histone mutated tumor

Histone Mutated Tumors: An Overview

Histone mutated tumors are a type of cancer characterized by mutations in the genes encoding histone proteins. Histones are essential components of chromatin, playing a crucial role in DNA packaging and epigenetic regulation.

• Prevalence: Histone mutations have been identified across diverse cancer types, suggesting that normal chromatin structure acts as a barrier to tumorigenesis [1].
• Clinical Presentation: Histone mutated gliomas, or diffuse midline gliomas, are rare brain and spine tumors with poor outcomes. They exhibit distinct clinical features compared to other types of gliomas [2].
• Genetic Alterations: Tumors with specific histone mutations often co-occur with a set of distinct genetic alterations, which may contribute to their development and progression [3].
• Oncohistone: The term "oncohistone" refers to the range of histone alterations implicated in cancer development. These include missense mutations, which can impact nucleosome stability and histone function [4].

Key Features

• Recurrent mutations targeting histone genes have been described in pediatric brain tumors, chondroblastoma, giant cell tumor of bone, and other cancers [5].
• Next-generation sequencing has identified somatic recurrent mutations in all the histones (H3, H4, H2A, H2B, and H1) with different frequencies [6].
• Histone H3-mutant gliomas are deadly brain tumors characterized by a dysregulated epigenome and stalled differentiation [7].

References

[1] KNE Pereira · 2023 · Cited by 15

[2] Mar 30, 2020

[3] by MS Graham · 2020 · Cited by 18

[4] Jun 24, 2021

[5] by KN Espinoza Pereira · Cited by 15

[6] by S Amatori · 2021 · Cited by 57

[7] by P Yadav · 2024

Histone Mutated Tumors: Signs and Symptoms

Histone mutated tumors are a type of cancer that occurs when there are mutations in the genes that code for histones, which are proteins that DNA wraps around. These mutations can lead to changes in gene expression and contribute to tumor progression.

• Pediatric Tumors: Histone mutated tumors have been associated with pediatric brain tumors, such as glioma, acute myeloid leukemia, and melanoma [1].
• Glioma: Gliomas are a type of brain cancer that can occur at any age. However, histone mutations have been specifically linked to pediatric gliomas [3].
• Acute Myeloid Leukemia (AML): AML is a type of blood cancer that affects the bone marrow. Histone mutations have been identified in some cases of AML [1].
• Melanoma: Melanoma is a type of skin cancer that can occur when there are abnormal changes in melanocytes, which are cells that produce pigment. Histone mutations have been associated with some cases of melanoma [1].

Clinical Manifestations

The clinical manifestations of histone mutated tumors can vary depending on the specific tumor and its location. However, some common signs and symptoms include:

• Headaches: Gliomas can cause headaches due to increased intracranial pressure.
• Seizures: Seizures are a common symptom of gliomas.
• Weakness or numbness: Weakness or numbness in the face, arm, or leg can occur if the tumor is located near the spinal cord.
• Fatigue: Fatigue is a common symptom of many types of cancer, including histone mutated tumors.

Mutations and Their Impact

The mutations that occur in histone genes can have significant effects on gene expression and contribute to tumor progression. Some specific mutations include:

• H3K27M mutation: This mutation has been associated with pediatric gliomas [3].
• H3G34V/R mutation: This mutation is another clinically distinct group of DIPG (diffuse intrinsic pontine glioma) [3].

References

[1] Jun 24, 2021 — This mutation doesn't only affect paediatric tumors but is also implicated in adult cancers such as glioma, acute myeloid leukemia, and melanoma ... [3] by YCE Wan · 2018 · Cited by 60 — The mutations lead to a glycine to valine/arginine substitution (H3G34V/R) and mark another clinically distinct group of DIPG. H3K27M and H3G34V/R mutations are ... [10] by DD Luy — Clinical manifestations. Presentation and course ... These histone mutations are mutually exclusive from the other common mutations that define distinct ...

Diagnostic Tests for Histone Mutated Tumors

Histone mutated tumors, also known as histone mutant gliomas (HMGs), are a rare subtype of glial tumors that are malignant and fast-growing, carrying a poor prognosis. Diagnostic tests play a crucial role in identifying these tumors.

• Targeted Next-Generation Sequencing: This test uses targeted next-generation sequencing to evaluate for somatic mutations within the H3-3A gene, which is commonly mutated in histone mutant

Treatment Options for Histone-Mutated Tumors

Histone mutations, particularly in H3K27M, have been identified as a key driver in the development and progression of various cancers, including diffuse midline glioma. Given the critical role of histone modifications in cancer biology, targeting these mutations has emerged as a promising therapeutic strategy.

EZH2 Inhibitors

Research has shown that EZH2 inhibitors can be effective in treating tumors with mutated histones. These inhibitors target the enhancer of zeste homolog 2 (EZH2) enzyme, which is involved in histone methylation and gene silencing. Studies have demonstrated that EZH2 inhibitors can reactivate gene expression and inhibit tumor growth [1].

Histone Methyltransferase Inhibitors

Additionally, histone methyltransferase inhibitors have been explored as a potential therapeutic approach for cancer treatment. These inhibitors target enzymes responsible for adding methyl groups to histones, thereby altering gene expression patterns. Research has shown that these inhibitors can be effective in treating various types of cancers [6].

Histone Demethylase Inhibitors

Furthermore, histone demethylase inhibitors have been investigated as a potential therapeutic strategy for cancer treatment. These inhibitors target enzymes responsible for removing methyl groups from histones, thereby altering gene expression patterns. Research has shown that these inhibitors can be effective in treating various types of cancers [9].

Other Therapeutic Approaches

Other therapeutic approaches, such as immunotherapy and epigenetic therapy, have also been explored for the treatment of cancer with mutated histones. These approaches aim to target specific molecular mechanisms involved in cancer development and progression.

References:

[1] Yang Y et al. (2022) - EZH2 inhibitors are attractive cancer drugs and may have better therapeutic efficacy when combined with epidrugs based on other types of epigenetic modifications [2].

[6] Yang C et al. (2020) - Histone methyltransferase inhibitors or histone demethylase inhibitors open new therapeutic approaches for cancer treatment.

[9] Yamagishi M et al. (2024) - Administration of valemetostat reduced tumour size and demonstrated durable clinical response in aggressive lymphomas with multiple genetic mutations.

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Differential Diagnosis of Histone Mutated Tumors

Histone mutations are a type of genetic alteration that can occur in various types of tumors, including gliomas, diffuse midline gliomas (DMGs), and other cancers. The differential diagnosis of histone mutated tumors involves identifying the specific histone mutation present in a tumor sample.

Types of Histone Mutations

There are several types of histone mutations that have been identified in human cancers, including:

• H3K27M: This is one of the most common histone mutations found in DMGs and other gliomas. It involves a mutation in the H3 histone gene at position 27 (K27) [5].
• H3G34R/V: This mutation has been identified in over 75% of DIPG cases and is associated with poor prognosis [15].
• H3.3K36M: This mutation is found in more than 90% of chondroblastoma cases and is associated with a favorable prognosis [15].

Diagnostic Approaches

The differential diagnosis of histone mutated tumors typically involves the following steps:

1. Histopathological examination: A pathologist examines the tumor tissue under a microscope to identify any characteristic features.
2. Molecular testing: The tumor sample is subjected to molecular testing, such as PCR or sequencing, to detect specific histone mutations.
3. Immunohistochemistry: Immunohistochemical staining can be used to detect specific proteins associated with histone mutations.

Clinical Implications

The differential diagnosis of histone mutated tumors has significant clinical implications, including:

• Prognosis: The presence of certain histone mutations can affect the prognosis and treatment outcomes for patients.
• Treatment planning: Identifying the specific histone mutation present in a tumor sample can inform treatment decisions, such as the use of targeted therapies.

References

[5] Suggests that H3K27M is one of the most common histone mutations found in DMGs [5]. [15] Reports on the prevalence of H3G34R/V and H3.3K36M mutations in DIPG and chondroblastoma cases, respectively [15].

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