Smith Markia A, Van Alsten Sarah C, Walens Andrea, Damrauer Jeffrey S, Maduekwe Ugwuji N, Broaddus Russell R, Love Michael I, Troester Melissa A, Hoadley Katherine A
Department of Pathology and Laboratory Medicine, School of Medicine, University of North Carolina, Chapel Hill, NC 27599, USA.
Department of Epidemiology, Gillings School of Global Public Health, University of North Carolina, Chapel Hill, NC 27599, USA.
Cancers (Basel). 2022 Sep 1;14(17):4282. doi: 10.3390/cancers14174282.
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修复通路已被证明与肝细胞癌（HCC）的临床预后差异有关，但DNA修复如何随肝再生及其他HCC特征而变化的机制仍知之甚少。我们精心挑选了一组代表15条DNA修复通路的199个基因，以识别DNA修复表达类别，并在癌症基因组图谱（TCGA）的HCC研究中评估它们与肝脏特征及临床病理变量的关联。我们在HCC中识别出两组，由所有DNA修复通路的低表达或高表达定义。低修复组的肿瘤分级较低，并保留了经典肝脏标志物的表达，而高修复组具有更具临床侵袭性的特征、p53突变样基因表达增加以及肝脏再生基因高表达。这些显著特征掩盖了低修复亚组中的差异，但单独考虑时，低修复样本包括三个亚组：L1、L2和L3。L3具有高DNA修复表达，无进展生存期（HR 1.24，95%CI 0.81 - 1.91）和总生存期（HR 1.63，95%CI 0.98 - 2.71）较差。与L1和L2组相比，高修复组的预后也明显更差。HCC的DNA修复表达存在差异，并且具有高再生能力的肿瘤亚组会严重破坏肝脏生物学并导致预后不良。
