Characterization of the genomic features and expressed fusion genes in micropapillary carcinomas of the breast.
Characterization of the genomic features and expressed fusion genes in micropapillary carcinomas of the breast.
复制标题
DOI：
10.1002/path.4325
复制
发表时间：
2014-04
影响因子：
7.3
通讯作者：
Reis-Filho, Jorge S.
中科院分区：
文献类型：
--
作者：
Natrajan, Rachael;Wilkerson, Paul M.;Marchio, Caterina;Piscuoglio, Salvatore;Ng, Charlotte K. Y.;Wai, Patty;Lambros, Maryou B.;Samartzis, Eleftherios P.;Dedes, Konstantin J.;Frankum, Jessica;Bajrami, Ilirjana;Kopec, Alicja;Mackay, Alan;A'hern, Roger;Fenwick, Kerry;Kozarewa, Iwanka;Hakas, Jarle;Mitsopoulos, Costas;Hardisson, David;Lord, Christopher J.;Kumar-Sinha, Chandan;Ashworth, Alan;Weigelt, Britta;Sapino, Anna;Chinnaiyan, Arul M.;Maher, Christopher A.;Reis-Filho, Jorge S.
关键词：
微乳头状癌（MPC）是一种罕见的组织学特殊类型乳腺癌，其特征是侵袭性临床行为和拷贝数畸变（CNA）模式，与级别和雌激素受体（ER）匹配的非特殊类型浸润性癌（IC-NST）不同。本研究的目的是确定 MPC 是否由乳腺癌中反复发生的融合基因或 273 个反复突变的基因的突变所支撑。对 16 个 MPC 进行基于微阵列的比较基因组杂交 (aCGH) 分析和 Sequenom OncoCarta 突变分析。分别对 8 个和 5 个 MPC 进行了靶向捕获和 RNA 测序。 aCGH 分析证实了我们之前对 MPC 的 CNA 指令集的观察。测序分析揭示了一系列与 luminal B IC-NST 类似的突变，以及影响丝裂原激活蛋白激酶家族基因和 NBPF10 的反复突变。 RNA 测序分析确定了 17 个高置信度融合基因，其中 8 个经过验证，其中 2 个符合读码框。在独立的 MPC 和 IC-NST 系列中未发现复发性融合。框内融合基因（SLC2A1-FAF1 和 BCAS4-AURKA）的强制表达导致乳腺癌细胞的活力增加。此外，通过对公开的大规模并行测序数据的重新分析，在一种 MPC 和 13% 的 HER2 阳性乳腺癌中发现了由框外重排引起的 CDK12 基因组破坏。体外分析表明，CDK12 基因破坏会导致对 PARP 抑制的敏感性，而在 CDK12 无效细胞系模型中强制表达野生型 CDK12 会导致对 PARP 抑制的相对抵抗。我们的研究结果表明，MPC 既不是由所测试的 273 个基因中高度重复的突变定义的，也不是由重复出现的融合基因支撑的。尽管看似私人的遗传事件，MPC 中发现的一些融合转录本可能在维持恶性表型中发挥作用，并可能提供治疗机会。
Micropapillary carcinoma (MPC) is a rare histological special type of breast cancer, characterized by an aggressive clinical behaviour and a pattern of copy number aberrations (CNAs) distinct from that of grade- and oestrogen receptor (ER)-matched invasive carcinomas of no special type (IC-NSTs). The aims of this study were to determine whether MPCs are underpinned by a recurrent fusion gene(s) or mutations in 273 genes recurrently mutated in breast cancer. Sixteen MPCs were subjected to microarray-based comparative genomic hybridization (aCGH) analysis and Sequenom OncoCarta mutation analysis. Eight and five MPCs were subjected to targeted capture and RNA sequencing, respectively. aCGH analysis confirmed our previous observations about the repertoire of CNAs of MPCs. Sequencing analysis revealed a spectrum of mutations similar to those of luminal B IC-NSTs, and recurrent mutations affecting mitogen-activated protein kinase family genes and NBPF10. RNA-sequencing analysis identified 17 high-confidence fusion genes, eight of which were validated and two of which were in-frame. No recurrent fusions were identified in an independent series of MPCs and IC-NSTs. Forced expression of in-frame fusion genes (SLC2A1–FAF1 and BCAS4–AURKA) resulted in increased viability of breast cancer cells. In addition, genomic disruption of CDK12 caused by out-of-frame rearrangements was found in one MPC and in 13% of HER2-positive breast cancers, identified through a re-analysis of publicly available massively parallel sequencing data. In vitro analyses revealed that CDK12 gene disruption results in sensitivity to PARP inhibition, and forced expression of wild-type CDK12 in a CDK12-null cell line model resulted in relative resistance to PARP inhibition. Our findings demonstrate that MPCs are neither defined by highly recurrent mutations in the 273 genes tested, nor underpinned by a recurrent fusion gene. Although seemingly private genetic events, some of the fusion transcripts found in MPCs may play a role in maintenance of a malignant phenotype and potentially offer therapeutic opportunities.
登录
查看更多内容
影响因子：
64.8
作者：
通讯作者：
--
影响因子：
64.8
作者：
Ellis, Matthew J.;Ding, Li;Shen, Dong;Luo, Jingqin;Suman, Vera J.;Wallis, John W.;Van Tine, Brian A.;Hoog, Jeremy;Goiffon, Reece J.;Goldstein, Theodore C.;Ng, Sam;Lin, Li;Crowder, Robert;Snider, Jacqueline;Ballman, Karla;Weber, Jason;Chen, Ken;Koboldt, Daniel C.;Kandoth, Cyriac;Schierding, William S.;McMichael, Joshua F.;Miller, Christopher A.;Lu, Charles;Harris, Christopher C.;McLellan, Michael D.;Wendl, Michael C.;DeSchryver, Katherine;Allred, D. Craig;Esserman, Laura;Unzeitig, Gary;Margenthaler, Julie;Babiera, G. V.;Marcom, P. Kelly;Guenther, J. M.;Leitch, Marilyn;Hunt, Kelly;Olson, John;Tao, Yu;Maher, Christopher A.;Fulton, Lucinda L.;Fulton, Robert S.;Harrison, Michelle;Oberkfell, Ben;Du, Feiyu;Demeter, Ryan;Vickery, Tammi L.;Elhammali, Adnan;Piwnica-Worms, Helen;McDonald, Sandra;Watson, Mark;Dooling, David J.;Ota, David;Chang, Li-Wei;Bose, Ron;Ley, Timothy J.;Piwnica-Worms, David;Stuart, Joshua M.;Wilson, Richard K.;Mardis, Elaine R.
通讯作者：
Mardis, Elaine R.
影响因子：
3.8
作者：
Horlings, Hugo M.;Weigelt, Britta;Reis-Filho, Jorge S.
通讯作者：
Reis-Filho, Jorge S.
使用下一代 DNA 测序数据进行变异发现和基因分型的框架。
影响因子：
30.8
作者：
通讯作者：
--
影响因子：
45.3
作者：
Harvey, JM;Clark, GM;Allred, DC
通讯作者：
Allred, DC