ecc: introduces H3 K27M mutation characteristics #10
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| state: proposed | ||||||
| name: H3 K27M Mutation | ||||||
| identifier: ECC-MOLEC-000001 | ||||||
| rfc: https://github.com/stjudecloud/ecc/issues/8 | ||||||
| description: | | ||||||
| The H3 K27M mutation is a lysine-to-methionine somatic substitution at position 27 on the histone H3 protein, most commonly occurring in the H3F3A (H3.3) or less frequently in HIST1H3B/C (H3.1) genes. | ||||||
| This mutation disrupts normal epigenetic regulation by inhibiting the trimethylation of histone H3 at lysine 27 (H3K27me3), leading to widespread changes in gene expression that drive tumorigenesis. | ||||||
| The H3 K27M mutation is primarily associated with diffuse midline gliomas (DMGs) [22286216](https://pubmed.ncbi.nlm.nih.gov/22286216/), a group of highly aggressive brain tumors that predominantly affect children, though they can also occur in adults. | ||||||
| This mutation is linked to a poor prognosis, with median overall survival ranging from 10 to 14 months after diagnosis [PMC7739048](https://pmc.ncbi.nlm.nih.gov/articles/PMC7739048/), [38102230](https://pubmed.ncbi.nlm.nih.gov/38102230/). | ||||||
| Note that the H3-K27M mutation is sometimes also referred to as K28M in annotations that include the initiator methionine in protein numbering. In histone biology literature, the convention is to exclude the initiator methionine [29766298](https://pubmed.ncbi.nlm.nih.gov/29766298/), thus the mutation is commonly described as K27M. | ||||||
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There was a problem hiding this comment. This is a very important comment. I was going to suggest it if it wasn't in here. |
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| values: | ||||||
| kind: binary | ||||||
| description: | ||||||
| "true": | ||||||
| summary: H3 K27M mutation is observed from the sample. | ||||||
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Suggested change
There was a problem hiding this comment. How about "The H3 K27M mutation is present in the sample." |
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| details: | | ||||||
| The presence of the H3 K27M mutation can be initially identified by positive nuclear staining in tumor cells using a H3 K27M mutation-specific immunohistochemistry (IHC) antibody, which strongly indicates the presence of the mutant histone protein. | ||||||
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There was a problem hiding this comment. I would think that for most modern datasets, we would be basing the call purely on NGS. The way this is written, it sounds like NGS would only be used for confirmation. Overall, I don't really like the details section here. The way I think of it is that we want the semantics to be clear, i.e. it's important that people know what true means and what false means. I think that's abundantly clear from the summary alone. However, different institutions may have different mechanisms and even possibly different standards for deciding the presence/absence of a variant, and I think it's OK (and even preferable) to allow that variation. And it can change over time. The more detail you give about what we really mean about presence and absence, the more in sync everybody will be in theory, but it's also more work to maintain the characteristics, and I think by being so proscriptive we could find that it opens up a lot of debate that we would be better to avoid by just leaving those details up to each user. In this version we partly specify the criteria for determining presence/absence, but we leave a lot of it open to interpretation (e.g. variant calling methods and criteria on the NGS data). I think it's probably the worst of both worlds. My suggestion is that we omit the information currently in details entirely, and I would say we shouldn't need value details for Booleans generally (and possibly not for some others as well). If the guidance that we put in here is from a referenced resource, then you could move this information to the "context" of that reference, where you could possibly summarize it as "This paper recommends practices for determining the presence of H3 K27M using immunohistochemistry and NGS testing". |
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| To confirm the mutation at the genetic level, molecular testing such as Sanger sequencing or next-generation sequencing (NGS) can be performed to detect the lysine-to-methionine substitution at position 27 in the H3F3A or HIST1H3B/C genes. | ||||||
| "false": | ||||||
| summary: The H3 K27M alteration is **not** observed in the associated sample. | ||||||
| details: | | ||||||
| In the absence of the mutation, immunohistochemistry (IHC) with a H3 K27M mutation-specific antibody shows no nuclear staining in tumor cells, indicating a lack of mutant histone protein expression. | ||||||
| Because IHC can occasionally yield false-negative results due to factors such as tissue preservation or antigen masking, molecular testing, such Sanger sequencing or next-generation sequencing (NGS), is recommended for confirmation. | ||||||
| A negative molecular result definitively confirms the absence of the H3 K27M mutation. | ||||||
| references: | ||||||
| - kind: manuscript | ||||||
| title: Inhibition of PRC2 activity by a gain-of-function H3 mutation found in pediatric glioblastoma | ||||||
| authors: Peter W Lewis, Manuel M Müller, Matthew S Koletsky, Francisco Cordero, Shu Lin, Laura A Banaszynski, Benjamin A Garcia, Tom W Muir, Oren J Becher, C David Allis | ||||||
| context: The paper highlights that the **K27M mutation** in histone H3 genes (**H3F3A** and **HIST1H3B**) defines **DIPGs** by reducing H3K27 trimethylation (H3K27me3) through inhibition of **PRC2** activity via the EZH2 subunit. It also notes that similar lysine-to-methionine mutations disrupt methylation, indicating a broader mechanism of epigenetic reprogramming in tumor development. | ||||||
| url: https://pubmed.ncbi.nlm.nih.gov/23539183/ | ||||||
| highlighted: true | ||||||
| - kind: manuscript | ||||||
| title: Reduced H3K27me3 and DNA hypomethylation are major drivers of gene expression in K27M mutant pediatric high-grade gliomas | ||||||
| authors: Sebastian Bender, Yujie Tang, Anders M Lindroth, Volker Hovestadt, David T W Jones, Marcel Kool, Marc Zapatka, Paul A Northcott, Dominik Sturm, Wei Wang, Bernhard Radlwimmer, Jonas W Højfeldt, Nathalène Truffaux, David Castel, Simone Schubert, Marina Ryzhova, Huriye Seker-Cin, Jan Gronych, Pascal David Johann, Sebastian Stark, Jochen Meyer, Till Milde, Martin Schuhmann, Martin Ebinger, Camelia-Maria Monoranu, Anitha Ponnuswami, Spenser Chen, Chris Jones, Olaf Witt, V Peter Collins, Andreas von Deimling, Nada Jabado, Stephanie Puget, Jacques Grill, Kristian Helin, Andrey Korshunov, Peter Lichter, Michelle Monje, Christoph Plass, Yoon-Jae Cho, Stefan M Pfister | ||||||
| context: The paper highlights that the **K27M mutation** in histone variant **H3.3** occurs in ~50% of **pediatric high-grade gliomas (pHGGs)** and defines a distinct subgroup with biological and clinical significance. The mutation causes a global reduction of the repressive mark **H3K27me3** by aberrantly recruiting the **PRC2 complex** and inhibiting its enzymatic component **EZH2**. Chromatin and DNA methylation analyses reveal that reduced H3K27me3 levels and DNA hypomethylation together drive gene activation in **K27M mutant pHGGs**. | ||||||
| url: https://pubmed.ncbi.nlm.nih.gov/24183680/ | ||||||
| highlighted: true | ||||||
| - kind: manuscript | ||||||
| title: The histone H3.3K27M mutation in pediatric glioma reprograms H3K27 methylation and gene expression | ||||||
| authors: Kui-Ming Chan 1, Dong Fang, Haiyun Gan, Rintaro Hashizume, Chuanhe Yu, Mark Schroeder, Nalin Gupta, Sabine Mueller, C David James, Robert Jenkins, Jann Sarkaria, Zhiguo Zhang | ||||||
| context: The paper highlights that the **K27M mutation** in one allele of the **H3F3A** gene, encoding histone variant **H3.3**, occurs in 60% of high-grade pediatric gliomas and is associated with a median survival of ~1 year. The mutation reduces global **H3K27me2** and **H3K27me3** levels but paradoxically increases their presence, along with **Ezh2**, at hundreds of gene loci in tumor cells. This localized enrichment at gene promoters alters the expression of cancer-related genes, demonstrating that the **H3.3K27M mutation** reprograms the epigenetic landscape and drives tumorigenesis. | ||||||
| url: https://pubmed.ncbi.nlm.nih.gov/23603901/ | ||||||
| highlighted: false | ||||||
| - kind: manuscript | ||||||
| title: A sensitive and specific histopathologic prognostic marker for H3F3A K27M mutant pediatric glioblastomas | ||||||
| authors: Sriram Venneti, Mariarita Santi, Michelle Madden Felicella, Dmitry Yarilin, Joanna J Phillips, Lisa M Sullivan, Daniel Martinez, Arie Perry, Peter W Lewis, Craig B Thompson, Alexander R Judkins | ||||||
| context: The paper highlights that the **K27M mutation** in the **H3F3A** gene, encoding histone variant **H3.3**, occurs in ~30% of pediatric glioblastomas (GBM) and ~80% of diffuse intrinsic pontine gliomas (DIPG), leading to a global reduction in **H3K27me3**. The study evaluated biomarkers for detecting these tumors, demonstrating that immunohistochemistry targeting the **H3.3 K27M mutation** showed 100% sensitivity and specificity, outperforming global H3K27me3 reduction as a diagnostic biomarker. Tumors positive for **H3.3 K27M** were associated with significantly poorer prognosis, establishing immunohistochemical detection as a reliable method to identify a high-risk subset of pediatric GBM. | ||||||
| url: https://pubmed.ncbi.nlm.nih.gov/25200322/ | ||||||
| highlighted: false | ||||||
| - kind: manuscript | ||||||
| title: H3K27M mutant glioma Disease definition and biological underpinnings | ||||||
| authors: Amanda M Saratsis 1, Truman Knowles 2, Antonela Petrovic 3, Javad Nazarian | ||||||
| context: The paper highlights that **high-grade glioma (HGG)** is a leading cause of cancer deaths in children and the most common primary CNS tumor in adults, with pediatric and adult forms being molecularly distinct but sharing certain events like the **H3K27M mutation**. This somatic missense mutation, found in **H3F3A (H3.3)** or **HIST1H3B (H3.1)**, occurs in up to 80% of pediatric diffuse midline gliomas and 60% of adult diffuse gliomas. The **H3K27M mutation** is linked to poorer survival and therapy response compared to **H3 wild-type tumors**. The paper reviews the clinical features and biological mechanisms of H3K27M mutant gliomas, providing a foundation for advancing research and treatment strategies for this aggressive disease. | ||||||
| url: https://pubmed.ncbi.nlm.nih.gov/37818718/ | ||||||
| highlighted: false | ||||||
| - kind: manuscript | ||||||
| title: Clinical, radiologic, and genetic characteristics of histone H3 K27M-mutant diffuse midline gliomas in adults | ||||||
| authors: Jessica D Schulte, Robin A Buerki, Sarah Lapointe, Annette M Molinaro, Yalan Zhang, Javier E Villanueva-Meyer, Arie Perry, Joanna J Phillips, Tarik Tihan, Andrew W Bollen, Melike Pekmezci, Nicholas Butowski, Nancy Ann Oberheim Bush, Jennie W Taylor, Susan M Chang, Philip Theodosopoulos, Manish K Aghi, Shawn L Hervey-Jumper, Mitchel S Berger, David A Solomon, Jennifer L Clarke | ||||||
| context: The paper highlights that **Diffuse midline glioma (DMG), H3 K27M-mutant** is a tumor entity identified in the 2016 WHO classification, characterized by a **K27M mutation** in histone variants **H3.3** or **H3.1**. While this tumor is associated with poor prognosis in children, clinical data in adults are limited. The study collected data on 60 adult patients with **H3 K27M-mutant DMG**, finding tumors in various midline structures like the thalamus, spinal cord, and brainstem. **Genomic profiling** showed mutations exclusively in **H3F3A**, with frequent mutations in **TP53**, **PPM1D**, and others. The overall survival for adults was **27.6 months**, longer than in pediatric cases and **IDH-wildtype glioblastoma**. These findings suggest that H3 K27M-mutant DMG is a heterogeneous disease, with distinct outcomes and molecular profiles in adults compared to children. | ||||||
| url: https://pmc.ncbi.nlm.nih.gov/articles/PMC7739048/ | ||||||
| highlighted: false | ||||||
| - kind: manuscript | ||||||
| title: H3 K27M-altered glioma and diffuse intrinsic pontine glioma Semi-systematic review of treatment landscape and future directions | ||||||
| authors: Martin van den Bent, Amanda M Saratsis, Marjolein Geurts, Enrico Franceschi | ||||||
| context: The paper highlights that **H3 K27M-mutant diffuse glioma** is a recently identified, highly aggressive brain tumor classified as a **grade IV glioma** by the **WHO** since 2016, associated with poor prognosis. Despite its recognition as a key diagnostic and prognostic marker, **radiation therapy** remains the sole standard of care, with no effective systemic treatments available. The review discusses treatments for **diffuse midline glioma** and **diffuse intrinsic pontine glioma (DIPG)** before the identification of the H3 K27M mutation, the current standard of care for **H3 K27M-mutant** gliomas, and **ongoing clinical trials**. Forty-one clinical trials, including those evaluating **H3 K27M vaccination**, **CAR T-cell therapy**, and **small molecule inhibitors**, are currently underway, highlighting the need for further evaluation of novel therapies for this underserved patient population. | ||||||
| url: https://pubmed.ncbi.nlm.nih.gov/38102230/ | ||||||
| highlighted: false | ||||||
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I submit we should center on the name ("" alteration) for point mutations.
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I'm not going to suggest changes for every instances of mutation -> alteration, but please make those (and use alteration in the future).
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Thanks for the suggestions, I'd like to note that alteration term is a board term in genetics definition, which can be refer to various type of DNA changes including stucture variations, deletions, insertions, and more; not just a point mutation. Personally, I think that mutation" or "mutant would be more percise in the context. These terms are commonly used in scientific papers. That said, I also understood that we might want to generalize our terminolgy, so let's discuss futher to find the best convention for us to avoid ambiguity.
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I lean towards mutation when the variant is limited to SNV and/or Indel such as in this case. When the type of hit can be more broad, then alteration.