The landscape of fusion transcripts in spitzoid melanoma and biologically indeterminate spitzoid tumors by RNA sequencing View Full Text


Ontology type: schema:ScholarlyArticle      Open Access: True


Article Info

DATE

2016-04

AUTHORS

Gang Wu, Raymond L Barnhill, Seungjae Lee, Yongjin Li, Ying Shao, John Easton, James Dalton, Jinghui Zhang, Alberto Pappo, Armita Bahrami

ABSTRACT

Kinase activation by chromosomal translocations is a common mechanism that drives tumorigenesis in spitzoid neoplasms. To explore the landscape of fusion transcripts in these tumors, we performed whole-transcriptome sequencing using formalin-fixed, paraffin-embedded (FFPE) tissues in malignant or biologically indeterminate spitzoid tumors from 7 patients (age 2-14 years). RNA sequence libraries enriched for coding regions were prepared and the sequencing was analyzed by a novel assembly-based algorithm designed for detecting complex fusions. In addition, tumor samples were screened for hotspot TERT promoter mutations, and telomerase expression was assessed by TERT mRNA in situ hybridization (ISH). Two patients had widespread metastasis and subsequently died of disease, and 5 patients had a benign clinical course on limited follow-up (mean: 30 months). RNA sequencing and TERT mRNA ISH were successful in six tumors and unsuccessful in one disseminating tumor because of low RNA quality. RNA sequencing identified a kinase fusion in five of the six sequenced tumors: TPM3-NTRK1 (2 tumors), complex rearrangements involving TPM3, ALK, and IL6R (1 tumor), BAIAP2L1-BRAF (1 tumor), and EML4-BRAF (1 disseminating tumor). All predicted chimeric transcripts were expressed at high levels and contained the intact kinase domain. In addition, two tumors each contained a second fusion gene, ARID1B-SNX9 or PTPRZ1-NFAM1. The detected chimeric genes were validated by home-brew break-apart or fusion fluorescence in situ hybridization (FISH). The two disseminating tumors each harbored the TERT promoter -124C>T (Chr 5:1,295,228 hg19 coordinate) mutation, whereas the remaining five tumors retained the wild-type gene. The presence of the -124C>T mutation correlated with telomerase expression by TERT mRNA ISH. In summary, we demonstrated complex fusion transcripts and novel partner genes for BRAF by RNA sequencing of FFPE samples. The diversity of gene fusions demonstrated by RNA sequencing defines the molecular heterogeneity of spitzoid neoplasms. More... »

PAGES

359-369

Identifiers

URI

http://scigraph.springernature.com/pub.10.1038/modpathol.2016.37

DOI

http://dx.doi.org/10.1038/modpathol.2016.37

DIMENSIONS

https://app.dimensions.ai/details/publication/pub.1040666189

PUBMED

https://www.ncbi.nlm.nih.gov/pubmed/26892443


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