Abstract 3474: Loss of function mutations in APOB and their clinical significance in hepatocellular carcinoma
Authors: Lee Gena , Jeong Yun Seong , Kwak Min Jun , DoWon Kim , Lee Ju-Seog , Young Yim Sun 
Published: August 2019

APOB is major lipid binding proteins of low-density lipoprotein (LDL) particles and responsible for carrying fat molecules to cells within all tissues. High levels of APOB are known to be related to heart disease and vascular disease. Interestingly, recent The Cancer Genome Atlas (TCGA) study revealed that APOB is one of frequently mutated genes in multiple cancers including melanoma, liver cancer, stomach, esophageal, head and neck, uterine, and lung cancers (from &gt;20 to 10%). Majority mutations are considered to cause loss of function as they are truncation mutations, suggesting that APOB might have tumor suppressive activity. However, because of its physiological roles in circulating fat molecules in our body, APOB has never been studied in cancer-related setting and thus its clinical relevance or biological roles of APOB in cancer development is currently unknown. Here we show that loss of APOB in hepatocellular carcinoma (HCC) is significantly associated with poor survival of HCC patients by applying comparative genomics approach that integrate genomic data from mouse 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 by integrating gene expression data from mouse models and human HCC. When HCC patients were stratified into APOB-active and APOB-inactive subgroups, overall survival (OS) rate and recurrence free survival (RFS) rate of patients in APOB-inactive group is significantly lower than those in APOB-active (P &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). Gene network analysis revealed that many of the regulators involved in cell growth were activated in Apob-silenced livers. Many of the upregulated genes in Apob-silenced livers are direct downstream targets of Erbb2, Vegfa, and regulator of metastasis and cancer initiation cells Cd44. Consistent with activation of many tumor-promoting regulators, Tp53, a major tumor suppressor, was inactivated in Apob-silenced livers, suggesting that loss of Apob in the liver may provoke initiation of tumor development. More interestingly, proliferation of three liver cancer cells was significantly increased when expression of APOB was silenced by siRNAs, further suggesting functional roles of APOB in tumor development. 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, Yun Seong Jeong, Min Jun Kwak, Kim DoWon, Ju-Seog Lee, Yim Sun Young. Loss of function mutations in APOB and their clinical significance in hepatocellular carcinoma [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 3474.