ROS1 rearrangements are uncommon in biliary tract cancers

Abstract

Biliary tract cancers (BTCs) are a pool of diseases with poor prognosis and there is no orphan drug available. Currently, no molecular targets have been tested as druggable oncogenic drivers. C-ros oncogene 1 (ROS1) rearrangements have been previously described in various tumors, including BTCs; however, data regarding their incidence and biological significance are controversial. Therefore, a retrospective multicenter study was performed to assess the incidence of ROS1 rearrangements in BTCs by means of immunohistochemistry and fluorescence in situ hybridization (FISH). The present study failed to demonstrate ROS1 expression in a multicenter series of 150 cases with BTCs and revealed that D4D6 was the most specific clone compared with other ROS1 primary antibodies, namely PA1-30318 and EPMGHR2. Notably, negative results obtained with D4D6 completely matched to data sorted out by FISH analysis, thus confirming a lack of ROS1 gene rearrangements in BTCs and false positive results when PA1-30318 and EPMGHR2 clones were used. These results suggest that ROS1 rearrangements may not be targets for molecular therapy of BTCs with specific inhibitors.

Keywords: ROS1 rearrangements; biliary tract cancers; biomarker; fluorescence in situ hybridization; immunohistochemistry; molecular target.

Figure 1.

Representative case of intrahepatic CAC. (A) H&E staining of intrahepatic CAC tissue. (B) IHC assay characterized by negative ROS1 staining using the monoclonal D4D6 Ab. (C) IHC assay characterized by positive ROS1 expression using the polyclonal PA1-30318 and (D) the monoclonal EPMGHR2 Abs. (E) Break-apart fluorescence in situ hybridization probe did not reveal gene rearrangements. Normal fused signals are indicated. (F) A case of ROS1 rearrangement detected with the D4D6 Ab in lung adenocarcinoma served as a positive external control in each bath. (A-D and F) Scale bar, 50 mm; (E) Scale bar, 5 mm. CAC, cholangiocarcinoma; H&E, hematoxylin-eosin; IHC, immunohistochemistry; Ab, antibody; ROS1, c-ros oncogene 1.