Original ArticlesActivation of human telomerase reverse transcriptase through gene fusion in clear cell sarcoma of the kidney
Introduction
CCSK is a rare neoplasm, accounting for 2–5% of all pediatric renal tumors. The overall survival for patients with CCSK has historically been low, but has now improved by intensified chemotherapy treatment [1]. CCSK is often described as a puzzling tumor, since its histological appearance does not resemble that of the kidney and there is no specific positive biological diagnostic marker available [2]. Furthermore, most CCSKs lack large-scale chromosomal alterations, while a subset shows a translocation between chromosomes 10 and 17 [3], [4], [5], [6], [7], [8], resulting in a fusion transcript between YWHAE and NUTM2B/NUTM2E (also known as FAM22B/FAM22E) [9].
Maintenance of telomere length is essential for the immortalization of tumor cells, and reactivation of telomerase is found in approximately 90% of all cancers [10]. Telomerase reverse transcriptase (TERT), the gene coding for the catalytic subunit of telomerase, can be activated by promoter mutations in different neoplasms [11], [12], [13]. However, such mutations are not present in all investigated tumor types [13], indicating that TERT can be activated via other, unknown mechanisms. We here describe TERT overexpression resulting from gene fusion between TERT and the transcription factor IRX2 in a CCSK. The novel IRX2-TERT fusion was found during exploratory RNA sequencing of a CCSK cohort.
Section snippets
Tumor and kidney tissue
The study was reviewed and approved by the regional ethics committee (L119-03) and by the review boards of the participating institutes. Frozen CCSKs were obtained from the Children's Oncology Group (COG) of North America and from Skåne University Hospital, Lund, Sweden. CCSK diagnoses were corroborated by reference pathologists of COG for the American cases and the International Society of Pediatric Oncology for the two Swedish cases. Wilms tumors for comparative studies were obtained from
Results
A panel of 22 CCSK tumors was subjected to RNA sequencing to investigate the occurrence of fusion transcripts. A novel IRX2-TERT gene fusion was identified in a CCSK from a 4 year old boy (Fig. 1a). The finding was confirmed with RT-PCR followed by Sanger sequencing (Fig. 1c). The fusion occurred between amino acid 332 in exon 3 of IRX2 and amino acid 2 in exon 1 of TERT (IRX2 transcripts NM_001134222 and NM_033267; TERT transcripts NM_198253 and NM_001193376). As a result, this in-frame fusion
Discussion
The mechanism behind the reactivation of telomerase in tumor cells has for a long time been unknown, but the recent discovery of activating mutations in the TERT promoter has offered an explanation applicable to several tumor types [11], [12], [13]. In this study, we show that TERT also can be activated via gene fusion.
By RNA sequencing of 22 cases of the uncommon pediatric tumor CCSK, we found a novel in-frame fusion transcript between IRX2 and TERT in one of the tumors, resulting from a
Conflict of interest
None.
Acknowledgements
We are grateful to the COG Renal Tumor Study Group and the Tissue Bank for contributing with CCSK samples and Dr Martin Johansson at the Center for Molecular Pathology, Lund University, SUS Malmö, Sweden, for providing kidney tissue. We would also like to thank the Swegene Centre for Integrative Biology at Lund University (SCIBLU).
This work was supported by the Swedish Childhood Cancer Foundation (PROJ 2013-0011), the Swedish Cancer Society (CAN 2012/318), the Swedish Research Council (2013-2543
References (21)
- et al.
Abnormalities of chromosomes 1 and 11 in Wilms’ tumor
Cancer Genet. Cytogenet
(1985) - et al.
Translocation 10;17 in clear cell sarcoma of the kidney. A first report
Cancer Genet. Cytogenet
(1989) - et al.
Translocation (10;17)(q22;p13): a recurring translocation in clear cell sarcoma of kidney
Cancer Genet. Cytogenet
(2004) - et al.
A survey of telomerase activity in human cancer
Eur. J. Cancer
(1997) - et al.
Regulation of the human catalytic subunit of telomerase (hTERT)
Gene
(2012) - et al.
Effect of duration of treatment on treatment outcome for patients with clear-cell sarcoma of the kidney: a report from the National Wilms’ Tumor Study Group
J. Clin. Oncol
(2004) - et al.
Clear cell sarcoma of the kidney: a review of 351 cases from the National Wilms Tumor Study Group Pathology Center
Am. J. Surg. Pathol
(2000) - et al.
Chromosome analysis of 31 Wilms’ tumors
Cancer Res
(1990) - et al.
Correlation of chromosome abnormalities with histological and clinical features in Wilms’ and other childhood renal tumors
Cancer Res
(1991) - et al.
Recurring translocation (10;17) and deletion (14q) in clear cell sarcoma of the kidney
Arch. Pathol. Lab. Med
(2007)
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