A role for SETD2 loss in tumorigenesis through DNA methylation dysregulation.
A role for SETD2 loss in tumorigenesis through DNA methylation dysregulation.
复制标题
通过DNA甲基化失调，SETD2缺失在肿瘤发生中的作用。
DOI：
10.1186/s12885-023-11162-0
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发表时间：
2023-08-01
期刊：
影响因子：
3.8
通讯作者：
Humphrey, Timothy C. C.
中科院分区：
文献类型：
--
作者：
Javaid, Hira;Barberis, Alessandro;Chervova, Olga;Nassiri, Isar;Voloshin, Vitaly;Sato, Yusuke;Ogawa, Seishi;Fairfax, Benjamin;Buffa, Francesca;Humphrey, Timothy C. C.
SETD 2依赖性H3赖氨酸-36三甲基化（H3 K36 me 3）最近已与从头DNA甲基化的沉积有关。SETD 2在癌症中经常发生突变，然而，目前尚不清楚SETD 2缺失和缺失对癌症类型和肿瘤发生中DNA甲基化的功能影响。在这里，我们进行了一项泛癌症分析，并表明SETD 2突变和表达减少与24种癌症类型中的21种的DNA甲基化失调有关。在肾癌中，这些DNA甲基化变化与癌基因、肿瘤抑制基因和肿瘤侵袭相关基因（包括TP 53、FOXO 1和CDK 4）的基因表达改变相关。这表明，通过DNA甲基化失调，SETD 2丢失在肿瘤发生和癌症侵袭性中的新作用。此外，使用强大的机器学习方法，我们开发并验证了3-CpG甲基化特征，该特征足以高准确性地预测SETD 2突变状态，并与患者预后相关。在线版本包含补充材料，可通过10.1186/s12885-023-11162-0获得。
SETD2-dependent H3 Lysine-36 trimethylation (H3K36me3) has been recently linked to the deposition of de-novo DNA methylation. SETD2 is frequently mutated in cancer, however, the functional impact of SETD2 loss and depletion on DNA methylation across cancer types and tumorigenesis is currently unknown. Here, we perform a pan-cancer analysis and show that both SETD2 mutation and reduced expression are associated with DNA methylation dysregulation across 21 out of the 24 cancer types tested. In renal cancer, these DNA methylation changes are associated with altered gene expression of oncogenes, tumour suppressors, and genes involved in neoplasm invasiveness, including TP53, FOXO1, and CDK4. This suggests a new role for SETD2 loss in tumorigenesis and cancer aggressiveness through DNA methylation dysregulation. Moreover, using a robust machine learning methodology, we develop and validate a 3-CpG methylation signature which is sufficient to predict SETD2 mutation status with high accuracy and correlates with patient prognosis. The online version contains supplementary material available at 10.1186/s12885-023-11162-0.
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影响因子：
46.9
作者：
Ball, Madeleine P.;Li, Jin Billy;Gao, Yuan;Lee, Je-Hyuk;LeProust, Emily M.;Park, In-Hyun;Xie, Bin;Daley, George Q.;Church, George M.
通讯作者：
Church, George M.
影响因子：
7.3
作者：
Gao J;Aksoy BA;Dogrusoz U;Dresdner G;Gross B;Sumer SO;Sun Y;Jacobsen A;Sinha R;Larsson E;Cerami E;Sander C;Schultz N
通讯作者：
Schultz N
DOI：
10.1038/nrm4043
发表时间：
2015-09
期刊：
Nature reviews. Molecular cell biology
影响因子：
--
作者：
Du J;Johnson LM;Jacobsen SE;Patel DJ
通讯作者：
Patel DJ
影响因子：
14.9
作者：
Colaprico A;Silva TC;Olsen C;Garofano L;Cava C;Garolini D;Sabedot TS;Malta TM;Pagnotta SM;Castiglioni I;Ceccarelli M;Bontempi G;Noushmehr H
通讯作者：
Noushmehr H
影响因子：
2.3
作者：
Dong Y;Zhao H;Li H;Li X;Yang S
通讯作者：
Yang S