Mariano Russo1,2, Jordan M Newell3, Laura Budurlean1,2, Kenneth R Houser1,2, Kathryn Sheldon1,2, Joshua Kesterson4, Rebecca Phaeton4, Carrie Hossler4, Jennifer Rosenberg5, David DeGraff3, Lauren Shuman3, James R Broach1,2, Joshua I Warrick3. 1. Department of Biochemistry, Penn State College of Medicine, Penn State Health, Hershey, Pennsylvania. 2. Institute for Personalized Medicine, Penn State College of Medicine, Penn State Health, Hershey, Pennsylvania. 3. Department of Pathology, Penn State College of Medicine, Penn State Health, Hershey, Pennsylvania. 4. Department of Obstetrics and Gynecology, Penn State College of Medicine, Penn State Health, Hershey, Pennsylvania. 5. Department of Radiation Oncology, Penn State College of Medicine, Penn State Health, Hershey, Pennsylvania.
Abstract
BACKGROUND: Endometrial hyperplasia is a precursor to endometrioid adenocarcinoma (EMC), the most common uterine cancer. The likelihood of progression to carcinoma may be evaluated by histologic subclassification of endometrial hyperplasia, although these subclasses are subjective and only modestly reproducible among pathologists. Patient care would be improved by a more objective test to predict the risk of cancer progression. METHODS: Next-generation sequencing was performed on archived endometrial biopsy specimens from a retrospective cohort of women with endometrial hyperplasia. Cases were considered to be either progressing if the patient subsequently developed EMC or resolving if the patient had a subsequent negative tissue sampling or no cancer during medium-term follow-up (32 patients: 15 progressing and 17 resolving). Somatic mutations in endometrial hyperplasia were assessed for enrichment in progressing cases versus resolving cases, with an emphasis on genes commonly mutated in EMC. RESULTS: Several mutations were more common in progressing hyperplasia than resolving hyperplasia, although significant overlap was observed between progressing and resolving cases. Mutations included those in PTEN, PIK3CA, and FGFR2, genes commonly mutated in EMC. Mutations in ARID1A and MYC were seen only in progressing hyperplasia, although these were uncommon; this limited diagnostic sensitivity. Progressing hyperplasia demonstrated an accumulation of mutations in oncogenic signaling pathways similarly to endometrial carcinoma. CONCLUSIONS: Because of mutational differences between progressing and nonprogressing hyperplasia, mutational analysis may predict the risk of progression from endometrial hyperplasia to EMC.
BACKGROUND:Endometrial hyperplasia is a precursor to endometrioid adenocarcinoma (EMC), the most common uterine cancer. The likelihood of progression to carcinoma may be evaluated by histologic subclassification of endometrial hyperplasia, although these subclasses are subjective and only modestly reproducible among pathologists. Patient care would be improved by a more objective test to predict the risk of cancer progression. METHODS: Next-generation sequencing was performed on archived endometrial biopsy specimens from a retrospective cohort of women with endometrial hyperplasia. Cases were considered to be either progressing if the patient subsequently developed EMC or resolving if the patient had a subsequent negative tissue sampling or no cancer during medium-term follow-up (32 patients: 15 progressing and 17 resolving). Somatic mutations in endometrial hyperplasia were assessed for enrichment in progressing cases versus resolving cases, with an emphasis on genes commonly mutated in EMC. RESULTS: Several mutations were more common in progressing hyperplasia than resolving hyperplasia, although significant overlap was observed between progressing and resolving cases. Mutations included those in PTEN, PIK3CA, and FGFR2, genes commonly mutated in EMC. Mutations in ARID1A and MYC were seen only in progressing hyperplasia, although these were uncommon; this limited diagnostic sensitivity. Progressing hyperplasia demonstrated an accumulation of mutations in oncogenic signaling pathways similarly to endometrial carcinoma. CONCLUSIONS: Because of mutational differences between progressing and nonprogressing hyperplasia, mutational analysis may predict the risk of progression from endometrial hyperplasia to EMC.
Authors: Amir Momeni-Boroujeni; Bastien Nguyen; Chad M Vanderbilt; Marc Ladanyi; Nadeem R Abu-Rustum; Carol Aghajanian; Lora H Ellenson; Britta Weigelt; Robert A Soslow Journal: Mod Pathol Date: 2022-04-01 Impact factor: 8.209