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

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

doi:10.1038/s41598-021-88585-x

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.

Highlights

Pathogenic mutations in fumarate hydratase (FH) drive hereditary leiomyomatosis and renal cell cancer (HLRCC) and increase the risk of developing uterine leiomyomas (ULMs)
We conducted a comprehensive proteogenomic analysis employing whole genome sequencing (WGS), RNA-seq, and quantitative mass spectrometry (MS)-based proteomics of fresh-frozen ULM specimens from NS women (n = 12) and from women (n = 16) with HLRCC based on genetic counseling and family history assessments (Supplemental Table 1)
Structural variants in Mediator Complex Subunit 12 (MED12) and high mobility group AThook 1 (HMGA1) were common in HLRCC patients with a subset exhibiting duplications or inversions in Collagen Type IV Alpha 5 Chain (COL4A5) and collagen type IV alpha 6 chain (COL4A6)

Summary

Introduction

Pathogenic mutations in fumarate hydratase (FH) drive hereditary leiomyomatosis and renal cell cancer (HLRCC) and increase the risk of developing uterine leiomyomas (ULMs). 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. Services University of the Health Sciences and Walter Reed National Military Medical Center, 8901 Wisconsin Avenue, Bethesda, MD 20889, USA. Murtha Cancer Center, Uniformed Services University of the Health Sciences and Walter Reed National Military Medical Center, 8901 Wisconsin Avenue, Bethesda, MD 20889, USA. Leiomyomas, leiomyosarcoma, and papillary renal cell c ancer[6] This syndrome is caused by deleterious mutations in the tumor suppressor gene that encodes fumarate hydratase (FH), an enzyme that converts fumarate to malate and is integral to the Krebs cycle and cellular metabolism[7]

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Results

Conclusion