TSC1/2 mutations define a molecular subset of HCC with aggressive behaviour and treatment implication

作者：Daniel Wai‐Hung Ho, Lo‐Kong Chan, Yung Tuen Chiu, Mingjing Xu, Ronnie T. P. Poon, Tan To Cheung, Chung Ngai Tang, Victor Wai‐Lun Tang, Irene Lai‐Oi Lo, Polly W.Y. Lam, Derek Tsz‐Wai Yau, Miao X Li, Chun‐Ming Wong, Irene Oi‐Lin Ng · 发表于：Gut · 年份：2016 · DOI：10.1136/gutjnl-2016-312734 · 被引用次数：110 · 研究领域：Tuberous Sclerosis Complex Research、PI3K/AKT/mTOR signaling in cancer、Polyomavirus and related diseases

Objective We investigated the mutational landscape of mammalian target of rapamycin (mTOR) signalling cascade in hepatocellular carcinomas (HCCs) with chronic HBV background, aiming to evaluate and delineate mutation-dependent mechanism of mTOR hyperactivation in hepatocarcinogenesis. Design We performed next-generation sequencing on human HCC samples and cell line panel. Systematic mutational screening of mTOR pathway-related genes was undertaken and mutant genes were evaluated based on their recurrence. Protein expressions of tuberous sclerosis complex (TSC)1, TSC2 and pRPS6 were assessed by immunohistochemistry in human HCC samples. Rapamycin sensitivity was estimated by colony-formation assay in HCC cell lines and the treatment was further tested using our patient-derived tumour xenograft (PDTX) models. Results We identified and confirmed multiple mTOR components as recurrently mutated in HBV-associated HCCs. Of significance, we detected frequent (16.2%, n=18/111) mutations of TSC1 and TSC2 genes in the HCC samples. The spectrum of TSC1/2 mutations likely disrupts the endogenous gene functions in suppressing the downstream mTOR activity through different mechanisms and leads to more aggressive tumour behaviour. Mutational disruption of TSC1 and TSC2 was also observed in HCC cell lines and our PDTX models. TSC -mutant cells exhibited reduced colony-forming ability on rapamycin treatment. With the use of biologically relevant TSC2 -mutant PDTXs, we demonstrated the therapeu...