TERT structural rearrangements in metastatic pheochromocytomas
- Trisha Dwight1,2⇑,
- Aidan Flynn3,4,
- Kaushalya Amarasinghe5,
- Diana E Benn1,2,
- Richard Lupat5,
- Jason Li5,
- Daniel L Cameron5,6,7,
- Annette Hogg5,
- Shiva Balachander5,
- Ida L M Candiloro8,9,
- Stephen Q Wong5,
- Bruce G Robinson1,2,
- Anthony T Papenfuss5,6,7,10,11,
- Anthony J Gill2,12,
- Alexander Dobrovic8,9,13,
- Rodney J Hicks5,10,
- Roderick J Clifton-Bligh1,2 and
- Richard W Tothill5,9,10⇑
- 1Cancer Genetics, Kolling Institute, Royal North Shore Hospital, Sydney, New South Wales, Australia
- 2The University of Sydney, Sydney, New South Wales, Australia
- 3The Finsen Laboratory, Rigshospitalet, Faculty of Health Sciences, University of Copenhagen, Copenhagen N, Denmark
- 4Biotech Research and Innovation Centre (BRIC), University of Copenhagen, Copenhagen N, Denmark
- 5The Peter MacCallum Cancer Centre, East Melbourne, Victoria, Australia
- 6Bioinformatics Division, The Walter and Eliza Hall Institute of Medical Research, Parkville, Victoria, Australia
- 7Department of Medical Biology, University of Melbourne, Melbourne, Victoria, Australia
- 8Olivia Newton-John Cancer Research Institute, Heidelberg, Victoria, Australia
- 9The Department of Pathology, University of Melbourne, Parkville, Victoria, Australia
- 10The Sir Peter MacCallum Department of Oncology, The University of Melbourne, Parkville, Victoria, Australia
- 11The Department of Mathematics and Statistics, University of Melbourne, Parkville, Victoria, Australia
- 12Cancer Diagnosis and Pathology Group, Kolling Institute, Royal North Shore Hospital, Sydney, New South Wales, Australia
- 13School of Cancer Medicine, La Trobe University, Bundoora, Victoria, Australia
- Correspondence should be addressed to T Dwight or R Tothill: trisha.dwight{at}sydney.edu.au or rtothill{at}unimelb.edu.au
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Figure 1
TERT expression in PC/PGL (n = 39) taken from RNA-seq data described in Flynn et al. (2015). (A) Square root of RNA-seq counts per million aligned to the TERT locus in 39 PC/PGL tumor samples. (B) Sashimi plot depicting mapped RNA-seq reads spanning TERT exons 6–9 (supporting read number shown in exon links) and read depth (maximum range shown in parenthesis). Exons 7–8 are spliced out in β-deletion (β.) isoform.
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Figure 2
Structural alterations involving the TERT promoter identified in metastatic pheochromocytomas. (A) Circos plots displaying global somatic copy-number and breakpoints detected by WGS analysis across the three TERT overexpressing PC tumors. No somatic breakpoints were detected in V-PH-01T. Chromosome ideograms displayed as outer ring, somatic copy-number changes detected as inner ring. Green line indicates neutral (diploid) or copy-number gain from segmentation, and red line indicates copy-number loss. Inner lines show detected breakpoints. Red lines highlight the validated TERT promoter rearrangements. Data for chrX and chrY not shown. (B) Chromosome level view of somatic copy-number alterations and breakpoints in V-PH-03T highlighting an intra-chromosomal deletion detected proximal to TERT as indicated by red line. (C) Sanger sequencing validation of 4.3 Mb deletion upstream of TERT in V-PH-03T. (D) Chromosome level view of somatic copy-number alterations and breakpoints in V-PH-04T involving chr5p and chr22q. Red line indicates TERT proximal breakpoint. (E) Sanger sequencing validation of non-reciprocal translocation (t(5;22)(p15.3;q12.3)) identified in V-PH-04T. Arrows in panels C and E indicates TERT proximal structural breakpoint previously described in aggressive neuroblastoma (Peifer et al. 2015).
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Figure 3
Structural rearrangements juxtapose TERT proximal to active enhancers in metastatic PC. The potential for enhancer-driven activation of TERT was assessed using dbSUPER (an integrative database of super-enhancers; Khan & Zhang 2016). Candidate super-enhancers are based on H3K27ac signals from normal adult adrenal tissue (GEO accession: GSM1013168). ENCODE data for H3K27ac (blue track) and DNase hypersensitivity (green track) in fetal adrenal tissue supporting super-enhancer features was accessed through UCSC browser (build hg19) (Rosenbloom et al. 2013). (A) The 4.3 Mb somatic deletion observed in V-PH-03T is predicted to result in placement of a super-enhancer 1.1 Mb from the TERT TSS (SE_01397, dbSUPER). (B) The somatic non-reciprocal translocation, t(5;22)(p15.3;q12.3), identified in V-PH-04T is predicted to result in the placement of a super-enhancer 1.9 Mb from the TERT TSS (SE_01144, dbSUPER).
- © 2018 Society for Endocrinology