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Cancers 2018, 10(10), 367; https://doi.org/10.3390/cancers10100367

Molecular Scoring of Hepatocellular Carcinoma for Predicting Metastatic Recurrence and Requirements of Systemic Chemotherapy

1
Department of Gastroenterology and Hepatology, Faculty of Medicine, Kindai University, 377-2 Ohno-higashi, Osaka-sayama, Osaka 589-8511, Japan
2
Department of Medical Oncology, Kitano Hospital, 2-4-20 Ohgi-machi, Kita-ku, Oaska 530-8511, Japan
3
Division Hepato-Biliary-Pancreatic Surgery and Transplantation, Department of Surgery, Kyoto University Graduate School of Medicine, 54 Karahara-cho, Syogoin, Sakyo-ku, Kyoto 606-8507, Japan
*
Author to whom correspondence should be addressed.
Received: 4 September 2018 / Revised: 25 September 2018 / Accepted: 26 September 2018 / Published: 29 September 2018
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Abstract

Hepatocellular carcinoma (HCC) causes one of the most frequent cancer-related deaths; an HCC subset shows rapid progression that affects survival. We clarify molecular features of aggressive HCC, and establish a molecular scoring system that predicts metastasis after curative treatment. In total, 125 HCCs were examined for TP53, CTNNB1, and TERT promoter mutation, methylation of 8 tumor suppressor genes, and 3 repetitive DNA sequences to estimate promoter hypermethylation and global hypomethylation. A fractional allelic loss (FAL) was calculated to represent chromosomal instability through microsatellite analysis. Molecular subclasses were determined using corresponding and hierarchical clustering analyses. Next, twenty-five HCC patients who underwent liver transplantation were analyzed for associations between molecular characteristics and metastatic recurrence; survival analyses were validated using a publicly available dataset of 376 HCC cases from the Cancer Genome Atlas (TCGA). An HCC subtype characterized by TP53 mutation, high FAL, and global hypomethylation was associated with aggressive tumor characteristics, like vascular invasion; CTNNB1 mutation was a feature of the less-progressive phenotype. A number of molecular risk factors, including TP53 mutation, high FAL, significant global hypomethylation, and absence of CTNNB1 mutation, were noted to predict shorter recurrence-free survival in patients who underwent liver transplantation (p = 0.0090 by log-rank test). These findings were validated in a cohort of resected HCC cases from TCGA (p = 0.0076). We concluded that molecular risks determined by common genetic and epigenetic alterations could predict metastatic recurrence after curative treatments, and could be a marker for considering systemic therapy for HCC patients. View Full-Text
Keywords: hepatocellular carcinoma; recurrence; molecular subclass; mutation; methylation; chromosomal alteration; liver transplantation; systemic chemotherapy hepatocellular carcinoma; recurrence; molecular subclass; mutation; methylation; chromosomal alteration; liver transplantation; systemic chemotherapy
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Nishida, N.; Nishimura, T.; Kaido, T.; Minaga, K.; Yamao, K.; Kamata, K.; Takenaka, M.; Ida, H.; Hagiwara, S.; Minami, Y.; Sakurai, T.; Watanabe, T.; Kudo, M. Molecular Scoring of Hepatocellular Carcinoma for Predicting Metastatic Recurrence and Requirements of Systemic Chemotherapy. Cancers 2018, 10, 367.

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