在循环肿瘤DNA中检测到的TP53 R249S突变与接受或未接受肝切除术的肝细胞癌患者的预后相关。

TP53 R249S mutation detected in circulating tumour DNA is associated with Prognosis of hepatocellular carcinoma patients with or without hepatectomy.

作者信息

Shen Ting, Li Shan-Feng, Wang Jia-Lin, Zhang Ting, Zhang Song, Chen Hai-Tao, Xiao Qian-Yi, Ren Wei-Hua, Liu Chao, Peng Bo, Ji Xiao-Na, Yang Yang, Lu Pei-Xin, Chen Tao-Yang, Yu Long, Ji Yuan, Jiang De-Ke

机构信息

State Key Laboratory of Organ Failure Research, Guangdong Key Laboratory of Viral Hepatitis Research, Institutes of Liver Diseases Research of Guangdong Province, Department of Infectious Diseases and Hepatology Unit, Nanfang Hospital, Southern Medical University, GuangZhou, China.

Institute of Cancer, Affiliated Hospital of Jiangnan University, Wuxi, China.

出版信息

Liver Int. 2020 Nov;40(11):2834-2847. doi: 10.1111/liv.14581. Epub 2020 Jul 7.

DOI:10.1111/liv.14581

PMID:32594568

Abstract

BACKGROUND AND AIMS

Somatic mutation R249S in TP53 is highly common in hepatocellular carcinoma (HCC). We aim to investigate the effects of R249S in ctDNA on the prognosis of HCC.

METHODS

We analysed three cohorts including 895 HCC patients. TP53 mutation spectrum was examined by direct sequencing of genomic DNA from tissue specimens in HCC patients with hepatectomy (Cohort 1, N = 260). R249S and other recurrent missense mutations were assessed for their biological functions and associations with overall survival (OS) and progression-free survival (PFS) of HCC patients in Cohort 1. R249S within circulating tumour DNA (ctDNA) was detected through droplet digital polymerase chain reaction (ddPCR) and its association with OS and PRS was analysed in HCC patients with (Cohort 2, N = 275) or without (Cohort 3, N = 360) hepatectomy.

RESULTS

In Cohort 1, R249S occupied 60.28% of all TP53 mutations. Overexpression of R249S induced more serious malignant phenotypes than those of the other three identified TP53 recurrent missense mutations. Additionally, R249S, but not other missense mutations, was significantly associated with worse OS (P = .006) and PFS (P = .01) of HCC patients. Consistent with the results in Cohort 1, HCC patients in Cohorts 2 and 3 with R249S had worse OS (P = 8.291 × 10 and 2.608 × 10 in Cohorts 2 and 3, respectively) and PFS (P = 5.115 × 10 and 5.900 × 10 in Cohorts 2 and 3, respectively) compared to those without this mutation.

CONCLUSIONS

TP53 R249S mutation in ctDNA may serve as a promising prognosis biomarker for HCC patients with or without hepatectomy.

摘要

背景与目的

TP53基因的体细胞突变R249S在肝细胞癌（HCC）中极为常见。我们旨在研究ctDNA中的R249S对HCC预后的影响。

方法

我们分析了三个队列，共895例HCC患者。通过对接受肝切除术的HCC患者组织标本的基因组DNA进行直接测序，检测TP53突变谱（队列1，N = 260）。评估R249S和其他复发性错义突变的生物学功能，以及它们与队列1中HCC患者总生存期（OS）和无进展生存期（PFS）的相关性。通过液滴数字聚合酶链反应（ddPCR）检测循环肿瘤DNA（ctDNA）中的R249S，并分析其与接受（队列2，N = 275）或未接受（队列3，N = 360）肝切除术的HCC患者的OS和PRS的相关性。

结果

在队列1中，R249S占所有TP53突变的60.28%。与其他三个已鉴定的TP53复发性错义突变相比，R249S的过表达诱导了更严重的恶性表型。此外，R249S而非其他错义突变与HCC患者较差的OS（P = 0.006）和PFS（P = 0.01）显著相关。与队列1的结果一致，与未发生该突变的患者相比，队列2和队列3中存在R249S的HCC患者的OS（队列2和队列3中分别为P = 8.291×10和2.608×10）和PFS（队列2和队列3中分别为P = 5.115×10和5.900×10）更差。