Abstract
Simple SummaryWe studied the relationship between enhancement of DNA repair and cancer aggressiveness, tumor immune microenvironment, and patient survival in 749 hepatocellular carcinoma (HCC) patients from 5 cohorts using a DNA repair pathway score. We show that the DNA repair pathway was enhanced by the stepwise carcinogenic process of HCC, notably in grade 3 compared to grade 1 or 2 HCC. DNA repair high HCC was associated with worse survival, elevated intratumor heterogeneity, and mutation load, but not with the fraction of immune cell infiltration nor cytolytic activity. The expression of proliferation- and other cancer aggressiveness-related gene sets was also increased. Interestingly, these features were more pronounced in low-grade compared to high-grade HCC. In conclusion, the DNA repair score may be used to understand the role of DNA repair pathways in patient prognosis and treatment sensitivity and be used to improve patient outcome. To our knowledge, this is the first study using DNA repair pathway-related gene set expression data to examine and validate the clinical relevance of DNA repair pathway activity in HCC.Hepatocellular carcinoma (HCC) is one of the most common malignancies and a leading cause of cancer-related deaths worldwide. In this study, a total of 749 HCC patients from 5 cohorts 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. Our findings suggest that the DNA repair pathway was not only enhanced by the stepwise carcinogenic process of HCC, but also significantly enhanced in grade 3 HCC compared with grade 1 and 2 tumors. DNA repair high HCC was associated with worse survival, elevated intratumor heterogeneity, and mutation load, but not with the fraction of immune cell infiltration nor immune response. HCC tumors with a DNA repair high score enriched the cell proliferation- and other cancer aggressiveness-related gene sets. Interestingly, these features were more pronounced in grade 1 and 2 HCC compared to 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. The DNA repair score may be used to better understand and predict prognosis in HCC.
Highlights
Liver cancer is the fourth most common cause of cancer-related deaths worldwide, and about 90% of primary liver cancers are hepatocellular carcinoma (HCC) [1]
In order to quantify the activity of the DNA repair pathway, we defined the DNA repair pathway score based on the gene set variation analysis (GSVA) score of the Molecular Signatures Database Hallmark DNA repair gene set (Table S1), using the methodology we previously reported [4,5,9,10,11]
The DNA repair score correlated with expression of BRCA1 and BRCA2, arguably the most clinically significant DNA repair genes associated with cancer prognosis and treatment sensitivity (Figure S1; Spearman’s rank correlation coefficient (r) = 0.576 (p < 0.01) and 0.471 (p < 0.01), respectively)
Summary
Liver cancer is the fourth most common cause of cancer-related deaths worldwide, and about 90% of primary liver cancers are hepatocellular carcinoma (HCC) [1]. Despite improvements in diagnosis and management of HCC, prognosis remains poor, with a 5-year survival rate less than 40% [2]. A prognostic biomarker based on cancer biology can tailor treatments according to patient prognosis. The DNA repair mechanisms activated following DNA damage are essential to suppress carcinogenesis. Carcinogens or metabolic processes can trigger genetic alteration, leading to genomic instability and malignant transformation. These DNA repair mechanisms counteract threats to genomic integrity [3]. Deficiencies in DNA damage repair pathways promote carcinogenesis. Many DNA repair mechanisms regulate gene functions as transcriptional factors or cofactors
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