SW
Kim
Chang-Min
CM
Choi
Seung-Il
SI
Park
Dong Kwan
DK
Kim
Yong-Hee
YH
Kim
Se Jin
SJ
Jang
D000230:Adenocarcinoma / Q000378:metabolism* / Q000473:pathology; D002289:Carcinoma, Non-Small-Cell Lung / Q000378:metabolism* / Q000473:pathology; D045744:Cell Line, Tumor; D016009:Chi-Square Distribution; D019175:DNA Methylation; D044127:Epigenesis, Genetic; D005260:Female; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D007150:Immunohistochemistry; D053208:Kaplan-Meier Estimate; D008175:Lung Neoplasms / Q000378:metabolism* / Q000473:pathology; D008297:Male; D008875:Middle Aged; D009364:Neoplasm Recurrence, Local / Q000235:genetics / Q000378:metabolism*; D011401:Promoter Regions, Genetic; D016016:Proportional Hazards Models; D011505:Protein-Tyrosine Kinases / Q000235:genetics* / Q000378:metabolism*; D000090063:Proto-Oncogene Mas; D011518:Proto-Oncogene Proteins / Q000235:genetics* / Q000378:metabolism*; D051567:Proto-Oncogene Proteins c-vav / Q000378:metabolism; D050796:STAT3 Transcription Factor / Q000378:metabolism
C000715470:MAS1 protein, human; D000090063:Proto-Oncogene Mas; D011518:Proto-Oncogene Proteins; D051567:Proto-Oncogene Proteins c-vav; D050796:STAT3 Transcription Factor; C494086:STAT3 protein, human; C496621:VAV3 protein, human; D011505:Protein-Tyrosine Kinases; C062333:ROS1 protein, human