Increased mRNA expression of CDKN2A is a transcriptomic marker of clinically aggressive meningiomas.
Increased mRNA expression of CDKN2A is a transcriptomic marker of clinically aggressive meningiomas.
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DOI：
10.1007/s00401-023-02571-3
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发表时间：
2023-07
影响因子：
12.7
通讯作者：
Zadeh, Gelareh
中科院分区：
文献类型：
--
作者：
Wang, Justin;Patil, Vikas;Liu, Jeff;Dogan, Helin;Tabatabai, Ghazaleh S.;Yefet, Leeor;Behling, Felix;Hoffman, Elgin;Bunda, Severa;Yakubov, Rebecca;Kaloti, Ramneet;Brandner, Sebastian;Gao, Andrew;Cohen-Gadol, Aaron;Barnholtz-Sloan, Jill;Skardelly, Marco;Tatagiba, Marcos R.;Raleigh, David;Sahm, Felix C.;Boutros, Paul;Aldape, Kenneth;Nassiri, Farshad;Zadeh, Gelareh
CDKN2A/B纯合缺失最近被纳入世界卫生组织3级脑膜瘤的分类。虽然该标记在脑膜瘤中非常罕见，但其在转录组学、表观基因组学和拷贝数水平上与其他CDKN2A改变的关系尚未确定。因此，我们利用来自临床侵袭性脑膜瘤的6个独立队列的1577个脑膜瘤样本的多维分子数据，通过DNA甲基化、拷贝数变异、转录组学和蛋白质组学等综合分子方法，全面探究CDKN2A改变的谱。纯合子CDKN2A/B缺失仅在7.1%的病例中被发现，但与没有这些缺失的肿瘤相比，其预后明显较差。杂合子CDKN2A/B缺失在2.6%的病例中被鉴定出来，其预后与纯合子缺失相似。在具有完整CDKN2A/B（没有纯合或杂合缺失）的肿瘤中，我们发现基于CDKN2A mRNA表达的结果有明显差异，mRNA表达升高（CDKN2Ahigh）的脑膜瘤的复发时间显著缩短。在考虑拷贝数丢失后，CDKN2A的表达是独立的预后因素，并且与WHO分级和更具侵袭性的分子和甲基化组一致增加，而与队列无关。尽管CDKN2A基因在这些组中存在不一致和相互排斥的状态，但CDKN2A高水平脑膜瘤和CDKN2A缺失的脑膜瘤在相似的细胞周期途径中富集，但在不同的检查点上富集。CDKN2A mRNA的高表达也与基因高甲基化、rb缺乏和对CDK抑制缺乏反应有关。p16免疫组织化学不能可靠地区分有或没有CDKN2A缺失的脑膜瘤，但似乎与mRNA表达有更好的相关性。这些发现支持CDKN2A mRNA表达作为临床侵袭性脑膜瘤的生物标志物的作用，具有潜在的治疗意义。在线版本包含补充材料，可在10.1007/s00401-023-02571-3获得。
Homozygous deletion of CDKN2A/B was recently incorporated into the World Health Organization classification for grade 3 meningiomas. While this marker is overall rare in meningiomas, its relationship to other CDKN2A alterations on a transcriptomic, epigenomic, and copy number level has not yet been determined. We therefore utilized multidimensional molecular data of 1577 meningioma samples from 6 independent cohorts enriched for clinically aggressive meningiomas to comprehensively interrogate the spectrum of CDKN2A alterations through DNA methylation, copy number variation, transcriptomics, and proteomics using an integrated molecular approach. Homozygous CDKN2A/B deletions were identified in only 7.1% of cases but were associated with significantly poorer outcomes compared to tumors without these deletions. Heterozygous CDKN2A/B deletions were identified in 2.6% of cases and had similarly poor outcomes as those with homozygous deletions. Among tumors with intact CDKN2A/B (without a homozygous or heterozygous deletion), we found a distinct difference in outcome based on mRNA expression of CDKN2A, with meningiomas that had elevated mRNA expression (CDKN2Ahigh) having a significantly shorter time to recurrence. The expression of CDKN2A was independently prognostic after accounting for copy number loss and consistently increased with WHO grade and more aggressive molecular and methylation groups irrespective of cohort. Despite the discordant and mutually exclusive status of the CDKN2A gene in these groups, both CDKN2Ahigh meningiomas and meningiomas with CDKN2A deletions were enriched for similar cell cycle pathways but at different checkpoints. High mRNA expression of CDKN2A was also associated with gene hypermethylation, Rb-deficiency, and lack of response to CDK inhibition. p16 immunohistochemistry could not reliably differentiate between meningiomas with and without CDKN2A deletions but appeared to correlate better with mRNA expression. These findings support the role of CDKN2A mRNA expression as a biomarker of clinically aggressive meningiomas with potential therapeutic implications. The online version contains supplementary material available at 10.1007/s00401-023-02571-3.
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DOI：
10.1111/bpa.13132
发表时间：
2023-05
期刊：
Brain pathology (Zurich, Switzerland)
影响因子：
--
作者：
通讯作者：
--
影响因子：
11.5
作者：
Chen, William S.;Alshalalfa, Mohammed;Feng, Felix Y.
通讯作者：
Feng, Felix Y.
影响因子：
2.1
作者：
Buj, Raquel;Aird, Katherine M.
通讯作者：
Aird, Katherine M.
影响因子：
13.6
作者：
Bayley, James C.;Hadley, Caroline C.;Patel, Akash J.
通讯作者：
Patel, Akash J.
影响因子：
7.4
作者：
Michelhaugh SK;Guastella AR;Varadarajan K;Klinger NV;Parajuli P;Ahmad A;Sethi S;Aboukameel A;Kiousis S;Zitron IM;Ebrahim SA;Polin LA;Sarkar FH;Bollig-Fischer A;Mittal S
通讯作者：
Mittal S