American Association for Cancer Research
Browse
ccr-21-3394_supplementary_data_1_supp1.xlsx (11.93 kB)

Supplementary Data from Integrated Analysis of Ovarian Juvenile Granulosa Cell Tumors Reveals Distinct Epigenetic Signatures and Recurrent TERT Rearrangements

Download (11.93 kB)
dataset
posted on 2023-03-31, 23:46 authored by Theodore Vougiouklakis, Kelsey Zhu, Varshini Vasudevaraja, Jonathan Serrano, Guomiao Shen, Rebecca L. Linn, Xiaojun Feng, Sarah Chiang, Julieta E. Barroeta, Kristen M. Thomas, Lauren E. Schwartz, Pratibha S. Shukla, Anais Malpica, Esther Oliva, Paolo Cotzia, Deborah F. DeLair, Matija Snuderl, George Jour
Supplementary Data from Integrated Analysis of Ovarian Juvenile Granulosa Cell Tumors Reveals Distinct Epigenetic Signatures and Recurrent TERT Rearrangements

Funding

MSK Cancer Center Support Grant

History

ARTICLE ABSTRACT

Adult granulosa cell tumor (AGCT) is characterized by the somatic FOXL2 p.C134W mutation, and recurrences have been associated with TERT promoter and KMT2D-truncating mutations. Conversely, the molecular underpinnings of the rare juvenile granulosa cell tumor (JGCT) have not been well elucidated. To this end, we applied a tumor-only integrated approach to investigate the genomic, transcriptomic, and epigenomic landscape of 31 JGCTs to identify putative oncogenic drivers. Multipronged analyses of 31 JGCTs were performed utilizing a clinically validated next-generation sequencing (NGS) panel targeting 580 cancer-related genes for genomic interrogation, in addition to targeted RNA NGS for transcriptomic exploration. Genome-wide DNA methylation profiling was conducted using an Infinium Methylation EPIC array targeting 866,562 CpG methylation sites. We identified frequent KMT2C-truncating mutations along with other mutated genes implicated in the switch/sucrose nonfermentable (SWI/SNF) chromatin remodeling complex, in addition to previously reported hotspot AKT1 and DICER1 mutations. Targeted transcriptome sequencing revealed recurrent TERT rearrangements (13%) involving partners CLPTM1L or DROSHA, and differential gene expression analysis showed FGFR1 upregulation in the TERT non-rearranged JGCTs under direct promoter control. Genome-wide DNA methylation rendered a clear delineation between AGCTs and JGCTs at the epigenomic level, further supporting its diagnostic utility in distinguishing among these tumors. This is the largest comprehensive molecular study of JGCTs, where we further expand our current understanding of JGCT pathogenesis and demonstrate putative oncogenic drivers and TERT rearrangements in a subset of tumors. Our findings further offer insights into possible targeted therapies in a rare entity.

Usage metrics

    Clinical Cancer Research

    Categories

    Keywords

    Licence

    Exports

    RefWorks
    BibTeX
    Ref. manager
    Endnote
    DataCite
    NLM
    DC