Loading…

Abstract 3404: Clinical significance of APOB inactivation in hepatocellular carcinoma

Hepatocellular carcinoma (HCC) is the seventh most common cancer and second the most lethal cancer globally. 5-year OS rates in US are only 11%. Sequencing of HCC genome revealed unexpected frequent mutations in serum proteins such as albumin (ALB) and apolipoprotein B (APOB), which are not frequent...

Full description

Saved in:
Bibliographic Details
Published in:Cancer research (Chicago, Ill.) Ill.), 2018-07, Vol.78 (13_Supplement), p.3404-3404
Main Authors: Lee, Gena, Kwak, Min Jun, Kim, Do Won, Koh, Jiwon, Joo, Eun Wook, Kah, Susie, Sim, Yeong-Eun, Yim, Sun Young, Lee, Ju-Seog
Format: Article
Language:English
Citations: Items that cite this one
Online Access:Get full text
Tags: Add Tag
No Tags, Be the first to tag this record!
Description
Summary:Hepatocellular carcinoma (HCC) is the seventh most common cancer and second the most lethal cancer globally. 5-year OS rates in US are only 11%. Sequencing of HCC genome revealed unexpected frequent mutations in serum proteins such as albumin (ALB) and apolipoprotein B (APOB), which are not frequently mutated in other cancers. However, clinical significance and underlying biology of loss of these serum proteins in HCC are currently unknown. Here we show that loss of APOB, major carrier of lipid in blood, in HCC is significantly associated with poor survival of HCC patients by applying comparative genomics approach that integrate genomic data from mouse models and human HCC tumors. We further show that loss of APOB leads to shifting balance of lipid metabolisms favoring for tumor growth. For development of genomic signature reflecting hepatic APOB activity and test and validation of its association with prognosis, we used unsupervised approach combined with supervised prediction models. First, gene expression signature were generated from Apob-silenced mouse livers and hepatic Apob-specific signature was identified by applying statistical analysis (P < 0.005 and 1.5-fold difference between Apob-silenced vs. Apob-Wt). Second, by applying unsupervised hierarchical clustering of mouse hepatic Apob signature in human HCC tumors first and constructing Bayesian prediction models later, HCC tumors with low APOB activity were identified. When HCC patients were stratified into APOB-high and APOB-low subgroups, overall survival (OS) rate and recurrence free survival (RFS) rate of patients in APOB-low group is significantly lower than those in APOB-high (P < 0.001), indicating that APOB activity in HCC is significantly associated with prognosis of patients. This association was validated in 4 independent cohorts of HCC patients (n=88, 240, 242, and 371 in total of 941 patients). Since APOB is one of major carrier proteins for lipid, loss of APOB in HCC would lead to accumulation of intracellular fatty acid. Many studies showed that fatty acid are necessary for proliferation of cancer cells as essential for cell membranes and de novo biogenesis rate of fatty acid is well associated with prognosis of cancer patients. APOB expression is negatively correlated with methylation of APOB promoter. Our study suggested potential novel strategy of cancer cells to increase supply of fatty acids for fast proliferation. HCC cells increase supply of intracellular fatty acids by inhi
ISSN:0008-5472
1538-7445
DOI:10.1158/1538-7445.AM2018-3404