Abstract 4814: Inferring liver cancer evolution from spatial and temporal genomic heterogeneity

Abstract

Abstract Background & Aims: The molecular pathogenesis of primary liver cancer is extremely complex and heterogeneous, which was further complicated by multiple carcinogenesis. We aimed to elucidate the pathogenesis of multifocal primary liver cancer by genomic profiling. Methods: A patient with synchronous hepatocellular carcinoma (HCC) and intrahepatic cholangiocarcinoma (ICC) who underwent resection and experienced post-operative intrahepatic metastases (IMs) was enrolled. Multiregion whole-exome sequencing was applied on the three primary tumors and two IMs to infer tumor clonality and evolution. The mutational and expression profiles, clinical relevance (n = 236) and functional implications of the identified potential driver gene FAT4 in HCC were investigated. Results: In total, we identified 12, 184, 126, and 54 of protein coding mutation in the cirrhotic liver, two HCCs (designated as HCC-A and HCC-B) and one ICC respectively. The mutational data of the two HCCs and one ICC showed almost no overlaps, suggesting that they developed through an accumulation of complete different sets of genetic alterations. For each tumor, multiregion sequencing data showed varied intratumoral heterogeneity (18.1% in HCC-A, 15.7% in HCC-B, 45.6% in ICC). The mutational profile of two IMs showed obvious similarity with HCC-A (87.6% and 87.7% shared with HCC-A respectively), rather than HCC-B and ICC tumors, indicating that they originated from HCC-A. Notably, FAT4 was the only gene that mutated in both HCCs and the two IMs, but in different locations (HCC-A and two IMs have the same G to A mutation at the coding position 2530, while HCC-B genomes have the A to C mutation at the coding position 14804). Prevalence screen revealed that FAT4 was mutated in over 15% of HCC patients and also several HCC cell lines. Significant down-regulation of FAT4 mRNA and protein expression was found in HCC, and loss of FAT4 independently correlated with early recurrence in HCC patients. In HCC cell lines, knockdown of FAT4 promoted and re-expression of FAT4 reduced cell growth and invasion. Conclusions: Spatial and temporal dissection of genomic alterations during the progression of liver cancer may help elucidate the basis for its dismal prognosis. FAT4 acts as a putative tumor suppressor that is frequently inactivated in human HCC. Citation Format: Qiang Gao, Zhi-Chao Wang, Rui-Bin Xi, Jia Fan. Inferring liver cancer evolution from spatial and temporal genomic heterogeneity. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 4814. doi:10.1158/1538-7445.AM2015-4814