Mutations in cancer-relevant genes are ubiquitous in histologically normal endometrial tissue.

Autor: Pandya D; The Rudy L. Ruggles Biomedical Research Institute, Nuvance Health, Danbury, CT 06902, United States of America., Tomita S; Departments of Obstetrics/Gynecology & Reproductive Sciences, Icahn School of Medicine at Mount Sinai, New York, NY 10029, United States of America., Rhenals MP; Genetics and Genomic Science, Icahn School of Medicine at Mount Sinai, New York, NY 10029, United States of America., Swierczek S; The Rudy L. Ruggles Biomedical Research Institute, Nuvance Health, Danbury, CT 06902, United States of America; Department of Obstetrics, Gynecology and Reproductive Sciences, Larner College of Medicine, University of Vermont, Burlington, VT, United States of America., Reid K; Genetics and Genomic Science, Icahn School of Medicine at Mount Sinai, New York, NY 10029, United States of America., Camacho-Vanegas O; Genetics and Genomic Science, Icahn School of Medicine at Mount Sinai, New York, NY 10029, United States of America., Camacho C; Genetics and Genomic Science, Icahn School of Medicine at Mount Sinai, New York, NY 10029, United States of America., Engelman K; Genetics and Genomic Science, Icahn School of Medicine at Mount Sinai, New York, NY 10029, United States of America., Polukort S; The Rudy L. Ruggles Biomedical Research Institute, Nuvance Health, Danbury, CT 06902, United States of America., RoseFigura J; Swift Biosciences, Ann Arbor, MI 48103, United States of America., Chuang L; The Rudy L. Ruggles Biomedical Research Institute, Nuvance Health, Danbury, CT 06902, United States of America., Andikyan V; The Rudy L. Ruggles Biomedical Research Institute, Nuvance Health, Danbury, CT 06902, United States of America., Cohen S; Genetics and Genomic Science, Icahn School of Medicine at Mount Sinai, New York, NY 10029, United States of America., Fiedler P; The Rudy L. Ruggles Biomedical Research Institute, Nuvance Health, Danbury, CT 06902, United States of America., Sieber S; The Rudy L. Ruggles Biomedical Research Institute, Nuvance Health, Danbury, CT 06902, United States of America., Shih IM; Department of Gynecology and Obstetrics, Johns Hopkins University School of Medicine, Baltimore, MD 21205, United States of America., Billaud JN; QIAGEN Bioinformatics, 1001 Marshall Street, Redwood City, CA 94063, United States of America., Sebra R; Genetics and Genomic Science, Icahn School of Medicine at Mount Sinai, New York, NY 10029, United States of America., Reva B; Genetics and Genomic Science, Icahn School of Medicine at Mount Sinai, New York, NY 10029, United States of America., Dottino P; Departments of Obstetrics/Gynecology & Reproductive Sciences, Icahn School of Medicine at Mount Sinai, New York, NY 10029, United States of America; MDDx Inc., Tarrytown, NY 10591., United States of America., Martignetti JA; The Rudy L. Ruggles Biomedical Research Institute, Nuvance Health, Danbury, CT 06902, United States of America; Departments of Obstetrics/Gynecology & Reproductive Sciences, Icahn School of Medicine at Mount Sinai, New York, NY 10029, United States of America; Genetics and Genomic Science, Icahn School of Medicine at Mount Sinai, New York, NY 10029, United States of America; MDDx Inc., Tarrytown, NY 10591., United States of America. Electronic address: john.martignetti@mssm.edu.
Jazyk: angličtina
Zdroj: Gynecologic oncology [Gynecol Oncol] 2024 Jun; Vol. 185, pp. 194-201. Date of Electronic Publication: 2024 Mar 06.
DOI: 10.1016/j.ygyno.2024.02.027
Abstrakt: Objective: Endometrial cancer (EndoCA) is the most common gynecologic cancer and incidence and mortality rate continue to increase. Despite well-characterized knowledge of EndoCA-defining mutations, no effective diagnostic or screening tests exist. To lay the foundation for testing development, our study focused on defining the prevalence of somatic mutations present in non-cancerous uterine tissue.
Methods: We obtained ≥8 uterine samplings, including separate endometrial and myometrial layers, from each of 22 women undergoing hysterectomy for non-cancer conditions. We ultra-deep sequenced (>2000× coverage) samples using a 125 cancer-relevant gene panel.
Results: All women harbored complex mutation patterns. In total, 308 somatic mutations were identified with mutant allele frequencies ranging up to 96.0%. These encompassed 56 unique mutations from 24 genes. The majority of samples possessed predicted functional cancer mutations but curiously no growth advantage over non-functional mutations was detected. Functional mutations were enriched with increasing patient age (p = 0.045) and BMI (p = 0.0007) and in endometrial versus myometrial layers (68% vs 39%, p = 0.0002). Finally, while the somatic mutation landscape shared similar mutation prevalence in key TCGA-defined EndoCA genes, notably PIK3CA, significant differences were identified, including NOTCH1 (77% vs 10%), PTEN (9% vs 61%), TP53 (0% vs 37%) and CTNNB1 (0% vs 26%).
Conclusions: An important caveat for future liquid biopsy/DNA-based cancer diagnostics is the repertoire of shared and distinct mutation profiles between histologically unremarkable and EndoCA tissues. The lack of selection pressure between functional and non-functional mutations in histologically unremarkable uterine tissue may offer a glimpse into an unrecognized EndoCA protective mechanism.
Competing Interests: Declaration of competing interest Drs. Dottino and Martignetti are cofounders and equity owners of MDDx, Inc. Dr. Sebra is a paid consultant and equity holder for GeneDx. Neither MDDx nor GeneDx played any role in funding of this study.
(Copyright © 2024 Elsevier Inc. All rights reserved.)
Databáze: MEDLINE
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