The GALNT9, BNC1 and CCDC8 genes are frequently epigenetically dysregulated in breast tumours that metastasise to the brain.
The GALNT9, BNC1 and CCDC8 genes are frequently epigenetically dysregulated in breast tumours that metastasise to the brain.
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DOI：
10.1186/s13148-015-0089-x
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发表时间：
2015
影响因子：
5.7
通讯作者：
Morris MR
中科院分区：
文献类型：
--
作者：
Pangeni RP;Channathodiyil P;Huen DS;Eagles LW;Johal BK;Pasha D;Hadjistephanou N;Nevell O;Davies CL;Adewumi AI;Khanom H;Samra IS;Buzatto VC;Chandrasekaran P;Shinawi T;Dawson TP;Ashton KM;Davis C;Brodbelt AR;Jenkinson MD;Bièche I;Latif F;Darling JL;Warr TJ;Morris MR
在某些癌症中，肿瘤转移到大脑是一种常见的致命发展；18%-30%的乳腺肿瘤转移到大脑。基因沉默通过表观遗传机制在这些转移性肿瘤中所起的作用还不是很清楚。我们对可在癌症基因组图谱(TCGA)获得的全基因组乳腺肿瘤甲基化数据进行了生物信息学筛选，并进行了广泛的文献综述，以确定可能导致乳腺到脑转移(BBM)的候选基因。这项分析确定了82名候选人。我们利用亚硫酸氢盐和限制性内切酶联合分析(Cobra)对这些基因的甲基化状态进行了研究，发现了21个在BBM中频繁甲基化的基因。我们已经鉴定出三个基因，GALNT9，CCDC8和BNC1，它们在BBM中频繁甲基化(分别为55%，73%和71%)，在BBM中沉默，在原发乳腺肿瘤中很少甲基化。CCDC8在脑转移瘤及其相关原发肿瘤中普遍甲基化，而GALNT9和BNC1仅在脑转移瘤中甲基化和沉默，而在个别患者相关的原发乳腺肿瘤中不表达。这表明这些基因在转移性肿瘤进化中的不同作用；CCDC8甲基化发生在转移进化的早期阶段，而GANLT9和BNC1的甲基化发生在肿瘤进化的后期阶段。这些基因被RNAi敲除后，乳腺癌细胞系的迁移和侵袭能力显著增加。这些发现表明，GALNT9(O-糖基化的启动子)、CCDC8(微管动力学的调节因子)和BNC1(一种具有广泛靶点的转录因子)可能在原发乳腺癌向脑转移的进展中发挥作用。这些基因可能是有用的预后标记物，其产物可能提供新的治疗靶点。本文的在线版本(doi：10.1186/s13148.0150089x)包含补充材料，授权用户可以使用。
Tumour metastasis to the brain is a common and deadly development in certain cancers; 18–30 % of breast tumours metastasise to the brain. The contribution that gene silencing through epigenetic mechanisms plays in these metastatic tumours is not well understood. We have carried out a bioinformatic screen of genome-wide breast tumour methylation data available at The Cancer Genome Atlas (TCGA) and a broad literature review to identify candidate genes that may contribute to breast to brain metastasis (BBM). This analysis identified 82 candidates. We investigated the methylation status of these genes using Combined Bisulfite and Restriction Analysis (CoBRA) and identified 21 genes frequently methylated in BBM. We have identified three genes, GALNT9, CCDC8 and BNC1, that were frequently methylated (55, 73 and 71 %, respectively) and silenced in BBM and infrequently methylated in primary breast tumours. CCDC8 was commonly methylated in brain metastases and their associated primary tumours whereas GALNT9 and BNC1 were methylated and silenced only in brain metastases, but not in the associated primary breast tumours from individual patients. This suggests differing roles for these genes in the evolution of metastatic tumours; CCDC8 methylation occurs at an early stage of metastatic evolution whereas methylation of GANLT9 and BNC1 occurs at a later stage of tumour evolution. Knockdown of these genes by RNAi resulted in a significant increase in the migratory and invasive potential of breast cancer cell lines. These findings indicate that GALNT9 (an initiator of O-glycosylation), CCDC8 (a regulator of microtubule dynamics) and BNC1 (a transcription factor with a broad range of targets) may play a role in the progression of primary breast tumours to brain metastases. These genes may be useful as prognostic markers and their products may provide novel therapeutic targets. The online version of this article (doi:10.1186/s13148-015-0089-x) contains supplementary material, which is available to authorized users.
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影响因子：
4.7
作者：
Ai, Lingbao;Tao, Qian;Robertson, Keith D.
通讯作者：
Robertson, Keith D.
影响因子：
64.8
作者：
Curtis, Christina;Shah, Sohrab P.;Chin, Suet-Feung;Turashvili, Gulisa;Rueda, Oscar M.;Dunning, Mark J.;Speed, Doug;Lynch, Andy G.;Samarajiwa, Shamith;Yuan, Yinyin;Graef, Stefan;Ha, Gavin;Haffari, Gholamreza;Bashashati, Ali;Russell, Roslin;McKinney, Steven;Langerod, Anita;Green, Andrew;Provenzano, Elena;Wishart, Gordon;Pinder, Sarah;Watson, Peter;Markowetz, Florian;Murphy, Leigh;Ellis, Ian;Purushotham, Arnie;Borresen-Dale, Anne-Lise;Brenton, James D.;Tavare, Simon;Caldas, Carlos;Aparicio, Samuel
通讯作者：
Aparicio, Samuel
DOI：
10.1038/nrclinonc.2011.58
发表时间：
2011-06
期刊：
Nature reviews. Clinical oncology
影响因子：
--
作者：
通讯作者：
--
影响因子：
3.7
作者：
Dunwell, Thomas L.;Hesson, Luke B.;Latif, Farida
通讯作者：
Latif, Farida
影响因子：
9.8
作者：
Hanson, Dan;Murray, Philip G.;Black, Graeme C. M.
通讯作者：
Black, Graeme C. M.