Abstract 2072: DNA repair pathway score is associated with cancer aggressiveness and worse survival in hepatocellular carcinoma (HCC)
Authors: Oshi Masanori , Kim Tae Hee , Tokumaru Yoshihisa , Yan Li , Matsuyama Ryusei , Endo Itaru , Cherkassky Leonid , Takabe Kazuaki 
Published: July 2021

Abstract
Background: Hepatocellular carcinoma (HCC) is one of the most common malignancies and a leading cause of cancer-related deaths worldwide. A prognostic biomarker based on cancer biology can tailor treatments according to patient prognosis. DNA repair mechanisms activated following DNA damage are essential to suppress carcinogenesis. Hence, deficiencies in DNA damage repair pathways promote carcinogenesis. The role of DNA repair genes in HCC is actively being investigated, but contradictory reports on some DNA repair-related genes have complicated our overall understanding of DNA repair in HCC progression. Though it is important to study the function of each individual DNA repair-related gene, it is more important to understand the role of the entire DNA repair pathway in HCC progression. We hypothesize that the enhancement of the DNA repair pathway is associated with worse survival in HCC patients.
Method: A total of 749 HCC patients from 5 cohorts (TCGA, GSE6764, GSE89377, GSE56545, GSE76427) were studied to examine the relationships between enhancement of DNA repair and cancer aggressiveness, tumor immune microenvironment, and patient survival in HCC utilizing a DNA repair pathway score, which was calculated by Gene Set Variation Analysis (GSVA) with Hallmark DNA repair gene set.
Results: We found that DNA repair pathway was enhanced by stepwise carcinogenic process of HCC and significantly enhanced in higher grade HCC compared with low grade tumor in two cohorts (both p &lt; 0.001). DNA repair high HCC was associated with worse survival (disease-free survival: p &lt; 0.001, disease-specific survival: p = 0.002, and overall survival: p &lt; 0.001), elevated intratumor heterogeneity (p = 0.036) and mutation load (p &lt; 0.001), but not with fraction of immune cell infiltration nor immune response in the TCGA cohort. HCC tumors with DNA repair high score enriched proliferation-related (E2F targets, G2M checkpoint, mitotic spindle, MYC target v1 and v2) and other cancer aggressiveness-related (unfolded protein response, PI3K/AKT/MTOR signaling, MTORC1, notch signaling, and WNT-β catenin signaling) gene sets. Interestingly, these features were more pronounced in early HCC compared to advanced HCC. DNA repair high HCC was associated with elevated mutation load, enriched proliferation- and other cancer aggressiveness-related gene sets and was associated with worse survival in early (grade 1 and grade 2) but not in advanced (grade 3) HCC. To our knowledge, this is the first study to use DNA repair pathway-related gene set expression data to examine and validate the clinical relevance of DNA repair pathway activity in HCC.
Conclusion: The DNA repair score may be used to better understand and predict prognosis in HCC.
Citation Format: Masanori Oshi, Tae Hee Kim, Yoshihisa Tokumaru, Li Yan, Ryusei Matsuyama, Itaru Endo, Leonid Cherkassky, Kazuaki Takabe. DNA repair pathway score is associated with cancer aggressiveness and worse survival in hepatocellular carcinoma (HCC) [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2021; 2021 Apr 10-15 and May 17-21. Philadelphia (PA): AACR; Cancer Res 2021;81(13_Suppl):Abstract nr 2072.