J Cancer 2021; 12(1):217-223. doi:10.7150/jca.48983

Research Paper

LRP1B or TP53 mutations are associated with higher tumor mutational burden and worse survival in hepatocellular carcinoma

Longrong Wang1*, Kai Yan2*, Xigan He1, Hongxu Zhu1, Jia Song3, Shiqing Chen3, Shangli Cai3, Yiming Zhao1✉, Lu Wang1✉

1. Liver Surgery Department, Shanghai Cancer Center, Fudan University; Department of Oncology, Shanghai Medical College, Fudan University, Shanghai 200032, China.
2. Fifth Department of Liver Surgery, Shanghai Eastern Hepatobiliary Surgery Hospital, Second Military Medical University, Shanghai, China.
3. The Medical Department, 3D Medicines Inc., Shanghai, China.
*Co-first authors.

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Citation:
Wang L, Yan K, He X, Zhu H, Song J, Chen S, Cai S, Zhao Y, Wang L. LRP1B or TP53 mutations are associated with higher tumor mutational burden and worse survival in hepatocellular carcinoma. J Cancer 2021; 12(1):217-223. doi:10.7150/jca.48983. Available from https://www.jcancer.org/v12p0217.htm

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Abstract

Background: Hepatocellular carcinoma (HCC) is one of the most leading causes of cancer-related mortality worldwide. Immune checkpoint inhibitors (ICIs) have been proved to be beneficial for advanced HCC. Tumor mutational burden (TMB) is an important predictor for efficacy of ICIs. However, the genetic landscape of Chinese HCC patients and the association between TMB and frequently mutated genes of HCC remain unclear.

Methods: Whole-exome sequencing data of 369 liver tumors from the Cancer Genome Altas (TCGA) and next generation sequencing (NGS) data of 657 liver tumors from Chinese clinical dataset were included.

Results: TP53 (61.8%) was the most frequently mutated gene in the Chinese cohort, followed by CTNNB1 (17.2%), RB1 (13.7%), and LRP1B (12.3%). The PI3K-Akt signaling (11.2%), the Rap1 signaling (8.1%), and Ras signaling (7.7%), were significantly mapped. LRP1B mutations were significantly associated with higher TMB in both TCGA cohort (P = 0.0003) and Chinese cohort (P = 0.0005). And TP53 mutations were also associated with higher TMB in the TCGA and Chinese cohort (P = 0.0005 and 0.0010, respectively). Prognosis analysis performed in TCGA cohort revealed LRP1B mutations were significantly associated with shorter overall survival (OS, median, 20.9 vs 61.7 months; HR, 2.22; P = 0.0012). TP53 mutation was an independent risk factor affecting both OS (HR 1.58, P = 0.0109) and PFS (HR 1.59, P = 0.0027).

Conclusions: The results suggest that LRP1B or TP53 mutations are associated with higher TMB and a poor prognostic factor in HCC.

Keywords: Hepatocellular carcinoma, LRP1B, TP53, tumor mutational burden, survival