Profiles of brain metastases: Prioritization of therapeutic targets.
Profiles of brain metastases: Prioritization of therapeutic targets.
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DOI：
10.1002/ijc.31624
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发表时间：
2018-12-01
影响因子：
6.4
通讯作者：
Heimberger AB
中科院分区：
文献类型：
--
作者：
Ferguson SD;Zheng S;Xiu J;Zhou S;Khasraw M;Brastianos PK;Kesari S;Hu J;Rudnick J;Salacz ME;Piccioni D;Huang S;Davies MA;Glitza IC;Heymach JV;Zhang J;Ibrahim NK;DeGroot JF;McCarty J;O'Brien BJ;Sawaya R;Verhaak RGW;Reddy SK;Priebe W;Gatalica Z;Spetzler D;Heimberger AB
我们试图比较常见癌症脑转移瘤与原发性肿瘤和颅外转移瘤的肿瘤特征，以确定潜在的靶点并优先考虑合理的治疗策略。从全球各地患者的非小细胞肺癌、乳腺癌和黑色素瘤的原发性和转移性部位采集肿瘤样本，并将其提交给Caris Life Sciences进行肿瘤多平台分析，包括基因测序（桑格和下一代测序，靶向47个基因组）、蛋白表达（通过免疫组化测定）和基因扩增（通过原位杂交测定）。数据分析考虑脑转移瘤、颅外转移瘤和原发肿瘤之间的差异蛋白表达、基因扩增和突变。分析人群包括：16，999例不匹配的原发性肿瘤和/或转移样本：8，178例非小细胞肺癌（5，098例原发癌; 2，787例全身转移癌; 293例脑转移癌），7，064例乳腺癌（3，496例原发瘤; 3，469例全身转移瘤; 99例脑转移瘤）和1，757例黑素瘤（660例原发瘤; 996例全身转移瘤; 101例脑转移瘤）。在所有3种癌症的脑转移瘤中，TOP 2A表达增加，并且脑转移瘤过表达多种蛋白质，这些蛋白质聚集在对DNA合成和修复至关重要的功能周围，并与化疗耐药性有关，包括RRM 1，TS，ERCC 1和TOPO 1。相对于原发性皮肤标本，cMET在黑素瘤脑转移瘤中过表达。脑转移患者可以特别受益于与DNA合成、复制和/或修复相关的酶的治疗靶向。 有什么新消息吗？ 脑转移瘤很难治疗，通常是致命的。在这里，作者通过比较肺癌、乳腺癌和皮肤癌与脑转移癌的分子特征来寻找可能的治疗靶点的线索。他们分析了超过17，000个样本的DNA序列，蛋白质表达和基因扩增，这是有史以来最大的转移队列研究。他们发现参与DNA转录的酶TOP 2A相对于原发性肿瘤细胞在转移性细胞中富集。其他参与DNA合成、修复和复制的酶在转移瘤中也过表达，可能成为有用的治疗靶点。
We sought to compare the tumor profiles of brain metastases from common cancers with those of primary tumors and extracranial metastases in order to identify potential targets and prioritize rational treatment strategies. Tumor samples were collected from both the primary and metastatic sites of nonsmall cell lung cancer, breast cancer and melanoma from patients in locations worldwide, and these were submitted to Caris Life Sciences for tumor multiplatform analysis, including gene sequencing (Sanger and next‐generation sequencing with a targeted 47‐gene panel), protein expression (assayed by immunohistochemistry) and gene amplification (assayed by in situ hybridization). The data analysis considered differential protein expression, gene amplification and mutations among brain metastases, extracranial metastases and primary tumors. The analyzed population included: 16,999 unmatched primary tumor and/or metastasis samples: 8,178 nonsmall cell lung cancers (5,098 primaries; 2,787 systemic metastases; 293 brain metastases), 7,064 breast cancers (3,496 primaries; 3,469 systemic metastases; 99 brain metastases) and 1,757 melanomas (660 primaries; 996 systemic metastases; 101 brain metastases). TOP2A expression was increased in brain metastases from all 3 cancers, and brain metastases overexpressed multiple proteins clustering around functions critical to DNA synthesis and repair and implicated in chemotherapy resistance, including RRM1, TS, ERCC1 and TOPO1. cMET was overexpressed in melanoma brain metastases relative to primary skin specimens. Brain metastasis patients may particularly benefit from therapeutic targeting of enzymes associated with DNA synthesis, replication and/or repair. What's new? Brain metastases are difficult to treat and generally lethal. Here, the authors sought clues to possible treatment targets by comparing the molecular characteristics of lung, breast, and skin cancers with those of brain metastases. They analyzed DNA sequence, protein expression, and gene amplification on over 17,000 samples, the largest metastases cohort ever studied. They found that the enzyme TOP2A, involved in DNA transcription, was enriched in the metastatic cells relative to the primary tumor cells. Other enzymes, involved in DNA synthesis, repair, and replication were also overexpressed in metastases, and could potentially be useful therapeutic targets.
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DOI：
10.1200/jco.2015.61.1525
发表时间：
2015-10-01
期刊：
Journal of clinical oncology : official journal of the American Society of Clinical Oncology
影响因子：
--
作者：
Gounder MM;Nayak L;Sahebjam S;Muzikansky A;Sanchez AJ;Desideri S;Ye X;Ivy SP;Nabors LB;Prados M;Grossman S;DeAngelis LM;Wen PY
通讯作者：
Wen PY
DOI：
10.1016/s1470-2045(16)30053-5
发表时间：
2016-07
期刊：
The Lancet. Oncology
影响因子：
--
作者：
Goldberg SB;Gettinger SN;Mahajan A;Chiang AC;Herbst RS;Sznol M;Tsiouris AJ;Cohen J;Vortmeyer A;Jilaveanu L;Yu J;Hegde U;Speaker S;Madura M;Ralabate A;Rivera A;Rowen E;Gerrish H;Yao X;Chiang V;Kluger HM
通讯作者：
Kluger HM
影响因子：
2.6
作者：
Ali, A.;Goffin, J. R.;Ellis, P. M.
通讯作者：
Ellis, P. M.
DOI：
10.1111/j.2517-6161.1995.tb02031.x
发表时间：
1995-01-01
影响因子：
5.8
作者：
BENJAMINI, Y;HOCHBERG, Y
通讯作者：
HOCHBERG, Y
影响因子：
8
作者：
Kauffmann, A.;Rosselli, F.;Sarasin, A.
通讯作者：
Sarasin, A.