DNA Damage Repair Classifier Defines Distinct Groups in Hepatocellular Carcinoma

Abstract

DNA repair pathways have been associated with variability in hepatocellular carcinoma (HCC) clinical outcomes, but the mechanism through which DNA repair varies as a function of liver regeneration and other HCC characteristics is poorly understood. We curated a panel of 199 genes representing 15 DNA repair pathways to identify DNA repair expression classes and evaluate their associations with liver features and clinicopathologic variables in The Cancer Genome Atlas (TCGA) HCC study. We identified two groups in HCC, defined by low or high expression across all DNA repair pathways. The low-repair group had lower grade and retained the expression of classical liver markers, whereas the high-repair group had more clinically aggressive features, increased p53 mutant-like gene expression, and high liver regenerative gene expression. These pronounced features overshadowed the variation in the low-repair subset, but when considered separately, the low-repair samples included three subgroups: L1, L2, and L3. L3 had high DNA repair expression with worse progression-free (HR 1.24, 95% CI 0.81–1.91) and overall (HR 1.63, 95% CI 0.98–2.71) survival. High-repair outcomes were also significantly worse compared with the L1 and L2 groups. HCCs vary in DNA repair expression, and a subset of tumors with high regeneration profoundly disrupts liver biology and poor prognosis.

DNA damage repair-related gene signature for identifying the immune status and predicting the prognosis of hepatocellular carcinoma

“…Our analysis revealed that the high-risk group was significantly associated with a shorter OS, advanced TNM stage, and higher tumor grade. Moreover, independent prognostic analysis confirmed that the risk score was an independent predictor of OS, this is similar to previous findings that high repair groups tend to be accompanied by a worse prognosis 15 .…”

“…Some DNA damage repair genes (DDRGs) have been employed to forecast the overall survival (OS) of HCC in addition to serum indicators 14 . Recent findings have shown that HCC was categorized into high-repair and low-repair groups based on the expression of DDRGs, and that the high-repair group had a worse prognosis, increased expression of p53 mutation-like genes, and more clinically aggressive features compared to the low-repair group 15 . However, additional research is necessary to determine the exact mechanism by which DDR causes cancer in HCC.…”

WHSC1 is involved in DNA damage, cellular senescence and immune response in hepatocellular carcinoma progression

“… 1 It has been reported that DDR is involved in prognosis, tumour initiation, metastasis and antitumor immune responses. 2 , 3 DDR status has been confirmed to serve as a potential biomarker to predict opposite clinical prognosis of immunotherapy. WHSC1 encodes a SET domain‐containing histone methyltransferase, which could catalyse the di‐methylation of H3K36 to involve in gene transcriptional regulation.…”

“…DDR pathway has become the target of antitumour drugs 1 . It has been reported that DDR is involved in prognosis, tumour initiation, metastasis and antitumor immune responses 2,3 . DDR status has been confirmed to serve as a potential biomarker to predict opposite clinical prognosis of immunotherapy.…”

BCL11B expression in hepatocellular carcinoma relates to chemosensitivity and clinical prognosis

“…[26][27][28] Hepatocellular carcinoma (HCC) is a malignancy related to DNA damage and mutagenesis caused by various hepatitis caused by virus, fatty infiltration, and alcoholic liver disease, which leads to carcinogenesis. 29 Some studies have recently reported that DNA repair signaling pathway in HCC cells contributed to worse prognosis [30][31][32][33] ; however, no detailed mechanisms have been reported in this regard. Based on the role of BCL11B in biology, it is reasonable to hypothesize that BCL11B is involved in the clinical course of HCC as it is treated with various DNA-damaging chemotherapy and radiotherapy agents.…”