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

Wang, Longrong; Yan, Kai; He, Xinhong; Zhu, Hongxu; Song, Jia; Chen, Shiqing; Cai, Shangli; Zhao, Yiming

doi:10.7150/jca.48983

Cited by 35 publications

(34 citation statements)

References 28 publications

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“…The somatic mutations of this important tumor suppressor may cause genomic instability and replication stress, which is closely related to tumorigenesis in various cancer types (Baker et al, 1989; Malekzadeh et al, 2019; Nigro et al, 1989; Stracquadanio et al, 2016). LRP1B may play an essential role in the tumorigenesis of NSCLCs, and mutations of this gene are associated with a higher TMB level (Lan et al, 2019; Wang et al, 2021). These factors may be involved in positive selection during tumor evolution and promote the occurrence of HLA‐I LOH.…”

Section: Discussionmentioning

confidence: 99%

The prevalence of HLA‐I LOH in Chinese pan‐cancer patients and genomic features of patients harboring HLA‐I LOH

Zhao

Xiao

et al. 2021

Human Mutation

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HLA‐I LOH may facilitate immune evasion. However, large population studies on the prevalence of HLA‐I LOH across different cancer types and in relation to mutational profiles are lacking, in particular, in the Chinese population. In this study, analysis was performed in 1504 advanced pan‐cancer patients and 134 early‐stage non‐small‐cell lung cancer patients using a 1021‐gene panel. The consistency between the 1021‐gene panel and whole‐exome sequencing was evaluated in 45 samples, where concordant results were obtained in 95.6% (43/45) of the samples. Analytical results revealed that the prevalence of HLA‐I LOH in tumor tissue presents considerable differences across cancer types. HLA‐I LOH was relevant to genomic instability, reflected in higher tumor mutation burden level. HLA‐I LOH occurs more frequently in MSS samples than in MSI‐H samples. The alteration frequencies of p53 pathway, RTK/RAS pathway, Notch pathway, Hippo pathway, and Nrf2 pathway in HLA‐I LOH group were significantly higher than that in HLA‐I stable group (p < .0001, p < .0001, p = .032, p = .013, p = .003, respectively). In DNA damage response pathways, alterations in the checkpoint factor pathway and Fanconi anemia pathway are enriched in HLA‐I LOH group (p < .0001, p = .023, respectively). Besides, HLA‐I LOH was accompanied by higher mutation rates of several tumor suppressors, including TP53 and LRP1B. These results may shed light on follow‐up tumor immunology research.

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Section: Discussionmentioning

confidence: 99%

The prevalence of HLA‐I LOH in Chinese pan‐cancer patients and genomic features of patients harboring HLA‐I LOH

Zhao

Xiao

et al. 2021

Human Mutation

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“…TMB is usually evaluated using expensive, massive next-generation, or whole-exome sequencing [ 120 ]. Nevertheless, specific single-gene mutation analysis has been presenting as a more accessible way to predict TMB in cancer patients [ 120 ], with LRP1B being one of those genes [ 61 , 120 , 121 ]. In HCC, LRP1B mutation significantly associated with a higher HHLA2 (human endogenous retrovirus-H long terminal repeat-associating protein 2), as well as with TMB, giving new insights into potential targets for immune checkpoint inhibition [ 61 ].…”

Section: Lrp1b Impairment In Cancermentioning

confidence: 99%

LRP1B: A Giant Lost in Cancer Translation

et al. 2021

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Low-density lipoprotein receptor-related protein 1B (LRP1B) is a giant member of the LDLR protein family, which includes several structurally homologous cell surface receptors with a wide range of biological functions from cargo transport to cell signaling. LRP1B is among the most altered genes in human cancer overall. Found frequently inactivated by several genetic and epigenetic mechanisms, it has mostly been regarded as a putative tumor suppressor. Still, limitations in LRP1B studies exist, in particular associated with its huge size. Therefore, LRP1B expression and function in cancer remains to be fully unveiled. This review addresses the current understanding of LRP1B and the studies that shed a light on the LRP1B structure and ligands. It goes further in presenting increasing knowledge brought by technical and methodological advances that allow to better manipulate LRP1B expression in cells and to more thoroughly explore its expression and mutation status. New evidence is pushing towards the increased relevance of LRP1B in cancer as a potential target or translational prognosis and response to therapy biomarkers.

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“…As a member of the low-density lipoprotein receptor family, LRP1B plays a tremendous function in maintaining lipid homeostasis. A study by Li and colleagues found that LRP1B knockdown caused the decrease in intracellular lipid content, down-regulated expressions of lipid synthesis-related enzymes as well as increased expressions of β-oxidation-related enzymes and enhanced activity of AMPK signaling [ 21 ]. These might offer a potential explanation for LRP1B roles in HCC development.…”

Section: Discussionmentioning

confidence: 99%

Development and validation of LRP1B mutation-associated prognostic model for hepatocellular carcinoma

Shen

Zhang

et al. 2021

Bioscience Reports

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Purpose: To develop a LRP1B gene mutation based prognostic model for hepatocellular carcinoma (HCC) patients risk prediction. Methods: The LRP1B gene mutation rate was calculated from HCC patient samples. Meanwhile, differentially expressed genes according to LRP1B mutant were screened out for prognostic model establishment. Based on this innovative model, HCC patients were categoried into high and low-risk group. The immune status including immune cell infiltration ratio and checkpoints have been explored in two groups. The functions of LRP1B and risk factors in the model were verified using both in vivo and in vitro experiments. Results: It could be demonstrated that LRP1B was a potential negative predictor for HCC patients prognosis with high mutation frequency. The functions of LRP1B was verified with ELISA assay and Quantitative Real-time PCR method based on clinical recruited HCC participants. 11 genes displayed significant differences according to LRP1B status, which could better predict HCC patient prognosis. The functions of these genes were examined using HCC cell line HCCLM3, suggesting they played a pivotal role in determining HCC cell proliferation and apoptosis. From the immune cell infiltration ratio analysis, there was a significant difference in the infiltration degree of 7 types of immune cells and 2 immune checkpoints between high and low-risk HCC patients. Conclusion: This study hypothesized a potential prognostic biomarker and developed a novel LRP1B mutation-associated prognostic model for hepatocellular carcinoma, which provided a systematic reference for future understanding of clinical research.

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

Cited by 35 publications

References 28 publications

The prevalence of HLA‐I LOH in Chinese pan‐cancer patients and genomic features of patients harboring HLA‐I LOH

The prevalence of HLA‐I LOH in Chinese pan‐cancer patients and genomic features of patients harboring HLA‐I LOH

LRP1B: A Giant Lost in Cancer Translation

Development and validation of LRP1B mutation-associated prognostic model for hepatocellular carcinoma

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