ROS1-GOPC/FIG: a novel gene fusion in hepatic angiosarcoma

Abstract

Hepatic angiosarcoma (HAS) is a rare and highly lethal malignancy with few effective systemic treatments. Relatively little is known about the genetic abnormalities that drive this disease. As a result, there has been minimal progress towards applying targeted therapies to the treatment of HAS. We describe the first reported case of a patient with HAS that harbored a fusion of ROS1 with GOPC/FIG. Similar to other rearrangements involving ROS1, the resulting fusion protein is believed to act as a major driver of carcinogenesis and may be subject to inhibition by drugs that target ROS1 such as crizotinib. We then queried the MSK-IMPACT clinical sequencing cohort and cBioportal datasets, demonstrating the previously unknown prevalence of ROS1-GOPC fusions in soft tissue sarcomas and hepatobiliary cancers. Amplification of these genes was also found to correlate with reduced overall survival. This is followed by a review of the role played by ROS1 rearrangements in cancer, as well as the evidence supporting the use of targeted therapies against the resulting fusion protein. We suggest that testing for ROS1 fusion and, if positive, treatment with a targeted therapy could be considered at the time of diagnosis for patients with angiosarcoma. This report also highlights the need for further investigation into the molecular pathophysiology of this deadly disease.

Keywords: FIG; GOPC; ROS1; Targeted Therapy; angiosarcoma.

Figure 1. CT scan of the abdomen and pelvis with intravenous contrast showing multiple masses throughout the liver, later biopsy-proven hepatic angiosarcoma

Figure 2. Histologic and immunohistochemical analysis of the liver tumor

(A) Low-power view of the biopsy cores containing hemorrhagic and necrotic tumor, hematoxylin and eosin (H&E), original magnification ×40. (B) On higher magnification tumor cells form irregular anastomosing vascular channels lined by cells with hyperchromatic atypical nuclei (H&E, original magnification ×200). Tumor cells express the endothelial markers CD31 (C), and CD34 (D).

Figure 3. Frequency of ROS1 gene fusions in cancer

(A) Combined ROS1 fusion frequency with all known gene partners in a large pan-cancer dataset. Number of patients for each cancer subtype is shown in blue. NSCLC: Non-Small Cell Lung Cancer. (B) Oncoprint of ROS1 and GOPC copy number alterations in a small angiosarcoma (n = 12) project dataset taken from cBioportal is shown. PRD Diagnosis refers to patient reported response to initial diagnosis location of angiosarcoma.

Figure 4. Gain in ROS1 and GOPC copy number is associated with poor overall survival

Kaplan–Meier survival curves for overall survival of patients with or without co-occurring ROS1 and GOPC copy number gain from (A) TCGA Soft Tissue Sarcoma dataset and (B) TCGA Hepatocellular carcinoma provisional dataset from cBioportal database were generated. Total number of patients in the two categories is shown. ^*P ≤ 0.05 for Log-rank (Mantel Cox) test.