Nicholas Nuechterlein, Sadie Cimino, Allison Shelbourn, Vinny Ha, Sonali Arora, Sharika Rajan, Linda G. Shapiro, Eric C. Holland, Kenneth Aldape, Tresa McGranahan, Mark R. Gilbert, Patrick J. Cimino
{"title":"HOXD12定义了一种与年龄相关的侵袭性少突胶质细胞瘤亚型","authors":"Nicholas Nuechterlein, Sadie Cimino, Allison Shelbourn, Vinny Ha, Sonali Arora, Sharika Rajan, Linda G. Shapiro, Eric C. Holland, Kenneth Aldape, Tresa McGranahan, Mark R. Gilbert, Patrick J. Cimino","doi":"10.1007/s00401-024-02802-1","DOIUrl":null,"url":null,"abstract":"<div><p>Oligodendroglioma, IDH-mutant and 1p/19q-codeleted has highly variable outcomes that are strongly influenced by patient age. The distribution of oligodendroglioma age is non-Gaussian and reportedly bimodal, which motivated our investigation of age-associated molecular alterations that may drive poorer outcomes. We found that elevated HOXD12 expression was associated with both older patient age and shorter survival in the TCGA (FDR < 0.01, FDR = 1e−5) and the CGGA (<i>p</i> = 0.03, <i>p</i> < 1e−3). <i>HOXD12</i> gene body hypermethylation was associated with older age, higher WHO grade, and shorter survival in the TCGA (<i>p</i> < 1e−6, <i>p</i> < 0.001, <i>p</i> < 1e−3) and with older age and higher WHO grade in Capper et al. (<i>p</i> < 0.002, <i>p</i> = 0.014). In the TCGA, <i>HOXD12</i> gene body hypermethylation and elevated expression were independently prognostic of <i>NOTCH1</i> and <i>PIK3CA</i> mutations, loss of 15q, MYC activation, and standard histopathological features. Single-nucleus RNA and ATAC sequencing data showed that HOXD12 activity was elevated in neoplastic tissue, particularly within cycling and OPC-like cells, and was associated with a stem-like phenotype. A pan-HOX DNA methylation analysis revealed an age and survival-associated HOX-high signature that was tightly associated with <i>HOXD12</i> gene body methylation. Overall, HOXD12 expression and gene body hypermethylation were associated with an older, atypically aggressive subtype of oligodendroglioma.</p></div>","PeriodicalId":7012,"journal":{"name":"Acta Neuropathologica","volume":null,"pages":null},"PeriodicalIF":9.3000,"publicationDate":"2024-09-11","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://link.springer.com/content/pdf/10.1007/s00401-024-02802-1.pdf","citationCount":"0","resultStr":"{\"title\":\"HOXD12 defines an age-related aggressive subtype of oligodendroglioma\",\"authors\":\"Nicholas Nuechterlein, Sadie Cimino, Allison Shelbourn, Vinny Ha, Sonali Arora, Sharika Rajan, Linda G. Shapiro, Eric C. Holland, Kenneth Aldape, Tresa McGranahan, Mark R. Gilbert, Patrick J. Cimino\",\"doi\":\"10.1007/s00401-024-02802-1\",\"DOIUrl\":null,\"url\":null,\"abstract\":\"<div><p>Oligodendroglioma, IDH-mutant and 1p/19q-codeleted has highly variable outcomes that are strongly influenced by patient age. The distribution of oligodendroglioma age is non-Gaussian and reportedly bimodal, which motivated our investigation of age-associated molecular alterations that may drive poorer outcomes. We found that elevated HOXD12 expression was associated with both older patient age and shorter survival in the TCGA (FDR < 0.01, FDR = 1e−5) and the CGGA (<i>p</i> = 0.03, <i>p</i> < 1e−3). <i>HOXD12</i> gene body hypermethylation was associated with older age, higher WHO grade, and shorter survival in the TCGA (<i>p</i> < 1e−6, <i>p</i> < 0.001, <i>p</i> < 1e−3) and with older age and higher WHO grade in Capper et al. (<i>p</i> < 0.002, <i>p</i> = 0.014). In the TCGA, <i>HOXD12</i> gene body hypermethylation and elevated expression were independently prognostic of <i>NOTCH1</i> and <i>PIK3CA</i> mutations, loss of 15q, MYC activation, and standard histopathological features. Single-nucleus RNA and ATAC sequencing data showed that HOXD12 activity was elevated in neoplastic tissue, particularly within cycling and OPC-like cells, and was associated with a stem-like phenotype. A pan-HOX DNA methylation analysis revealed an age and survival-associated HOX-high signature that was tightly associated with <i>HOXD12</i> gene body methylation. Overall, HOXD12 expression and gene body hypermethylation were associated with an older, atypically aggressive subtype of oligodendroglioma.</p></div>\",\"PeriodicalId\":7012,\"journal\":{\"name\":\"Acta Neuropathologica\",\"volume\":null,\"pages\":null},\"PeriodicalIF\":9.3000,\"publicationDate\":\"2024-09-11\",\"publicationTypes\":\"Journal Article\",\"fieldsOfStudy\":null,\"isOpenAccess\":false,\"openAccessPdf\":\"https://link.springer.com/content/pdf/10.1007/s00401-024-02802-1.pdf\",\"citationCount\":\"0\",\"resultStr\":null,\"platform\":\"Semanticscholar\",\"paperid\":null,\"PeriodicalName\":\"Acta Neuropathologica\",\"FirstCategoryId\":\"3\",\"ListUrlMain\":\"https://link.springer.com/article/10.1007/s00401-024-02802-1\",\"RegionNum\":1,\"RegionCategory\":\"医学\",\"ArticlePicture\":[],\"TitleCN\":null,\"AbstractTextCN\":null,\"PMCID\":null,\"EPubDate\":\"\",\"PubModel\":\"\",\"JCR\":\"Q1\",\"JCRName\":\"CLINICAL NEUROLOGY\",\"Score\":null,\"Total\":0}","platform":"Semanticscholar","paperid":null,"PeriodicalName":"Acta Neuropathologica","FirstCategoryId":"3","ListUrlMain":"https://link.springer.com/article/10.1007/s00401-024-02802-1","RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":null,"EPubDate":"","PubModel":"","JCR":"Q1","JCRName":"CLINICAL NEUROLOGY","Score":null,"Total":0}
HOXD12 defines an age-related aggressive subtype of oligodendroglioma
Oligodendroglioma, IDH-mutant and 1p/19q-codeleted has highly variable outcomes that are strongly influenced by patient age. The distribution of oligodendroglioma age is non-Gaussian and reportedly bimodal, which motivated our investigation of age-associated molecular alterations that may drive poorer outcomes. We found that elevated HOXD12 expression was associated with both older patient age and shorter survival in the TCGA (FDR < 0.01, FDR = 1e−5) and the CGGA (p = 0.03, p < 1e−3). HOXD12 gene body hypermethylation was associated with older age, higher WHO grade, and shorter survival in the TCGA (p < 1e−6, p < 0.001, p < 1e−3) and with older age and higher WHO grade in Capper et al. (p < 0.002, p = 0.014). In the TCGA, HOXD12 gene body hypermethylation and elevated expression were independently prognostic of NOTCH1 and PIK3CA mutations, loss of 15q, MYC activation, and standard histopathological features. Single-nucleus RNA and ATAC sequencing data showed that HOXD12 activity was elevated in neoplastic tissue, particularly within cycling and OPC-like cells, and was associated with a stem-like phenotype. A pan-HOX DNA methylation analysis revealed an age and survival-associated HOX-high signature that was tightly associated with HOXD12 gene body methylation. Overall, HOXD12 expression and gene body hypermethylation were associated with an older, atypically aggressive subtype of oligodendroglioma.
期刊介绍:
Acta Neuropathologica publishes top-quality papers on the pathology of neurological diseases and experimental studies on molecular and cellular mechanisms using in vitro and in vivo models, ideally validated by analysis of human tissues. The journal accepts Original Papers, Review Articles, Case Reports, and Scientific Correspondence (Letters). Manuscripts must adhere to ethical standards, including review by appropriate ethics committees for human studies and compliance with principles of laboratory animal care for animal experiments. Failure to comply may result in rejection of the manuscript, and authors are responsible for ensuring accuracy and adherence to these requirements.