Cancer Metastasis Rev DOI 10.1007/s10555-015-9556-2 Association of chromosome 19 to lung cancer genotypes and phenotypes Xiangdong Wang1 & Yong Zhang 1 & Carol L. Nilsson2 & Frode S. Berven3 & Per E. Andrén4 & Elisabet Carlsohn5 & Johan Malm7 & Manuel Fuentes7 & Ákos Végvári6,8 & Charlotte Welinder6,9 & Thomas E. Fehniger6,10 & Melinda Rezeli8 & Goutham Edula11 & Sophia Hober12 & Toshihide Nishimura13 & György Marko-Varga6,8,13 # Springer Science+Business Media New York 2015 Abstract The Chromosome 19 Consortium, a part of the aberrations include translocation t(15, 19) (q13, p13.1) fusion Chromosome-Centric Human Proteome Project (C-HPP, oncogene BRD4-NUT, DNA repair genes (ERCC1, ERCC2, http://www.C-HPP.org), is tasked with the understanding XRCC1), TGFβ1 pathway activation genes (TGFB1, LTBP4) chromosome 19 functions at the gene and protein levels, as , Dyrk1B, and potential oncogenesis protector genes such as well as their roles in lung oncogenesis. Comparative genomic NFkB pathway inhibition genes (NFKBIB, PPP1R13L) and hybridization (CGH) studies revealed chromosome aberration EGLN2. In conclusion, neXtProt is an effective resource for in lung cancer subtypes, including ADC, SCC, LCC, and the validation of gene aberrations identified in genomic SCLC. The most common abnormality is 19p loss and 19q studies. It promises to enhance our understanding of lung gain. Sixty-four aberrant genes identified in previous genomic cancer oncogenesis. studies and their encoded protein functions were further vali- dated in the neXtProt database (http://www.nextprot.org/). Among those, the loss of tumor suppressor genes STK11, Keywords Proteins . Genes . Antibodies . mRNA . Mass MUM1, KISS1R (19p13.3), and BRG1 (19p13.13) is spectrometry . Bioinformatics . Protein microarray . Human associated with lung oncogenesis or remote metastasis. Gene disease Xiangdong Wang and Yong Zhang contributed equally to this work. * Xiangdong Wang 7 Centro de Investigación del Cáncer/IBMCC (USAL/CSIC)-IBSAL, [email protected] Unidad de Proteomica, Departamento de Medicina and Servicio General de Citometría-Nucleus, University of Salamanca, * György Marko-Varga 37007 Salamanca, Spain [email protected] 8 Clinical Protein Science & Imaging, Biomedical Center, Department 1 Zhongshan Hospital, Shanghai Institute of Clinical Bioinformatics, of Measurement Technology and Industrial Electrical Engineering, Fudan University, Shanghai, China Lund University, BMC C13, 221 84 Lund, Sweden 2 Department of Pharmacology and Toxicology, UTMB Cancer 9 Department of Oncology and Pathology, Clinical Sciences, Lund Center, University of Texas Medical Branch, Galveston, TX 77555, University, 221 85 Lund, Sweden USA 3 Department of Biomedicine, University of Bergen, 10 Institute of Clinical Medicine, Tallinn University of Technology, 5009 Bergen, Norway 12618 Tallinn, Estonia 4 Department of Pharmaceutical Biosciences, Uppsala University, 751 11 24 Uppsala, Sweden Clinnovo Research Labs, Hyderabad, India 5 Proteomics Core Facility, Göteborg University, 413 12 School of Biotechnology, Department of Proteomics, Royal Institute 90 Göteborg, Sweden of Technology, 106 91 Stockholm, Sweden 6 Department of Laboratory Medicine, Section for Clinical Chemistry, Lund University, Skåne University Hospital in Malmö, 205 13 First Department of Surgery, Tokyo Medical University, 6-7-1 02 Malmö, Sweden Nishishinjiku Shinjiku-ku, Tokyo 160-0023, Japan Cancer Metastasis Rev 1 Introduction Lung cancer Lung cancer Lung cancer risk subtype prognosis Lung cancer is the leading diagnosed cancer as well as CGH study the leading cause of cancer death globally. It accounts for 13 % (1.82 million) of the total new cancer cases Gene aberraon in chromosome 19 and 18 % (1.59 million) of the deaths in cancer in 2012 around the world [1]. Lung cancer is also the leading Protein level validaon in cause of death accounting for 29 % and 26 % of total C-HPP based database cancer deaths in men and women, respectively. The five year survival for all stage lung cancer patients is only Gene and protein funcon annotaon about 15 %, and for stage IV patients, just 3–4%[2, 3]. Chromosome aberrations related to lung oncogenesis Potenal lung mechanisms have been revealed recently. About 50 % oncogenesis of the lung adenocarcinoma (ADC) tumors bear Bdriver mechanism mutations^. EGFR mutations are the most common Fig. 1 Workflow identifying molecular mechanism of lung oncogenesis. drive mutations in lung ADC, usually due to losses in To decipher the oncogenesis mechanism chromosome 19 gene exon 19, or point mutations of exon 21 in chromosome aberrations identified in GCH studies with lung cancer subtype, risk, 7[4]. About 4 % of lung ADCs are caused by EML4- and prognosis were enrolled. The indentified aberration genes were integrated and further inquired in chromosome centric neXProt to ALK fusion genes, usually intron 13 of EML4 in chro- explore potential lung oncogenesis mechanism mosome 1 fused to intron 20 of ALK in chromosome 2 [5]. Targeted treatments aimed at the driver mutation proteins remarkably increase the overall survival of lung Chromosome 19 has the highest gene density of all human ADC patients. With comparative genomic hybridization chromosomes, more than double the genome-wide average. (CGH) methods and high throughout genome-wide as- Furthermore, it has large clusters of gene families that corre- sociation studies (GWAS), more chromosomal variants spond to high G + C content and CpG islands which indicate associated with lung oncogenesis have been identified. its rich biological and evolutionary significance. Chromosome The importance of chromosome 19 gene aberrations was 19 is also unique in its density of repeat sequences (55 % vs clearly demonstrated by the previous studies. the genome average of 44.8 %) [14]. The Chromosome-Centric Human Proteome Project (C- The C-HPP project targets the identification of all HPP) is a global consortium dedicated to mapping the entire gene-coding proteins with a special emphasis on the human complement of proteins, with global membership missing proteins, which account for almost 30 % of (http://www.c-hpp.org)[6–10]. The Chromosome 19 the proteins in the human proteome. The ENCODE ini- Consortium has investigated gene expression using tiative has been linked to the C-HPP initiative and pro- complementary analysis platforms, to provide a genome- vides newly identified gene activity that may predict wide human protein resource database, and detailed maps of novel proteoforms [13]. The data resources of the HPP protein molecular pathways, interactions, and networks. The are comprised of Ensemble, which is linked to the Chromosome 19 project has already contributed to the anno- neXtProt, PeptideAtlas, and gpmDB databases. Recently, tations of severe diseases, especially glioblastoma [11–13]. the numbers of highly confident protein identifications The present article focuses on chromosome 19 gene aber- in these data resources that were announced recently by rations in different lung cancer subtypes, including non-small Marko-Varga et al [15]. The number of missing proteins cell lung cancer (NSCLC): ADC, squamous cell carcinoma during one year was decreased from 32.7 % in 2012 to (SCC), large cell carcinoma (LCC), and small cell lung cancer 26.2 % in 2013 (September, lecture by G. Omenn, at (SCLC), and their potential role in lung oncogenesis. We have HUPO World Congress, Yokohama, Japan). In the Sep- explored gene polymorphisms on chromosome 19 that are tember 19, 2014, release of neXtProt, the number of translated into protein variants, and offer potential mecha- protein-coding genes is about 20000. Roughly 18 % of nisms involved, as well as potential targeted therapeutics for the complete set of human protein coding genes is miss- the future (Fig. 1). ing at the protein level currently. As for chromosome 19, according to of neXtProt database released on Jan- uary 2015, there are estimated 1,432 protein-coding 2 Bioinformatic annotation of chromosome 19 genes, including 244 genes with transcript-based evi- dence (PE2) available. Of these 1,432 genes, 2,707 al- Chromosome 19 spans about 64 million base pairs, ternative splicing variants are listed, as well as 199N- representing more than 2 % of the human genome. acetylated and 407 phorphoproteins. Cancer Metastasis Rev 19P In SCC, the aberrations of chromosome 19 losses or gains DNA loss were both indentified. One CGH study in Eastern lung SCC DNA gain demonstrated DNA amplifications on 19p [21]. Gains of 19q13.13 were increased in Western lung SCC patients ADC 19p13.11 [22]. Furthermore, gene losses of chromosome 19 in adja- cent bronchial mucosa were detected in SCC and LCC both in primary lung carcinomas. Chromosome 19 losses may be the early event in SCC oncogenesis [23]. Whole exon se- Asbstos 19p13.3 SCC quencing (n= 51) and copy number analysis (n=47) of induced ADC resected SCLC tumors was compared with matched non- cancer samples from Eastern SCLC patients. Genetic am- Smoker ADC 19p13.1 plifications in the PI3K/AKT/mTOR pathway were detect- ed in 36 % of SCLC, including AKT2 (9 %), located in 19q13.2 [24]. Western people showed two amplified re- gions in chromosome 19q13.2-3 in 4 types of lung cancer (ADC, SCC, LCC, and SCLC). 265 lung cancer samples were compared with 272 non-malignant samples. Single 19q12 SCC nucleotide polymorphism (SNP) RT-PCR revealed a vari- Non-smoker ADC 19q13.1 Smoker SCC ant allele of DNA repair gene ERCC2 rs1052559a and rs1799793 in 19q13.2–3 were significantly