Fibroblast growth factor receptor 2 tyrosine kinase fusions define a unique molecular subtype of cholangiocarcinoma

Abstract

Cholangiocarcinoma is an intractable cancer, with limited therapeutic options, in which the molecular mechanisms underlying tumor development remain poorly understood. Identification of a novel driver oncogene and applying it to targeted therapies for molecularly defined cancers might lead to improvements in the outcome of patients. We performed massively parallel whole transcriptome sequencing in eight specimens from cholangiocarcinoma patients without KRAS/BRAF/ROS1 alterations and identified two fusion kinase genes, FGFR2-AHCYL1 and FGFR2-BICC1. In reverse-transcriptase polymerase chain reaction (RT-PCR) screening, the FGFR2 fusion was detected in nine patients with cholangiocarcinoma (9/102), exclusively in the intrahepatic subtype (9/66, 13.6%), rarely in colorectal (1/149) and hepatocellular carcinoma (1/96), and none in gastric cancer (0/212). The rearrangements were mutually exclusive with KRAS/BRAF mutations. Expression of the fusion kinases in NIH3T3 cells activated MAPK and conferred anchorage-independent growth and in vivo tumorigenesis of subcutaneous transplanted cells in immune-compromised mice. This transforming ability was attributable to its kinase activity. Treatment with the fibroblast growth factor receptor (FGFR) kinase inhibitors BGJ398 and PD173074 effectively suppressed transformation. Conclusion: FGFR2 fusions occur in 13.6% of intrahepatic cholangiocarcinoma. The expression pattern of these fusions in association with sensitivity to FGFR inhibitors warrant a new molecular classification of cholangiocarcinoma and suggest a new therapeutic approach to the disease. (HEPATOLOGY 2014;59:1427-1434 C holangiocarcinoma (CC) is a highly malignant invasive carcinoma that arises through malignant transformation of cholangiocytes.1 It is an intractable tumor with poor prognosis, whose incidence and mortality rates are high in East Asia and have been rapidly increasing worldwide.1,2 CC can be subdivided into intrahepatic (ICC) and extrahepatic (ECC) types, which show distinct etiological and clinical features.2 ICC is the second most common primary hepatic malignancy after hepatocellular carcinoma, and is associated with hepatitis virus infection. Somatic mutations of KRAS and BRAF are the most common genetic alterations in CC.3,4 Surgical resection is the only curative treatment for CC, and no standard chemotherapy regimens have been established for inoperative cases or those showing recurrence after surgical resection. 5,6

DNAJB1-PRKACA is specific for fibrolamellar carcinoma

“…In addition, subsets of cholangiocarcinomas have recently been shown to have recurrent translocations. 7,8 However, none of the cholangiocarcinomas in this studied revealed a DNAJB1-PRKACA translocation.…”

Massive parallel sequencing uncovers actionable FGFR2–PPHLN1 fusion and ARAF mutations in intrahepatic cholangiocarcinoma

“…FGFR fusion events have been recently identified in several cancers. Multiple partners have been discovered including BICC1, AFF3, CASP7 and CCDC6 among others [17][18][19][20] . These different partners play an important role in the control of enforced oligomerization and subsequent trans-autophosphorylation and activation of the tyrosine kinase gene involved in the rearrangement 12,17,21 .…”

“…These data are consistent with recent reports where FGFR2 fusions were reported in iCCA (9/66, 14%) but rarely in HCC (1/98) (ref. 19). Nonetheless, the incidence of FGFR2 fusions strikingly differs across the iCCA published cohorts, with a range between 50% in small series 17,18 to 10-15% in series of up to 96 patients 19,20,30 .…”

“…In fact, one of such fusions (the EML-ALK fusion in lung cancer) has emerged as a druggable target and its inhibition leads to survival improvements 16 . Interestingly, a variety of FGFR2 gene fusions have been recently identified in iCCA [17][18][19][20] , suggesting that these events may represent novel candidate therapeutic targets and that similar strategies could be used for its clinical management.…”

E7090, a Novel Selective Inhibitor of Fibroblast Growth Factor Receptors, Displays Potent Antitumor Activity and Prolongs Survival in Preclinical Models

“…These abnormalities have been reported to be involved in cancer types including lung cancer (3)(4)(5)(6), breast cancer (3, 7), multiple myeloma (1), endometrial cancer (8), gastric cancer (9), glioblastoma (10), cholangiocarcinoma (11), and urothelial cancer (3,12,13). Therefore, FGFRs are considered promising targets for cancer therapy, and FGFR inhibitors may serve as therapeutic agents.…”