View metadata, citation and similar papers at core.ac.uk brought to you by CORE provided by Springer - Publisher Connector Zhrebker et al. BMC Cancer (2017) 17:17 DOI 10.1186/s12885-016-3000-z CASE REPORT Open Access Case report: whole exome sequencing of primary cardiac angiosarcoma highlights potential for targeted therapies Leah Zhrebker1,2*, Irene Cherni3, Lara M. Gross2, Margaret M. Hinshelwood1, Merrick Reese1,4, Jessica Aldrich3, Joseph M. Guileyardo5, William C. Roberts2,5, David Craig3, Daniel D. Von Hoff6, Robert G. Mennel1,4,7 and John D. Carpten3 Abstract Background: Primary cardiac angiosarcomas are rare, but they are the most aggressive type of primary cardiac neoplasms. When patients do present, it is with advanced pulmonary and/or cardiac symptoms. Therefore, many times the correct diagnosis is not made at the time of initial presentation. These patients have metastatic disease and the vast majority of these patients die within a few months after diagnosis. Currently the treatment choices are limited and there are no targeted therapies available. Case presentation: A 56-year-old male presented with shortness of breath, night sweats, and productive cough for a month. Workup revealed pericardial effusion and multiple bilateral pulmonary nodules suspicious for metastatic disease. Transthoracic echocardiogram showed a large pericardial effusion and a large mass in the base of the right atrium. Results of biopsy of bilateral lung nodules established a diagnosis of primary cardiac angiosarcoma. Aggressive pulmonary disease caused rapid deterioration; the patient went on hospice and subsequently died. Whole exome sequencing of the patient’s postmortem tumor revealed a novel KDR (G681R) mutation, and focal high-level amplification at chromosome 1q encompassing MDM4, a negative regulator of TP53. Conclusion: Mutations in KDR have been reported previously in angiosarcomas. Previous studies also demonstrated that KDR mutants with constitutive KDR activation could be inhibited with specific KDR inhibitors in vitro. Thus, patients harboring activating KDR mutations could be candidates for treatment with KDR-specific inhibitors. Keywords: Cardiac angiosarcoma, Whole exome sequencing, Activating gene mutation, Targeted therapies Background sarcomas, normally originate in the right atrium near Primary cardiac tumors are very rare; the reported inci- the atrioventricular groove [4, 5]. dence in most autopsy and surgery series varies from Initially, there are no noticeable symptoms for patients 0.001 to 0.3% [1–3]. Of tumors that arise in the heart, with cardiac angiosarcoma. When patients do present they most are benign and approximately 25% are malignant. tend to have locally advanced or metastatic disease. Most About 95% of the malignant tumors are sarcomas, and symptoms are related to intracardiac flow obstruction, they comprise 10 to 15% of the total primary cardiac pericardial effusion and tamponade, tumor embolism, and tumors. Sarcomas can develop in any site in the heart, systemic or constitutional symptoms due to metastatic but angiosarcomas, which account for a third of all disease [6–8]. Lung metastases are common at presenta- tion [4, 9]. Additionally, metastases have been reported in liver, lymph nodes, bone, adrenal glands, and to a lesser * Correspondence: [email protected] extent the central nervous system (CNS) and spleen [4, 9]. 1 Baylor Charles A. Sammons Cancer Center at Dallas, Baylor University Due to the late stage at presentation, prognosis for Medical Center at Dallas, 3410 Worth Street, Dallas, TX 75246, USA 2Department of Internal Medicine, Baylor University Medical Center at Dallas, patients with primary angiosarcoma of the heart is poor; 3500 Gaston Ave, Dallas, TX 75246, USA median overall survival varies from 6 months or less for Full list of author information is available at the end of the article © The Author(s). 2017 Open Access This article is distributed under the terms of the Creative Commons Attribution 4.0 International License (http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated. Zhrebker et al. BMC Cancer (2017) 17:17 Page 2 of 10 untreated patients to 12 months for patients with incom- phosphatase, receptor type, B (PTPRB) and Phospholipase plete tumor resection [6, 10–12]. Tumor often invades C, gamma 1 (PLCG1), a signal transducer of tyrosine kin- into the adjacent tissues, making complete resection chal- ase activators [31]. In the current study, we used custom- lenging, if not impossible. In some cases, cardiac trans- designed expanded exome capture to interrogate the plantation for patients with primary cardiac angiosarcoma genome of an aggressive primary cardiac angiosarcoma has been reported, albeit with poor outcomes, with most case using a genome-wide sequencing approach that in- patients dying from recurrence within 1 year of surgery. cluded analysis of the annotated coding exome along with Cardiac transplantation is not currently recommended additional probes that allowed for genome-wide copy num- even for patients without evidence of metastatic disease ber analysis and the structural analysis of specific regions due to lack of survival benefit to patients with transplant- of the genome to capture translocations and inversions. ation [13–15]. This analysis allowed for a comprehensive assessment of Existing treatment strategies include resection for the genomic landscape of this aggressive angiosarcoma. non-metastatic disease, chemotherapy, and radiation. Herein we describe the results of whole exome se- There are limited data showing chemotherapy treatment quencing a primary, cardiac angiosarcoma. We found a algorithms for cardiac angiosarcoma. Currently used novel KDR (G681R) mutation which is a putative ligand- chemotherapies include traditional agents such as pacli- independent activating mutation. Additionally, we dis- taxel, docetaxel, and doxorubicin. Angiogenesis inhibi- covered a focal high-level amplification at chromosome tors, drugs that target the growth of endothelial cells, 1q encompassing MDM4 p53 binding protein homolog such as bevacizumab, sunitinib, and sorafenib, have been (MDM4), a negative regulator of TP53. We discuss po- used as well. Although some therapies may extend the tential therapeutic therapies which may be effective in lifespan of patients when combined with other modal- treating patients with tumors containing these muta- ities [16], none of the traditional chemotherapies or tions/amplifications. newer agents have been shown to eradicate microscopic disease [17–20]. Lack of efficacy in existing treatment Case presentation options highlights the need for targeted cancer therapies This case was presented previously [32]. Briefly, a 56- for patients with cardiac angiosarcoma. year-old Caucasian male was transferred to our hospital To date, various studies investigated specific genes for possible pericardial window by cardiothoracic sur- and pathways altered in angiosarcoma. V-Myc Avian gery after a transthoracic echocardiogram revealed a Myelocytomatosis Viral Oncogene Homolog (MYC)amp- large pericardial effusion. A computed tomography scan lified tumors are common in radiation-induced and of the chest revealed numerous pulmonary nodules sur- lymphedema-associated angiosarcomas [21]. Moreover, rounded by ground glass densities, along with small Fms Related Tyrosine Kinase 4 (FLT4)andMYC co- pleural effusions, and moderate to large pericardial effu- amplification was observed in 25% of secondary angiosar- sion. Approximately 1250 ml of fluid was removed by comas [22]. Point mutations in V-Ki-ras2 Kirsten rat pericardiocentesis, and the fluid was negative for the sarcoma viral oncogene homolog (KRAS) oncogene were presence of infection or malignancy. Whole body posi- found in liver angiosarcoma [23]. In other reports, a pri- tron emission tomography scan revealed a large, irregu- mary skin angiosarcoma and liver angiosarcoma lacked larly shaped, strikingly hypermetabolic cardiac lesion of expression of p16, the product of the Cyclin Dependent probable right atrium origin (Fig. 1a). Moreover, there Kinase Inhibitor 2A (CDKN2A)gene[24–26]. A number were extensive hypermetabolic pulmonary nodules in a of studies found high expression of mutated Tumor pro- background of ground glass infiltrates (Fig. 1b). A tein P53 (TP53) gene in the tumor cells of angiosarcoma provisional diagnosis of cardiac sarcoma was made, and from various tissues of origin [26–29]. Microarray expres- the patient underwent a left video-assisted thoracotomy, sion studies revealed upregulation of a number of pericardial window and biopsy, and left lower lobe resec- vascular-specific receptor tyrosine kinases, including tion. Tumor cells in the lung nodules were both epithe- Tyrosine Kinase with Immunoglobulin like and EGF Like liod and spindle-shaped in appearance. They were Domains 1 (TIE1), Kinase Insert Domain Receptor (KDR), immunoreactive for Cluster of Differentiation (CD)31, SNF Related Kinase (SNRK), TEK Receptor Tyrosine Kin- CD34, and Factor VIII-related antigen, findings that ase (TEK), and Fms Related Tyrosine Kinase 1 (FLT1)in were consistent