ORIGINAL PAPER Journal of Pathology J Pathol (2012) Published online in Wiley Online Library (wileyonlinelibrary.com) DOI: 10.1002/path.3985 Characterization of the chromosomal translocation t(10;17)(q22;p13) in clear cell sarcoma of kidney Elaine O’Meara, 1# Deirdre Stack, 1# Cheng-Han Lee, 2 A Julian Garvin, 3 Thomas Morris, 4 Pedram Argani, 5 Jeong S Han, 5 Jenny Karlsson, 6 David Gisselson, 6 Ivo Leuschner, 7 Manfred Gessler, 8 Norbert Graf, 9 Jonathan A Fletcher 10 and Maureen J O’Sullivan 1,11 * 1 National Children’s Research Centre, Our Lady’s Children’s Hospital, Crumlin, Dublin, Ireland 2 Anatomical Pathology, Vancouver General Hospital, BC, Canada 3 Department of Pathology, Wake Forest University School of Medicine, Winston-Salem, NC, USA 4 National Centre for Medical Genetics, Our Lady’s Childrens Hospital, Crumlin, Dublin, Ireland 5 Department of Pathology, Johns Hopkins Medical Institution, Baltimore, MD, USA 6 Department of Clinical Genetics, Lund University, Sweden 7 Kiel Paediatric Cancer Registry, Christian Albrechts University, Kiel, Germany 8 Theodor-Boveri-Institute, Biocentre, Developmental Biochemistry, Am Hubland, W¨ urzburg, Germany 9 Universit¨ atsklinikum des Saarlandes, Klinik f¨ ur P¨ ad. Onkologie und H¨ amatologie, Homburg, Germany 10 Department of Pathology, Brigham and Women’s Hospital, Boston, MA, USA 11 Trinity College Dublin and Histology Laboratory, Our Lady’s Children’s Hospital, Crumlin, Dublin, Ireland *Correspondence to: Maureen J O’Sullivan, Histology Laboratory, Our Lady’s Children’s Hospital, Crumlin, Dublin 12, Ireland. e-mail: maureen.osullivan@tcd.ie # These authors contributed equally to this study. Abstract Clear cell sarcoma of kidney (CCSK) is classified as a tumour of unfavourable histology by the National Wilms’ Tumor Study Group. It has worse clinical outcomes than Wilms’ tumour. Virtually nothing is known about CCSK biology, as there have been very few genetic aberrations identified to act as pointers in this cancer. Three cases of CCSK bearing a chromosomal translocation, t(10;17)(q22;p13), have been individually reported but not further investigated to date. The aim of this research was to characterize t(10;17)(q22;p13) in CCSK to identify the genes involved in the translocation breakpoints. Using fluorescently labelled bacterial artificial chromosomes (BACs) and a chromosome-walking strategy on an index case of CCSK with t(10;17)(q22;p13) by karyotype, we identified the chromosomal breakpoints on 17p13.3 and 10q22.3. The translocation results in rearrangement of YWHAE on chromosome 17 and FAM22 on chromosome 10, producing an in-frame fusion transcript of ∼3 kb, incorporating exons 1–5 of YWHAE and exons 2-7 of FAM22, as determined by RT-PCR using YWHAE- and FAM22-specific primers. The YWHAE-FAM22 transcript was detected in six of 50 further CCSKs tested, therefore showing an overall incidence of 12% in our cohort. No transcript-positive cases presented with stage I disease, despite this being the stage for 31% of our cohort. Tumour cellularity was significantly higher in the cases that were transcript-positive. Based on the chromosome 10 breakpoint identified by FISH and the sequences of the full-length transcripts obtained, the FAM22 members involved in the translocation in these CCSK cases include FAM22B and FAM22E. Elucidation of the role of YWHAE-FAM22 in CCSK will assist development of more efficient and targeted therapies for this childhood cancer, which currently has poor outcomes. Copyright  2012 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd. Keywords: clear cell sarcoma of kidney; YWHAE; FAM22; chromosomal translocation; childhood Received 25 October 2011; Revised 22 December 2011; Accepted 22 December 2011 No conflicts of interest were declared. Introduction Clear cell sarcoma of kidney (CCSK), the second com- monest paediatric renal cancer, arises generally before the age of 5 years and shows a predilection for males [1,2]. It was classified by the National Wilms’ Tumor Study Group as a tumour of unfavourable histology. CCSK has a propensity to metastasize to bone and is associated overall with worse clinical outcomes than Wilms’ tumour [1]. To date, as CCSK has lacked a specific diagnostic immunohistochemical profile or consistent genetic alteration that could reliably dis- tinguish it from other renal tumours, diagnosis has been based solely on histological features, which them- selves may vary considerably [1,3]. The current treat- ment for CCSK is by combined nephrectomy and chemotherapy including the anthracycline doxorubicin, which has been shown to improve clinical outcome [1]. Copyright  2012 Pathological Society of Great Britain and Ireland. J Pathol (2012) Published by John Wiley & Sons, Ltd. www.pathsoc.org.uk www.thejournalofpathology.com