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Pathways Impacted by Genomic Alterations in Pulmonary Carcinoid Tumors Michael K

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Pathways Impacted by Genomic Alterations in Pulmonary Carcinoid Tumors Michael K Published OnlineFirst January 19, 2018; DOI: 10.1158/1078-0432.CCR-17-0252 Cancer Therapy: Preclinical Clinical Cancer Research Pathways Impacted by Genomic Alterations in Pulmonary Carcinoid Tumors Michael K. Asiedu1, Charles F. Thomas Jr2, Jie Dong1, Sandra C. Schulte1, Prasidda Khadka1, Zhifu Sun3, Farhad Kosari3, Jin Jen3, Julian Molina4, George Vasmatzis3, Ray Kuang5, Marie Christine Aubry3, Ping Yang3, and Dennis A.Wigle1 Abstract Purpose: Pulmonary carcinoid tumors account for up to 5% of RAB38, NF1, RAD51C, TAF1L, EPHB2, POLR3B,andAGFG1. all lung malignancies in adults, comprise 30% of all carcinoid The mutated genes are involved in biological processes includ- malignancies, and are defined histologically as typical carcinoid ing cellular metabolism, cell division cycle, cell death, (TC) and atypical carcinoid (AC) tumors. The role of specific apoptosis, and immune regulation. The top most significantly genomic alterations in the pathogenesis of pulmonary carcinoid mutated genes were TMEM41B, DEFB127, WDYHV1, and tumors remains poorly understood. We sought to identify geno- TBPL1. Pathway analysis of significantly mutated and cancer mic alterations and pathways that are deregulated in these tumors driver genes implicated MAPK/ERK and amyloid beta precur- to find novel therapeutic targets for pulmonary carcinoid tumors. sor protein (APP) pathways whereas analysis of CNV and Experimental Design: We performed integrated genomic anal- gene expression data suggested deregulation of the NF-kBand ysis of carcinoid tumors comprising whole genome and exome MAPK/ERK pathways. The mutation signature was predomi- sequencing, mRNA expression profiling and SNP genotyping of nantly C>T and T>C transitions with a minor contribution of specimens from normal lung, TC and AC, and small cell lung T>G transversions. carcinoma (SCLC) to fully represent the lung neuroendocrine Conclusions: This study identified mutated genes affecting can- tumor spectrum. cer relevant pathways and biological processes that could provide Results: Analysis of sequencing data found recurrent muta- opportunities for developing targeted therapies for pulmonary tions in cancer genes including ATP1A2, CNNM1, MACF1, carcinoid tumors. Clin Cancer Res; 24(7); 1691–704. Ó2018 AACR. Introduction behavior, prognosis, and treatment response within the spectrum of pulmonary NETs (4). Unfortunately, an immense scientific gap Pulmonary neuroendocrine tumors (NET) include a spectrum exists in understanding the biology of these tumors, in part due to of tumors, classified as typical carcinoid (TC) tumors, atypical the lack of genomic information and suitable reagents such as cell carcinoid (AC) tumors, large-cell neuroendocrine carcinoma lines and tumor xenograft models. As a consequence, there have (LCNEC), and small-cell lung cancer (SCLC; ref. 1). Pulmonary been no major advances in the treatment and prognosis for these carcinoid tumors account for up to 5% of all lung cancers, and for cancers (2, 3, 5, 6). Currently, the only effective treatment to unclear reasons have shown the greatest increase in incidence achieve cure is complete surgical excision, which may be unat- compared with NETs from other sites from 1973 to 2005 accord- tainable depending upon the location and extent of the tumor. ing to epidemiological data from the SEER database (2, 3). Both chemotherapy and radiation therapy have limited success in Despite similarities in their morphology, structure, and immu- treating these tumors and therefore the outcome for patients with nohistochemistry, there are dramatic differences in clinical metastatic disease is poor. A recent study advancing the field by Fernandez-Cuesta and colleagues, examining genomic alterations 1 in pulmonary carcinoids using copy number analysis, exome/ Division of General Thoracic Surgery, Department of Surgery, Mayo Clinic fi College of Medicine, Rochester, Minnesota. 2Thoracic Diseases Research Unit, genome, and transcriptome sequencing identi ed recurrent muta- Division of Pulmonary, Critical Care, and Internal Medicine, Mayo Clinic College of tions in chromatin remodeling genes. The study found that 40% Medicine, Rochester, Minnesota. 3Department of Laboratory Medicine and of the cases studied harbored mutations in histone modifier genes Pathology, Mayo Clinic College of Medicine, Rochester, Minnesota. 4Department such as MEN1, PSIP1, and ARID1A, and 20% of cases had 5 of Oncology, Mayo Clinic College of Medicine, Rochester, Minnesota. University mutations in the components of the SWI/SNF complex (7). The of Minnesota, Minneapolis, Minnesota. study found MEN1, ARID1A, and EIF1AX to be significantly Note: Supplementary data for this article are available at Clinical Cancer mutated (q < 0.2; ref. 7). These results remain to be confirmed Research Online (http://clincancerres.aacrjournals.org/). in further studies. Corresponding Authors: Michael K. Asiedu, Mayo Clinic, 200 First Street SW We analyzed genomic alterations in pulmonary carcinoid Rochester, 228 Medical Science Building, MN 55905. Phone: 507-284-3482; Fax: tumors using a variety of approaches, including mRNA expres- 507-266-1163; E-mail: [email protected]; and Dennis A. Wigle, Phone: sion, SNP genotyping, and a combination of exome, and whole 507-284-8462; Fax: 507-284-0058; E-mail: [email protected] genome sequencing. Hierarchical clustering of differentially doi: 10.1158/1078-0432.CCR-17-0252 expressed genes clearly segregated histologies of normal lung, Ó2018 American Association for Cancer Research. carcinoid, and SCLC from each other. Despite this, relatively little www.aacrjournals.org 1691 Downloaded from clincancerres.aacrjournals.org on September 30, 2021. © 2018 American Association for Cancer Research. Published OnlineFirst January 19, 2018; DOI: 10.1158/1078-0432.CCR-17-0252 Asiedu et al. mutated genes. Pathway analysis of differentially expressed genes Translational Relevance with CNV changes identified the involvement of NF-kB and Pulmonary neuroendocrine tumors are classified into typ- MAPK/ERK signaling pathways. These results suggest several ical carcinoid tumors, atypical carcinoid tumors, small-cell potential opportunities for development of new therapeutic lung cancers, and large-cell neuroendocrine carcinoma. Com- approaches to treat pulmonary carcinoid tumors. plete surgical resection of the tumor remains the treatment of choice for cure in patients able to tolerate surgery. For patients Materials and Methods with tumors not amenable to surgical resection, there are This study was reviewed and approved by the Mayo Clinic currently no targeted therapies available and chemotherapeu- Institutional Review Board and the Biospecimen Protocol tic options have low response rates of 20% or less. There is Review Group. Informed consent was obtained prior to speci- therefore the need to identify genomic alterations and signal- men collection and medical chart review for each patient. ing pathways deregulated in these tumors to aid the develop- Prospectively collected samples of surgically resected TC tumors ment of alternative therapies. We performed integrated geno- n ¼ n ¼ n ¼ fi ( 39), AC tumors ( 12), SCLC ( 12), and corresponding mic analysis and identi ed recurrent mutated genes including n ¼ ATP1A2, CNNM1, MACF1, RAB38, NF1, RAD51C, TAF1L, normal lung tissue ( 26) were obtained from the Mayo Clinic Lung Tissue Registry. Patient demographics, clinical, surgical EPHB2, POLR3B, and AGFG1. Pathway analysis of mutated and pathologic data, including tumor recurrence, tumor metas- genes implicated MAPK/ERK and APP signaling pathways tasis, and patient survival were extracted from medical records. whereas analysis of CNV and gene expression data identified The tumor stage was adjusted according to the seventh edition of deregulation of the NF-B and MAPK/ERK pathways. Targeting the TNM classification of malignant tumors (6, 8, 9). A summary recurrent mutated genes as well as ERK and NF-B pathways of the patient characteristics is provided in Table 1 and Supple- might represent therapeutic options for pulmonary carcinoid mentary Table S1. tumors. Sample acquisition and preparation The specimens utilized in this study were snap frozen in liquid nitrogen in the frozen section pathology laboratory within 30 separation was found between the 31 TC and 11 AC tumors in the minutes of resection and then transferred to À80C for permanent cohort. We also sequenced the exomes of 20 tumor–normal pairs storage in the Mayo Clinic Lung Tissue Registry. Prior to proces- and performed whole genome sequencing on a subset of 5 sing, the histology of the tumor specimens and the nonneoplastic tumor–normal pairs and found 126 functional and disease- histology of the matched surrounding normal lung tissue were causing mutations in 114 genes with known biological or clinical confirmed by a dedicated lung pathologist (M.C. Aubry). RNA significance. The overall number of genomic rearrangements and DNA extraction from macrodissected specimens was con- identified from whole genome sequencing showed a relatively ducted through the institutional Biospecimen Accessioning and low frequency of genomic rearrangements compared with that Processing (BAP) Shared Resource. present in lung adenocarcinoma from either smoker or non- smoker patients. Recurrent mutations were identified in ATP1A2, Gene expression profiling CNNM1, MACF1, RAB38, NF1, RAD51C, TAF1L, EPHB2, RNA for gene expression analysis was extracted using the POLR3B, and AGFG1. RNeasy Mini Kit and TissueLyser (Qiagen) according to the We identified cancer
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