Recurrent hyperactive ESR1 fusion proteins in endocrine therapy-resistant breast cancer.
Recurrent hyperactive ESR1 fusion proteins in endocrine therapy-resistant breast cancer.
复制标题
DOI：
10.1093/annonc/mdy025
复制
发表时间：
2018-04-01
期刊：
影响因子：
--
通讯作者：
Lee AV
中科院分区：
文献类型：
--
作者：
Hartmaier RJ;Trabucco SE;Priedigkeit N;Chung JH;Parachoniak CA;Vanden Borre P;Morley S;Rosenzweig M;Gay LM;Goldberg ME;Suh J;Ali SM;Ross J;Leyland-Jones B;Young B;Williams C;Park B;Tsai M;Haley B;Peguero J;Callahan RD;Sachelarie I;Cho J;Atkinson JM;Bahreini A;Nagle AM;Puhalla SL;Watters RJ;Erdogan-Yildirim Z;Cao L;Oesterreich S;Mathew A;Lucas PC;Davidson NE;Brufsky AM;Frampton GM;Stephens PJ;Chmielecki J;Lee AV
雌激素受体阳性（ER阳性）转移性乳腺癌由于内分泌治疗耐药而往往难以治疗。虽然ESR 1启动子转换事件与内分泌治疗耐药相关，但在晚期乳腺癌中尚未发现复发性ESR 1融合蛋白。为了鉴定基因组结构重排（RE），包括获得性耐药中的基因融合，我们在三个乳腺癌患者队列中进行了多模式测序：（i）在6个患者匹配的原发性转移性肿瘤和51个转移瘤中的配对和/或RNAseq，（ii）9542个实体瘤中287-395个癌症相关基因的高覆盖率（>500倍）全面基因组分析（5216个来自转移性疾病），和（iii）254个ctDNA样品中62个癌症相关基因的超高覆盖率（>5000×）基因组谱分析。除了传统的基因融合检测方法（即不一致读段、分裂读段）外，还通过应用一种新算法（copyshift）从靶向测序数据中检测ESR 1 RE，该算法可识别重排热点处的主要拷贝数偏移。我们在83名独特患者中鉴定了88种ESR 1 RE，并直接确认了9种ESR 1融合蛋白（包括2种通过免疫印迹）。ESR 1 RE在ER阳性、转移性疾病中高度富集，并与已知的ESR 1错义改变共同发生，提示多克隆耐药。重要的是，所有融合都是由ESR 1内含子6中或附近的断点产生的，因此缺乏完整的配体结合结构域（LBD）。三种融合体的体外表征揭示了依赖于3′伴侣基因的配体独立性和活性亢进。我们对ESR 1融合的下限估计至少为转移性实体乳腺癌的1%，ctDNA中的患病率至少为10倍富集。我们推测这种富集可能代表了对ESR 1 LBD错义改变患者更积极的内分泌治疗的继发性抵抗。总的来说，这些数据表明，涉及外显子6-7的N-末端ESR 1融合是内分泌治疗抗性的复发驱动因素，并且不受ER靶向治疗的影响。
Estrogen receptor-positive (ER-positive) metastatic breast cancer is often intractable due to endocrine therapy resistance. Although ESR1 promoter switching events have been associated with endocrine-therapy resistance, recurrent ESR1 fusion proteins have yet to be identified in advanced breast cancer. To identify genomic structural rearrangements (REs) including gene fusions in acquired resistance, we undertook a multimodal sequencing effort in three breast cancer patient cohorts: (i) mate-pair and/or RNAseq in 6 patient-matched primary-metastatic tumors and 51 metastases, (ii) high coverage (>500×) comprehensive genomic profiling of 287–395 cancer-related genes across 9542 solid tumors (5216 from metastatic disease), and (iii) ultra-high coverage (>5000×) genomic profiling of 62 cancer-related genes in 254 ctDNA samples. In addition to traditional gene fusion detection methods (i.e. discordant reads, split reads), ESR1 REs were detected from targeted sequencing data by applying a novel algorithm (copyshift) that identifies major copy number shifts at rearrangement hotspots. We identify 88 ESR1 REs across 83 unique patients with direct confirmation of 9 ESR1 fusion proteins (including 2 via immunoblot). ESR1 REs are highly enriched in ER-positive, metastatic disease and co-occur with known ESR1 missense alterations, suggestive of polyclonal resistance. Importantly, all fusions result from a breakpoint in or near ESR1 intron 6 and therefore lack an intact ligand binding domain (LBD). In vitro characterization of three fusions reveals ligand-independence and hyperactivity dependent upon the 3′ partner gene. Our lower-bound estimate of ESR1 fusions is at least 1% of metastatic solid breast cancers, the prevalence in ctDNA is at least 10× enriched. We postulate this enrichment may represent secondary resistance to more aggressive endocrine therapies applied to patients with ESR1 LBD missense alterations. Collectively, these data indicate that N-terminal ESR1 fusions involving exons 6–7 are a recurrent driver of endocrine therapy resistance and are impervious to ER-targeted therapies.
登录
查看更多内容
DOI：
10.1158/1078-0432.ccr-13-2332
发表时间：
2014-04-01
期刊：
Clinical cancer research : an official journal of the American Association for Cancer Research
影响因子：
--
作者：
Jeselsohn R;Yelensky R;Buchwalter G;Frampton G;Meric-Bernstam F;Gonzalez-Angulo AM;Ferrer-Lozano J;Perez-Fidalgo JA;Cristofanilli M;Gómez H;Arteaga CL;Giltnane J;Balko JM;Cronin MT;Jarosz M;Sun J;Hawryluk M;Lipson D;Otto G;Ross JS;Dvir A;Soussan-Gutman L;Wolf I;Rubinek T;Gilmore L;Schnitt S;Come SE;Pusztai L;Stephens P;Brown M;Miller VA
通讯作者：
Miller VA
影响因子：
5.8
作者：
Shugay, Mikhail;Ortiz de Mendibil, Inigo;Novo, Francisco J.
通讯作者：
Novo, Francisco J.
影响因子：
8.8
作者：
Li S;Shen D;Shao J;Crowder R;Liu W;Prat A;He X;Liu S;Hoog J;Lu C;Ding L;Griffith OL;Miller C;Larson D;Fulton RS;Harrison M;Mooney T;McMichael JF;Luo J;Tao Y;Goncalves R;Schlosberg C;Hiken JF;Saied L;Sanchez C;Giuntoli T;Bumb C;Cooper C;Kitchens RT;Lin A;Phommaly C;Davies SR;Zhang J;Kavuri MS;McEachern D;Dong YY;Ma C;Pluard T;Naughton M;Bose R;Suresh R;McDowell R;Michel L;Aft R;Gillanders W;DeSchryver K;Wilson RK;Wang S;Mills GB;Gonzalez-Angulo A;Edwards JR;Maher C;Perou CM;Mardis ER;Ellis MJ
通讯作者：
Ellis MJ
影响因子：
46.9
作者：
Frampton GM;Fichtenholtz A;Otto GA;Wang K;Downing SR;He J;Schnall-Levin M;White J;Sanford EM;An P;Sun J;Juhn F;Brennan K;Iwanik K;Maillet A;Buell J;White E;Zhao M;Balasubramanian S;Terzic S;Richards T;Banning V;Garcia L;Mahoney K;Zwirko Z;Donahue A;Beltran H;Mosquera JM;Rubin MA;Dogan S;Hedvat CV;Berger MF;Pusztai L;Lechner M;Boshoff C;Jarosz M;Vietz C;Parker A;Miller VA;Ross JS;Curran J;Cronin MT;Stephens PJ;Lipson D;Yelensky R
通讯作者：
Yelensky R
影响因子：
56.9
作者：
Tomlins, SA;Rhodes, DR;Chinnaiyan, AM
通讯作者：
Chinnaiyan, AM