Abstract | BACKGROUND: Recently, chromosomal rearrangements involving receptor tyrosine kinases (RTKs) have been described in common epithelial malignancies, including nonsmall cell lung cancer (NSCLC), colorectal cancer, and breast cancer. One of these RTKs, c-ros oncogene 1, receptor tyrosine kinase (ROS1), has been identified as a driver mutation in NSCLC, because its inhibition by crizotinib, an anaplastic lymphoma receptor tyrosine kinase (ALK)/met proto-oncogene hepatocyte growth factor receptor (MET)/ROS1 inhibitor, led to significant tumor shrinkage in ROS1-rearranged NSCLC. Currently, only human epidermal growth factor 2 (HER2)-targeted therapy in combination with chemotherapy has been successful in significantly prolonging the survival of patients with advanced gastric cancer (GC). There is a need for the discovery of additional novel targets in GC. METHODS: Anti-ROS1 immunohistochemistry (IHC) was used to screen 495 GC samples and was followed by simultaneous ROS1 break-apart fluorescence in situ hybridization (FISH) and reverse transcriptase-polymerase chain reaction (RT-PCR) analyses in IHC-positive samples. Fusion partners in ROS1-rearranged GC were determined by RT-PCR. In all 495 samples, HER2 amplification was identified with FISH, and MET expression was identified by IHC. RESULTS: Twenty-three tumor samples were ROS1 IHC-positive. Three of 23 patients were ROS1 FISH positive, HER2 FISH negative, and negative for MET overexpression; and 2 of those 3 patients harbored a solute carrier family 34 ( sodium phosphate), member 2 (SLC34A2)-ROS1 fusion transcripts. No fusion partner was identified in the third patient. Both patients who had SLC34A2-ROS1 transcripts had poorly differentiated histology with recurrence and death within 2 years of curative surgery. ROS1 IHC-positive status was not identified as an independent prognostic factor for overall survival. CONCLUSIONS: In this study, an SLC34A2-ROS1 rearrangement was identified in GC, and the results provide a rationale for investigating the clinical efficacy of ROS1 inhibitors in this unique molecular subset of GC. Society.
|
Authors | Jeeyun Lee, Seung Eun Lee, So Young Kang, In-Gu Do, Sujin Lee, Sang Yun Ha, Jeonghee Cho, Won Ki Kang, Jiryeon Jang, Sai-Hong Ignatius Ou, Kyoung-Mee Kim |
Journal | Cancer
(Cancer)
Vol. 119
Issue 9
Pg. 1627-35
(May 01 2013)
ISSN: 1097-0142 [Electronic] United States |
PMID | 23400546
(Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
|
Copyright | Copyright © 2013 American Cancer Society. |
Chemical References |
- MAS1 protein, human
- Proto-Oncogene Mas
- Proto-Oncogene Proteins
- Protein-Tyrosine Kinases
- ROS1 protein, human
|
Topics |
- Adenocarcinoma
(enzymology)
- Adult
- Aged
- Female
- Gene Rearrangement
- Humans
- Immunohistochemistry
- In Situ Hybridization, Fluorescence
- Male
- Middle Aged
- Protein-Tyrosine Kinases
(genetics)
- Proto-Oncogene Mas
- Proto-Oncogene Proteins
(genetics)
- Reverse Transcriptase Polymerase Chain Reaction
- Stomach Neoplasms
(enzymology)
|