Analysis of DNA damage repair pathway gene mutations in Chinese patients with hepatocellular carcinoma

Population characteristics and incidence of DDR pathway mutations in patients with HCC

In this study, 1427 patients with hepatocellular carcinoma (concomitantly excluding other cancers) operated in our establishment during the last 5 years confirmed by a pathology were included, of which 86.8% were men and 30.9 % were over 60 years old. We first analyzed the DDR gene mutation. Of these patients, 18.8% carried somatic DDR gene mutations and only 3.5% carried germline DDR gene mutations. Among the DDR pathway, the HRR pathway had the highest mutation rate, which was 6.1%. The second was double-stranded (DS), FA and MMR, with mutations of 3.2%, 2.5% and 2.2%, respectively. The incidence of mutations in the NER, BER, and NHEJ pathways was relatively low (0.3%, 0.6%, and 0.6%, respectively) (Table 1).

Table 1 Population characteristics and incidence of DDR pathway mutations in patients with hepatocellular carcinoma.

Types of DDR Gene Mutations in HCC

Statistical analysis showed that the three most common types of mutations in DDR pathway genes were Loss (28.11%), Frameshift (21.89%) and Nonsense (20%). (Fig. 1).

Figure 1

The statistical figure for types of DDR pathway gene mutations in hepatocellular carcinoma.

Frequency of DDR pathway gene mutations in HCC

In terms of single gene mutation frequency, the gene with the highest incidence of somatic mutations was PTEN (5.2%), followed by ATM (2.6%), BRCA2 (2.2%) , SMARCA4 (1.6%), ATRX (1.4%), IDH1 (1.26%), FANCA (0.9%), PALB2 (0.8%) and MLH1 (0.7%) (Fig 2A). Compared to somatic mutations, the incidence of germline mutations was lower, less than 1%, and genes with higher mutation frequency were BLM (0.42%), BRCA1 (0.35%), FANCA ( 0.35%), MUTYH (0.35%), BRCA2 (0.28%) and BRIP1 (0.28%). (Fig. 2B).

Figure 2
Figure 2

Frequency of DDR pathway gene mutations in HCC. (A) The gene with the highest incidence of somatic mutations. (B) The gene with the highest incidence of germline mutations.

Correlation between DDR gene mutation and TMB in patients with HCC

TMB data were available in 1335 patients with a median TMB of 7.899 (0–83.818) Mut/Mb. We analyzed the association between DDR mutation and TMB, finding that TMB was significantly higher in HCC patients with somatic DDR mutations than in non-carriers (Fig. 3A), while TMB of patients HCC with DDR germline mutations did not differ in this study (Figure S1). Analysis of the effect of DDR mutations on TMB per pathway showed that TMB in patients with HRR, MMR, DS, and FA mutations was significantly higher than in wild-type patients (Fig. 3B–E ). Patients with NER and BER pathway mutations also showed a higher trend in TMB, but the difference has no statistical significance (Figure S2).

picture 3
picture 3

Correlation between DDR gene mutation and TMB in HCC. (A) The association between DDR somatic mutations and TMB. (BE) By pathway analysis, the associations between HRR, MMR, DS, FA and TMB. (F–O) By single gene analysis, the associations between RAD50, MSH2, FANCD2, ATM, MLH1, CHEK2, SMARCA4, FANCE, FANCC, WEE1 and TMB. All quantifications are presented as mean ± SD and p-values ​​calculated by t-test,*ppp

Single gene analysis results showed that mutations in DDR genes such as RAD50, MSH2, FANCD2, ATM, MLH1, CHEK2, SMARCA4, FANCE, FANCC, and WEE1 were significantly correlated with elevated TMB ( Fig. 3F–O).

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