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Identification of MED12 and RBM10 As Novel Thyroid Cancer Genes Associated with Tumor Virulence

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Identification of MED12 and RBM10 As Novel Thyroid Cancer Genes Associated with Tumor Virulence Published OnlineFirst June 20, 2017; DOI: 10.1158/1078-0432.CCR-17-1183 Biology of Human Tumors Clinical Cancer Research Genomic Alterations in Fatal Forms of Non-Anaplastic Thyroid Cancer: Identification of MED12 and RBM10 as Novel Thyroid Cancer Genes Associated with Tumor Virulence Tihana Ibrahimpasic1,2, Bin Xu3,Inigo~ Landa1, Snjezana Dogan3, Sumit Middha3, Venkatraman Seshan4, Shyam Deraje1, Diane L. Carlson5, Jocelyn Migliacci2, Jeffrey A. Knauf1, Brian Untch1, Michael F. Berger1,3, Luc Morris1,2, R. Michael Tuttle6, Timothy Chan1, James A. Fagin1,6, Ronald Ghossein3, and Ian Ganly1,2 Abstract Purpose: Patients with anaplastic thyroid cancer (ATC) have a were identified. There was a high frequency of mutations in very high death rate. In contrast, deaths from non-anaplastic MED12 and these were mutually exclusive to TERT promoter thyroid (NAT) cancer are much less common. The genetic altera- mutations and also to BRAF and RAS mutations. In addition, a tions in fatal NAT cancers have not been reported. high frequency of mutations in RBM10 was identified and these Experimental Design: We performed next-generation sequenc- co-occurred with RAS mutations and PIK3CA mutations. Com- ing of 410 cancer genes from 57 fatal NAT primary cancers. Results pared with the PTCs in TCGA, there were higher frequencies of were compared with The Cancer Genome Atlas study (TCGA mutations in TP53, POLE, PI3K/AKT/mTOR pathway effectors, study) of papillary thyroid cancers (PTCs) and to the genomic SWI/SNF subunits, and histone methyltransferases. changes reported in ATC. Conclusions: These data support a model, whereby fatal NAT Results: There was a very high prevalence of TERT promoter cancers arise from well-differentiated tumors through the accu- mutations, comparable with that of ATC, and these co-occurred mulation of key additional genetic abnormalities. The high rate of with BRAF and RAS mutations. A high incidence of chromosome TERT promoter mutations, MED12 mutations, RBM10 muta- 1q gain was seen highlighting its importance in tumor aggres- tions, and chromosome 1q gain highlight their likely association siveness. Two novel fusion genes DLG5–RET and OSBPL1A–BRAF with tumor virulence. Clin Cancer Res; 23(19); 5970–80. Ó2017 AACR. Introduction TERT promoter mutations in 73% of cases with a co-occurrence with either BRAF or RAS mutations (1). We also identified a Patients diagnosed with anaplastic thyroid cancer (ATC) high rate of mutations in TP53 (73%)aswellasahigher have a very high death rate. Such patients have a mean survival frequency of alterations in genes such as EIF1AX (9%), PIK3CA after diagnosis of only 6 months. We have recently reported the (18%), and ATM (9%) as compared to those reported by The genomic hallmarks of ATC showing a very high incidence of Cancer Genome Atlas Network (TCGA Network) study of well- differentiated papillary thyroid cancer (PTC), which showed a low frequency of somatic alterations (2). 1Human Oncology and Pathogenesis Program, Memorial Sloan Kettering Cancer Center, New York, New York. 2Department of Head and Neck Surgery, Memorial Non-anaplastic thyroid cancers (NATs) derived from thyroid Sloan Kettering Cancer Center, New York, New York. 3Department of Pathology, follicular cells comprise well-differentiated (WDTC) and poorly Memorial Sloan Kettering Cancer Center, New York, New York. 4Department of differentiated thyroid cancer (PDTC). Deaths from WDTC are Epidemiology and Biostatistics, Memorial Sloan Kettering Cancer Center, New extremely rare occurring in 1% to 2%, however, because these 5 York, New York. Department of Pathology, Cleveland Clinic, Memorial Sloan tumors are the most common form of the disease, this small Kettering Cancer Center, New York, New York. 6Department of Medicine, percentage represents a significant fraction of patient dying from Memorial Sloan Kettering Cancer Center, New York, New York. thyroid cancer. Deaths from PDTC are more common, occurring Note: Supplementary data for this article are available at Clinical Cancer in 30% of patients (3). The genomic characteristics of fatal cases Research Online (http://clincancerres.aacrjournals.org/). of NAT cancers (FNAT) has not been reported before. We T. Ibrahimpasic and B. Xu contributed equally to this article. hypothesized that such cancers may harbor genetic similarities Corresponding Authors: Ian Ganly, Memorial Sloan Kettering Cancer Center, to ATC. The objective of our study was to report the genetic 1275 York Avenue, Room C1079, New York, NY 10065. Phone: 212-639-6244; alterations in fatal cases of NAT cancer and compare their Fax: 212-396-5560; E-mail: [email protected]; and Ronald Ghossein, molecular profile with that of ATC and to the TCGA landscape [email protected] of PTCs. Fatal cases of NAT cancer are invariably refractory to doi: 10.1158/1078-0432.CCR-17-1183 radioiodine therapy, and traditional chemotherapy and radio- Ó2017 American Association for Cancer Research. therapy are of marginal benefit (4). Two multikinase inhibitors, 5970 Clin Cancer Res; 23(19) October 1, 2017 Downloaded from clincancerres.aacrjournals.org on October 1, 2021. © 2017 American Association for Cancer Research. Published OnlineFirst June 20, 2017; DOI: 10.1158/1078-0432.CCR-17-1183 Genomics of Fatal Forms of Non-Anaplastic Thyroid Cancer Sloan Kettering Integrated Mutation Profiling of Actionable Can- Translational Relevance cer Targets) platform, a deep-coverage, targeted next-generation We report the mutational profile of the largest series of fatal sequencing (NGS) assay encompassing 410 cancer-related genes non-anaplastic thyroid cancer that has not been reported and approved for clinical use by the NY State Department of before. We have identified TERT promoter mutations in a very Health (7). Of the 35 PDTC, 20 had previously been sequenced high percentage of tumors indicating its importance in thyroid using an earlier iteration of MSK-IMPACT comprising 341 genes cancer virulence. We report a high incidence of chromosome and reported as part of a cohort of 84 PDTC (1). The MSK-IMPACT 1q gain that highlights its importance in tumor aggressiveness. assay is an NGS assay approved for clinical use through CLIA We have identified two novel fusion genes DLG5–RET and (Clinical Laboratory Improvement Amendments) by the Centers OSBPL1A–BRAF. Finally, we report on many novel genes not for Medicare and Medicaid Services (8). MSK-IMPACT is opti- previously reported in differentiated thyroid cancer, including mized for DNA extracted from low-input formalin-fixed, paraffin MED12 and RBM10, suggesting a role for these novel genes in embedded (FFPE) samples. The assay is designed to detect single- tumor virulence. These genes are targetable mutations and nucleotide variants (SNV), indels, copy-number variants (CNVs), therefore have translational importance in thyroid cancer and structural variants in genes that are functionally relevant to management. The study also has diagnostic importance as cancer and/or clinically actionable targets. The current assay uses these genetic alterations may predict for poor outcome in hybrid capture technology (NimbleGen SeqCap EZ library cus- patients presenting with thyroid cancer allowing the early tom oligo) to perform deep (>200x) sequencing (Illumina HiSeq identification of patients who may benefit from more aggres- 2500) of all 5781 exons and selected introns of 410 cancer genes, sive therapy. including canonical and selected non-canonical transcripts, the TERT promoter region, and 33 introns of 14 rearranged genes (Supplementary Table S1). The panel includes 1,042 tiling probes covering single-nucleotide polymorphisms (SNP), allowing gen- sorafenib and lenvatinib, have been approved for treatment of otyping to ensure tumor-normal matching, identify contaminat- radioiodine refractory NAT cancer. Other drugs are currently ing DNA, and serve as a low-density SNP array for CNV analysis. being tested in early human clinical trials (5), but these efforts MSK-IMPACT has been extensively validated. fi are hindered by the lack of knowledge on the genomics of fatal Copy-number aberrations were identi ed by comparing cases of NAT cancer. The identification of the genetic alterations sequence coverage of targeted regions in a tumor sample relative fi in these cancers will, therefore, have major implications both in to a standard diploid normal sample (7). To call allele-speci c our ability to identify those rare patients at high risk of death somatic DNA copy number, we also applied an integrated pipe- fi and also to develop novel drugs, which target the pathways line called FACETS (9) to Tumor/Normal pairs of bam les fi responsible for their poor prognosis. according to authors' recommendations. The bam les were processed to generate a read count matrix for all the potentially Materials and Methods polymorphic sites from dbSNP/1000-genome database as well as pseudo SNPs to account for regions that have large gaps between Patients and tumor samples consecutive SNPs. The read counts are then used to compute the After IRB approval, patients with fatal NAT cancer (FNAT) were GC-corrected normalized log-ratio of tumor to normal read identified from a database of 3,774 patients who had primary depths for total copy number and log odds ratio from cross- surgery treatment at Memorial Sloan Kettering Cancer Center from tabulating the tumor and normal reads into ref and alt alleles for 1985 to 2010. Eighty-six (2.3%) patients were identified who had loci that are heterozygous in the germline. These are then seg- either died from
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