Molecular profiling and analysis of genetic aberrations aimed at identifying potential therapeutic targets in fibrolamellar carcinoma of the liver

Abstract

Background Fibrolamellar carcinoma (FLC) is a rare primary liver cancer of young adults. A functional chimeric transcript resulting from the in‐frame fusion of the DNAJ homolog, subfamily B, member 1 (DNAJB1), and the catalytic subunit of protein kinase A (PRKACA) genes on chromosome 19 is believed to be unique in FLC, with a possible role in pathogenesis, yet with no established therapeutic value. The objective of the current study was to understand the molecular landscape of FLC and to identify potential novel therapeutic targets. Methods Archival fresh, formalin‐fixed, paraffin‐embedded samples from patients with FLC who prospectively consented to an institutional review board–approved protocol were analyzed using Memorial Sloan Kettering–Integrated Mutation Profiling of Actionable Cancer Targets (MSK‐IMPACT), a next‐generation sequencing assay encompassing up to 468 key cancer genes. Custom targeted RNA‐Seq was performed in selected patients. Demographics, treatment, and outcome data were collected prospectively. Survival outcomes were estimated and correlated with mutation and/or copy number alterations. Results A total of 33 tumor samples from 31 patients with FLC were analyzed. The median age of the patients at the time of diagnosis was 18 years and approximately 53% were women. The DNAJB1‐PRKACA fusion transcript was detected in 100% of patients. In 10 of 31 patients in which MSK‐IMPACT did not detect the fusion, its presence was confirmed by targeted RNA‐Seq. TERT promoter mutation was the second most common, and was detected in 7 patients. The median follow up was 30 months (range, 6‐153 months). The 3‐year overall survival rate was 84% (95% CI, 61%‐93%). Conclusions The DNAJB1‐PRKACA fusion transcript is nonspecific and nonsensitive to FLC. Its potential therapeutic value currently is under evaluation. Opportunities currently are under development for therapy that may be driven or related to the DNAJB1‐PRKACA fusion transcript or any therapeutic target identified from next‐generation sequencing in patients with FLC.

Fibrolamellar hepatocellular carcinoma that was successfully treated with surgical resection: a case report

“…However, recent studies have reported that this fusion gene is also detected in other pancreatic and biliary tumors 14 , whereas FLHCC without the fusion gene has also been reported. 15 We were not able to test this case for the DNAJB1-PRKACA alteration; however, the pathological features were typical of FLHCC and sufficient for its diagnosis. Further studies are needed to explain the roles of DNAJB1-PRKACA and other genes in the pathogenesis of FLHCC.…”

Organoid models of fibrolamellar carcinoma mutations reveal hepatocyte transdifferentiation through cooperative BAP1 and PRKAR2A loss

“…However, another possible scenario is the need of additional mutation(s) to complement/synergize with the chimeric fusion for the appearance of a more cancer-like phenotype 76 , possibly through a similar hepatocyte transdifferentiation event as observed for BAP1 KO ;PRKAR2A KO . Indeed, various genomic studies have identified additional mutations in some fusion-driven FLC tumors, such as those in TERT, CTNNB1 , or MUC4 6 , 77 . Finally, cell-to-cell contact with different liver cell types as well as changes in the niche environment or organ crosstalk may be important to ultimately drive cancer.…”

Development of pre-clinical murine models for fibrolamellar hepatocellular carcinoma

“…However, the small part of DNAJ1B fused to PKA in FLC tumors also contributes to tumor development in mice [27], an observation supported by biochemical and structural studies [31][32][33][34][35][36]. Few additional alterations have been found in the genome of FLC tumors, but accumulating evidence suggests a role for telomerase activity, MAPK signaling, and WNT signaling [26,27,35,[37][38][39][40][41].…”