Characterization of genes involved in chromatin remodeling complexes and their functional role in hepatocarcinogenesis.
Cell Biology
Final Report Abstract
From the clinical and histopathological point of view, hepatocellular carcinoma (HCC) is a highly heterogeneous disease resulting from a complex molecular background. As seen in other malignant solid tumors, HCC contains a complex genetic diversity and genomic instability, driving hepatocarcinogenesis. Regardless of numerous targeted agents, multiple clinical trials, implementing small molecular inhibitors and monoclonal antibodies into clinical practice, failed in recent years, and sorafenib remains to be the only agent proofing a benefit in overall survival. Among other reasons, inadequate patient selection, which led to a “diluted” treatment effect, is thought to be the reason of treatment failure. Therefore, future clinical trial design needs to implement the individual molecular profile to allocate patients to an adequate targeted treatment and next-generation sequencing studies promise to improve the tumor characterization to optimize personalized treatment for patients with HCC. Within this research fellowship project we were able to define 161 potential cancer driver genes participating in 11 intracellular pathways in HCC by performing whole exome sequencing of 242 hepatic tumors. Associations of mutations centered on three mutated genes related to specific risk factors: CTNNB1 (alcohol), TP53 (hepatitis B virus, HBV) and AXIN1. Furthermore, we identified 2 novel mutational signatures in HCC – signature 23, significantly associated with a new unknown mutagenic mechanism, and signature 24, associated with aflatoxin B1 – and demonstrated that 28% of HCC contain at least one alterations potentially targetable by US Food and Drug Administration (FDA)–approved drugs. Taking into account that the functionality of alterations needs to be further defined in future experimental studies, this could be the first promising step to develop genome-based clinical trials.
Publications
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Current Issues on Tumor Genomic Heterogeneity and its Implication in Clinical Practice. Hepatic Oncology 2015; Vol. 2, No. 3, Pages 291- 302
Schulze K., Zucman-Rossi J.
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Exome sequencing of 243 liver tumors identifies new mutational signatures and potential therapeutic targets; American Association for Cancer Research, Annual Meeting 2015, Philadelphia
Schulze K., Imbeaud S., Letouzé E., Alexandrov L., Calderaro J., Rebouissou S., Couchy G., Meiller C., Shinde J., Datta S., Soysouvanh F., Calatayud A., Pinyol R., Pelletier L., Balabaud C., Laurent A., Blanc J.F., Mazzaferro V., Calvo F., Villanueva A., Nault J.C., Bioulac-Sage P., Stratton M.R., Llovet J.M., Zucman- Rossi J.
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Exome sequencing of 243 liver tumors identifies new mutational signatures and potential therapeutic targets; European Association for the Study of the Liver, International Liver Congress 2015, Vienna
Schulze K., Imbeaud S., Letouzé E., Alexandrov L., Calderaro J., Rebouissou S., Couchy G., Meiller C., Soysouvanh F., Calatayud A., Pinyol R., Pelletier L., Balabaud C., Laurent A., Blanc J.F., Mazzaferro V., Calvo F., Villanueva A., Nault J.C., Bioulac-Sage P., Stratton M.R., Llovet J.M., Zucman-Rossi J.
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Exome sequencing of hepatocellular carcinomas identifies new mutational signatures and potential therapeutic targets. Nature Genetics 2015;47:505-11
Schulze K., Imbeaud S., Letouzé E., Alexandrov L., Calderaro J., Rebouissou S., Couchy G., Meiller C., Shinde J., Datta S., Soysouvanh F., Calatayud A., Pinyol R., Pelletier L., Balabaud C., Laurent A., Blanc J.F., Mazzaferro V., Calvo F., Villanueva A., Nault J.C., Bioulac-Sage P., Stratton M.R., Llovet J.M., Zucman-Rossi J.
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Translating molecular diversity of hepatocellular carcinoma into clinical practice. Molecular and Cellular Oncology 2015
Schulze K., Zucman-Rossi J.
