Abstract 3404: Clinical significance of APOB inactivation in hepatocellular carcinoma
Authors: Gena Lee, Min Jun Kwak, Do Won Kim, Jiwon Koh, Eun Wook Joo, Susie Kah, Yeong-Eun Sim, Sun Young Yim, Ju-Seog Lee
Journal: Cancer Research (2018)

Abstract 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 &amp;lt; 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 &amp;lt; 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 inhibiting export of fatty acids through inactivation of APOB. Further analysis of multiple genomic data revealed oncogenic YAP1 are highly active in APOB-low subgroup as evidenced by expression of downstream targets such as FOXM1 and TEAD4, suggesting that alteration in lipid metabolism could lead to activation of YAP1. For the first time, we showed that APOB inactivation has a clinical impact in HCC patients with significant alteration in regulators associated with tumorigenesis. Citation Format: Gena Lee, Min Jun Kwak, Do Won Kim, Jiwon Koh, Eun Wook Joo, Susie Kah, Yeong-Eun Sim, Sun Young Yim, Ju-Seog Lee. Clinical significance of APOB inactivation in hepatocellular carcinoma [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 3404.