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Genomic Analysis Revealed New Oncogenic Signatures in TP53-Mutant Hepatocellular Carcinoma

Kancherla, Venkatesh and Abdullazade, Samir and Matter, Matthias S. and Lanzafame, Manuela and Quagliata, Luca and Roma, Guglielmo and Hoshida, Yujin and Terracciano, Luigi M. and Ng, Charlotte K. Y. and Piscuoglio, Salvatore. (2018) Genomic Analysis Revealed New Oncogenic Signatures in TP53-Mutant Hepatocellular Carcinoma. Frontiers in genetics, 9. p. 2.

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Abstract

The TP53 gene is the most commonly mutated gene in human cancers and mutations in; TP53; have been shown to have either gain-of-function or loss-of-function effects. Using the data generated by The Cancer Genome Atlas, we sought to define the spectrum of; TP53; mutations in hepatocellular carcinomas (HCCs) and their association with clinicopathologic features, and to determine the oncogenic and mutational signatures in; TP53; -mutant HCCs. Compared to other cancer types, HCCs harbored distinctive mutation hotspots at V157 and R249, whereas common mutation hotspots in other cancer types, R175 and R273, were extremely rare in HCCs. In terms of clinicopathologic features, in addition to the associations with chronic viral infection and high Edmondson grade, we found that; TP53; somatic mutations were less frequent in HCCs with cholestasis or tumor infiltrating lymphocytes, but were more frequent in HCCs displaying necrotic areas. An analysis of the oncogenic signatures based on the genetic alterations found in genes recurrently altered in HCCs identified four distinct; TP53; -mutant subsets, three of which were defined by; CTNNB1; mutations, 1q amplifications or 8q24 amplifications, respectively, that co-occurred with; TP53; mutations. We also found that mutational signature 12, a liver cancer-specific signature characterized by T>C substitutions, was prevalent in HCCs with wild-type; TP53; or with missense; TP53; mutations, but not in HCCs with deleterious; TP53; mutations. Finally, whereas patients with HCCs harboring deleterious; TP53; mutations had worse overall and disease-free survival than patients with; TP53; -wild-type HCCs, patients with HCCs harboring missense; TP53; mutations did not have worse prognosis. In conclusion, our results highlight the importance to consider the genetic heterogeneity among; TP53; -mutant HCCs in studies of biomarkers and molecular characterization of HCCs.
Faculties and Departments:03 Faculty of Medicine
03 Faculty of Medicine > Bereich Querschnittsfächer (Klinik) > Pathologie USB
03 Faculty of Medicine > Departement Klinische Forschung > Bereich Querschnittsfächer (Klinik) > Pathologie USB
UniBasel Contributors:Piscuoglio, Salvatore
Item Type:Article, refereed
Article Subtype:Research Article
Publisher:Frontiers Media
ISSN:1664-8021
Note:Publication type according to Uni Basel Research Database: Journal article
Language:English
Identification Number:
Last Modified:25 Jan 2019 10:30
Deposited On:25 Jan 2019 10:30

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