Proteogenomic landscape of uterine leiomyomas from hereditary leiomyomatosis and renal cell cancer patients

Nicholas W. Bateman, Christopher M. Tarney, Tamara Abulez, Anthony R. Soltis, Ming Zhou, Kelly Conrads, Tracy Litzi, Julie Oliver, Brian Hood, Paul Driggers, Coralie Viollet, Clifton Dalgard, Matthew Wilkerson, William Catherino, Chad A. Hamilton, Kathleen M. Darcy, Yovanni Casablanca, Ayman Al-Hendy, James Segars, Thomas P. ConradsG. Larry Maxwell

Research output: Contribution to journalArticlepeer-review

Abstract

Pathogenic mutations in fumarate hydratase (FH) drive hereditary leiomyomatosis and renal cell cancer (HLRCC) and increase the risk of developing uterine leiomyomas (ULMs). An integrated proteogenomic analysis of ULMs from HLRCC (n = 16; FH-mutation confirmed) and non-syndromic (NS) patients (n = 12) identified a significantly higher protein:transcript correlation in HLRCC (R = 0.35) vs. NS ULMs (R = 0.242, MWU p = 0.0015). Co-altered proteins and transcripts (228) included antioxidant response element (ARE) target genes, such as thioredoxin reductase 1 (TXNRD1), and correlated with activation of NRF2-mediated oxidative stress response signaling in HLRCC ULMs. We confirm 185 transcripts previously described as altered between HLRCC and NS ULMs, 51 co-altered at the protein level and several elevated in HLRCC ULMs are involved in regulating cellular metabolism and glycolysis signaling. Furthermore, 367 S-(2-succino)cysteine peptides were identified in HLRCC ULMs, of which sixty were significantly elevated in HLRCC vs. NS ULMs (LogFC = 1.86, MWU p < 0.0001). These results confirm and define novel proteogenomic alterations in uterine leiomyoma tissues collected from HLRCC patients and underscore conserved molecular alterations correlating with inactivation of the FH tumor suppressor gene.

Original languageEnglish (US)
Article number9371
JournalScientific reports
Volume11
Issue number1
DOIs
StatePublished - Dec 2021
Externally publishedYes

ASJC Scopus subject areas

  • General

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