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 Conrads; G Larry Maxwell

doi:10.1038/s41598-021-88585-x

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

Sci Rep. 2021 Apr 30;11(1):9371. doi: 10.1038/s41598-021-88585-x.

Authors

Nicholas W Bateman^#^{1

2

3}, Christopher M Tarney^#¹, Tamara Abulez^{1

3}, Anthony R Soltis^{3

4}, Ming Zhou⁵, Kelly Conrads^{1

3}, Tracy Litzi^{1

3}, Julie Oliver^{1

3}, Brian Hood^{1

3}, Paul Driggers⁶, Coralie Viollet⁴, Clifton Dalgard⁴, Matthew Wilkerson^{3

4}, William Catherino⁷, Chad A Hamilton¹, Kathleen M Darcy^{1

2

3}, Yovanni Casablanca^{1

2}, Ayman Al-Hendy⁸, James Segars⁶, Thomas P Conrads^{9

10

11

12}, G Larry Maxwell^{13

14

15}

Affiliations

¹ Gynecologic Cancer Center of Excellence, Department of Gynecologic Surgery and Obstetrics, Uniformed Services University of the Health Sciences and Walter Reed National Military Medical Center, 8901 Wisconsin Avenue, Bethesda, MD, 20889, USA.
² The John P. Murtha Cancer Center, Uniformed Services University of the Health Sciences and Walter Reed National Military Medical Center, 8901 Wisconsin Avenue, Bethesda, MD, 20889, USA.
³ Henry M. Jackson Foundation for the Advancement of Military Medicine, Inc, 6720A Rockledge Dr., Suite 100, Bethesda, MD, 20817, USA.
⁴ The American Genome Center, Department of Anatomy, Physiology, and Genetics, Collaborative Health Initiative Research Program, Uniformed Services University of the Health Sciences, 4301 Jones Bridge Road, Bethesda, MD, 20814, USA.
⁵ Women's Health Integrated Research Center, Women's Service Line, Inova Health System, 3300 Gallows Rd, Falls Church, VA, 22042, USA.
⁶ Johns Hopkins University School of Medicine, Baltimore, MD, USA.
⁷ Department of Gynecologic Surgery and Obstetrics, Uniformed Services University of the Health Sciences, Bethesda, MD, USA.
⁸ University of Illinois College of Medicine, Chicago, IL, 60612, USA.
⁹ Gynecologic Cancer Center of Excellence, Department of Gynecologic Surgery and Obstetrics, Uniformed Services University of the Health Sciences and Walter Reed National Military Medical Center, 8901 Wisconsin Avenue, Bethesda, MD, 20889, USA. conrads@whirc.org.
¹⁰ The John P. Murtha Cancer Center, Uniformed Services University of the Health Sciences and Walter Reed National Military Medical Center, 8901 Wisconsin Avenue, Bethesda, MD, 20889, USA. conrads@whirc.org.
¹¹ Women's Health Integrated Research Center, Women's Service Line, Inova Health System, 3300 Gallows Rd, Falls Church, VA, 22042, USA. conrads@whirc.org.
¹² , 3289 Woodburn Rd, Suite 375, Annandale, VA, 22003, USA. conrads@whirc.org.
¹³ Gynecologic Cancer Center of Excellence, Department of Gynecologic Surgery and Obstetrics, Uniformed Services University of the Health Sciences and Walter Reed National Military Medical Center, 8901 Wisconsin Avenue, Bethesda, MD, 20889, USA. george.maxwell@inova.org.
¹⁴ The John P. Murtha Cancer Center, Uniformed Services University of the Health Sciences and Walter Reed National Military Medical Center, 8901 Wisconsin Avenue, Bethesda, MD, 20889, USA. george.maxwell@inova.org.
¹⁵ Women's Health Integrated Research Center, Women's Service Line, Inova Health System, 3300 Gallows Rd, Falls Church, VA, 22042, USA. george.maxwell@inova.org.

^# Contributed equally.

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.

Publication types

Research Support, U.S. Gov't, Non-P.H.S.

MeSH terms

Biomarkers, Tumor / analysis*
Biomarkers, Tumor / genetics
Biomarkers, Tumor / metabolism
Case-Control Studies
Female
Fumarate Hydratase / genetics*
Genetic Predisposition to Disease*
Humans
Leiomyomatosis / metabolism
Leiomyomatosis / pathology*
Mutation*
Neoplastic Syndromes, Hereditary / metabolism
Neoplastic Syndromes, Hereditary / pathology*
Proteogenomics / methods*
Proteome / analysis
Proteome / metabolism*
Skin Neoplasms / metabolism
Skin Neoplasms / pathology*
Uterine Neoplasms / metabolism
Uterine Neoplasms / pathology*

Substances

Biomarkers, Tumor
Proteome
Fumarate Hydratase

Supplementary concepts

Hereditary leiomyomatosis and renal cell cancer

Grants and funding

R01 HD094378/HD/NICHD NIH HHS/United States