A case study of an integrative genomic and experimental therapeutic approach for rare tumors: identification of vulnerabilities in a pediatric poorly differentiated carcinoma.
A case study of an integrative genomic and experimental therapeutic approach for rare tumors: identification of vulnerabilities in a pediatric poorly differentiated carcinoma.
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DOI：
10.1186/s13073-016-0366-0
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发表时间：
2016-10-31
期刊：
影响因子：
12.3
通讯作者：
Kung AL
中科院分区：
文献类型：
--
作者：
Dela Cruz FS;Diolaiti D;Turk AT;Rainey AR;Ambesi-Impiombato A;Andrews SJ;Mansukhani MM;Nagy PL;Alvarez MJ;Califano A;Forouhar F;Modzelewski B;Mitchell CM;Yamashiro DJ;Marks LJ;Glade Bender JL;Kung AL
精确医学方法非常适合于罕见肿瘤，其中综合表征可能具有诊断，预后和治疗价值。我们描述了一个青少年转移性低分化癌（PDC）的临床病例和分子特征。鉴于PDC在儿童中的罕见性和不良预后，我们利用基因组分析和临床前模型来验证致癌驱动因素并确定分子脆弱性。我们利用全外显子组测序（WES）和转录组分析来鉴定患者肿瘤的种系和体细胞改变。计算机和体外研究被用来确定基因组改变的功能后果。原发肿瘤用于生成患者源性异种移植（PDX）模型，该模型用于预测治疗方案的体内评估。WES在APC中发现了一个新的种系移码变异（p.E1554fs），确定了Gardner综合征的诊断，并在肿瘤中发现了一个体细胞无意义（p.R790*） APC突变。TP53、MAX、BRAF、ROS1和RPTOR的体细胞突变也被发现，转录组和免疫组织化学分析表明Wnt/ß-catenin和AKT/mTOR通路过度激活。硅和生化分析表明，MAX p.R60Q和BRAF p.K483E突变是激活突变，而ROS1和RPTOR突变对治疗靶向的效用较低。利用患者特异性PDX模型，我们证明了替西莫司对mTOR抑制的体内活性以及对MEK抑制的部分反应。这一临床病例说明了研究的深度，需要充分表征通过基因组分析确定的改变广度的功能意义。本文的在线版本（doi:10.1186/ s130773 -016-0366-0）包含补充材料，可供授权用户使用。
Precision medicine approaches are ideally suited for rare tumors where comprehensive characterization may have diagnostic, prognostic, and therapeutic value. We describe the clinical case and molecular characterization of an adolescent with metastatic poorly differentiated carcinoma (PDC). Given the rarity and poor prognosis associated with PDC in children, we utilized genomic analysis and preclinical models to validate oncogenic drivers and identify molecular vulnerabilities. We utilized whole exome sequencing (WES) and transcriptome analysis to identify germline and somatic alterations in the patient’s tumor. In silico and in vitro studies were used to determine the functional consequences of genomic alterations. Primary tumor was used to generate a patient-derived xenograft (PDX) model, which was used for in vivo assessment of predicted therapeutic options. WES revealed a novel germline frameshift variant (p.E1554fs) in APC, establishing a diagnosis of Gardner syndrome, along with a somatic nonsense (p.R790*) APC mutation in the tumor. Somatic mutations in TP53, MAX, BRAF, ROS1, and RPTOR were also identified and transcriptome and immunohistochemical analyses suggested hyperactivation of the Wnt/ß-catenin and AKT/mTOR pathways. In silico and biochemical assays demonstrated that the MAX p.R60Q and BRAF p.K483E mutations were activating mutations, whereas the ROS1 and RPTOR mutations were of lower utility for therapeutic targeting. Utilizing a patient-specific PDX model, we demonstrated in vivo activity of mTOR inhibition with temsirolimus and partial response to inhibition of MEK. This clinical case illustrates the depth of investigation necessary to fully characterize the functional significance of the breadth of alterations identified through genomic analysis. The online version of this article (doi:10.1186/s13073-016-0366-0) contains supplementary material, which is available to authorized users.
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