Mutant p53 drives clonal hematopoiesis through modulating epigenetic pathway

Chen, Sisi; Wang, Qiang; Yu, Hao; Capitano, Maegan L.; Vemula, Sasidhar; Nabinger, Sarah C.; Gao, Rui; Yao, Chonghua; Kobayashi, Michihiro; Geng, Zhuangzhuang; Fahey, Aidan; Henley, Danielle; Liu, Stephen Z.; Barajas, Sergio; Cai, Wenjie; Wolf, Eric R.; Ramdas, Baskar; Cai, Zhigang; Gao, Hongyu; Luo, Na; Sun, Yang; Wong, Terrence N.; Link, Daniel C.; Liu, Yunlong; Boswell, H. Scott; Mayo, Lindsey D.; Huang, Gang; Kapur, Reuben; Yöder, Mervin C.; Broxmeyer, Hal E.; Gao, Zhonghua; Liu, Yan

doi:10.1038/s41467-019-13542-2

Cited by 89 publications

(58 citation statements)

References 63 publications

Supporting

Mentioning

Contrasting

Unclassified

Order By: Relevance

“…Some of these p53 mutations have been shown to be a result of clonal hematopoiesis. This is a process whereby expansion of blood cell clones occurs due to advantageous somatic mutations, which often accumulate with age, and may contribute to hematological malignancies [35][36][37][38]. Having a broad NGS panel, that can simultaneously detect multiple low frequency variants becomes critical in defining the significance of circulating mutations.…”

Section: Discussionmentioning

confidence: 99%

Design and Testing of a Custom Melanoma Next Generation Sequencing Panel for Analysis of Circulating Tumor DNA

Diefenbach

Lee²,

Menzies

et al. 2020

Cancers

View full text Add to dashboard Cite

Detection of melanoma-associated mutations using circulating tumor DNA (ctDNA) from plasma is a potential alternative to using genomic DNA from invasive tissue biopsies. In this study, we developed a custom melanoma next-generation sequencing (NGS) panel which includes 123 amplicons in 30 genes covering driver and targetable mutations and alterations associated with treatment resistance. Analysis of a cohort of 74 stage III and IV treatment-naïve melanoma patients revealed that sensitivity of ctDNA detection was influenced by the amount of circulating-free DNA (cfDNA) input and stage of melanoma. At the recommended cfDNA input quantity of 20 ng (available in 28/74 patients), at least one cancer-associated mutation was detected in the ctDNA of 84% of stage IV patients and 47% of stage III patients with a limit of detection for mutant allele frequency (MAF) of 0.2%. This custom melanoma panel showed significant correlation with droplet digital PCR (ddPCR) and provided a more comprehensive melanoma mutation profile. Our custom panel could be further optimized by replacing amplicons spanning the TERT promoter, which did not perform well due to the high GC content. To increase the detection rate to 90% of stage IV melanoma and decrease the sensitivity to 0.1% MAF, we recommend increasing the volume of plasma to 8 mL to achieve minimal recommended cfDNA input and the refinement of poorly performing amplicons. Our panel can also be expanded to include new targetable and treatment resistance mutations to improve the tracking of treatment response and resistance in melanoma patients treated with systemic drug therapies.

show abstract

Section: Discussionmentioning

confidence: 99%

Design and Testing of a Custom Melanoma Next Generation Sequencing Panel for Analysis of Circulating Tumor DNA

Diefenbach

Lee²,

Menzies

et al. 2020

Cancers

View full text Add to dashboard Cite

show abstract

“…In this study, three mutp53 versions (R248W, R273H and R175H) showed increased association with EZH2 (Enhancer of Zeste Homolog 2), which is part of PCR2 (Polycomb Repressive Complex-2), compared with wtp53, improving EZH2 binding to chromatin. Nonetheless, mutp53 promoted the presence of H3K27me3 rather than altering genomic distribution (Chen et al, 2019 ). Moreover, mutp53 also indirectly upregulates EZH2 by attenuating miR-26a, a negative regulator of EZH2, supporting another mechanism in the regulation of EZH2 activity (Jiang et al, 2015 ).…”

Section: Impact Of Mutp53 Gain-of-functionmentioning

confidence: 99%

Mutant p53 Gain-of-Function: Role in Cancer Development, Progression, and Therapeutic Approaches

Alvarado-Ortiz

Cruz-López

Becerril-Rico

et al. 2021

Front. Cell Dev. Biol.

104

View full text Add to dashboard Cite

Frequent p53 mutations (mutp53) not only abolish tumor suppressor capacities but confer various gain-of-function (GOF) activities that impacts molecules and pathways now regarded as central for tumor development and progression. Although the complete impact of GOF is still far from being fully understood, the effects on proliferation, migration, metabolic reprogramming, and immune evasion, among others, certainly constitute major driving forces for human tumors harboring them. In this review we discuss major molecular mechanisms driven by mutp53 GOF. We present novel mechanistic insights on their effects over key functional molecules and processes involved in cancer. We analyze new mechanistic insights impacting processes such as immune system evasion, metabolic reprogramming, and stemness. In particular, the increased lipogenic activity through the mevalonate pathway (MVA) and the alteration of metabolic homeostasis due to interactions between mutp53 and AMP-activated protein kinase (AMPK) and Sterol regulatory element-binding protein 1 (SREBP1) that impact anabolic pathways and favor metabolic reprograming. We address, in detail, the impact of mutp53 over metabolic reprogramming and the Warburg effect observed in cancer cells as a consequence, not only of loss-of-function of p53, but rather as an effect of GOF that is crucial for the imbalance between glycolysis and oxidative phosphorylation. Additionally, transcriptional activation of new targets, resulting from interaction of mutp53 with NF-kB, HIF-1α, or SREBP1, are presented and discussed. Finally, we discuss perspectives for targeting molecules and pathways involved in chemo-resistance of tumor cells resulting from mutp53 GOF. We discuss and stress the fact that the status of p53 currently constitutes one of the most relevant criteria to understand the role of autophagy as a survival mechanism in cancer, and propose new therapeutic approaches that could promote the reduction of GOF effects exercised by mutp53 in cancer.

show abstract

“…These mutant p53/transcription factor interactions lead to changes in expression of both protein coding genes and a range of different noncoding RNAs, including miRNAs and lncRNAs (Zhang et al 2020a), all of which can contribute to the GOF phenotype. The activity of mutant p53s is further expanded by the ability to bind and modulate the activity of nontranscription factor proteins, resulting in the impairment of the DNA damage response, increased rates of glycolysis and lipid production (Zhu et al 2020), and increased histone methylation (Chen et al 2019). More generally, mutant p53s can bind to a variety of proteins controlling the epigenome, including those that regulate chromatin structure, histone modifications, and splicing, resulting in genome-wide dysregulation (Escobar-Hoyos et al 2020;Zhang et al 2020a).…”

Section: Oncogenic Gains Of Functionmentioning

confidence: 99%

Mutant p53 in cell-cell interactions

2021

View full text Add to dashboard Cite

p53 is an important tumor suppressor, and the complexities of p53 function in regulating cancer cell behaviour are well established. Many cancers lose or express mutant forms of p53, with evidence that the type of alteration affecting p53 may differentially impact cancer development and progression. It is also clear that in addition to cell-autonomous functions, p53 status also affects the way cancer cells interact with each other. In this review, we briefly examine the impact of different p53 mutations and focus on how heterogeneity of p53 status can affect relationships between cells within a tumor.

show abstract

Mutant p53 drives clonal hematopoiesis through modulating epigenetic pathway

Cited by 89 publications

References 63 publications

Design and Testing of a Custom Melanoma Next Generation Sequencing Panel for Analysis of Circulating Tumor DNA

Design and Testing of a Custom Melanoma Next Generation Sequencing Panel for Analysis of Circulating Tumor DNA

Mutant p53 Gain-of-Function: Role in Cancer Development, Progression, and Therapeutic Approaches

Mutant p53 in cell-cell interactions

Contact Info

Product

Resources

About