The spectrum of MAPK-ERK pathway genomic alterations in gynecologic malignancies: Opportunities for novel therapeutic approaches

Dimitrios Nasioudis; Marta Llaurado Fernandez; Nelson Wong; Daniel J Powell Jr; Gordon B Mills; Shannon Westin; Amanda N Fader; Mark S Carey; Fiona Simpkins

doi:10.1016/j.ygyno.2023.08.007

The spectrum of MAPK-ERK pathway genomic alterations in gynecologic malignancies: Opportunities for novel therapeutic approaches

Gynecol Oncol. 2023 Oct:177:86-94. doi: 10.1016/j.ygyno.2023.08.007. Epub 2023 Aug 30.

Authors

Dimitrios Nasioudis¹, Marta Llaurado Fernandez², Nelson Wong³, Daniel J Powell Jr⁴, Gordon B Mills⁵, Shannon Westin⁶, Amanda N Fader⁷, Mark S Carey⁸, Fiona Simpkins⁹

Affiliations

¹ Ovarian Cancer Research Center, Division of Gynecologic Oncology, Department of Obstetrics & Gynecology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA.
² Department of Obstetrics & Gynaecology, Faculty of Medicine, University of British Columbia, Vancouver, BC, Canada.
³ Department of Experimental Therapeutics, BC Cancer, BC, Canada.
⁴ Ovarian Cancer Research Center, Division of Gynecologic Oncology, Department of Obstetrics & Gynecology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA; Department of Pathology and Laboratory Medicine, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA.
⁵ Knight Cancer Institute, Oregon Health & Science University, Portland, OR, USA.
⁶ Department of Gynecologic Oncology and Reproductive Medicine, The University of Texas MD Anderson Cancer Center, Houston, TX, USA.
⁷ Kelly Gynecologic Oncology Service, Department of Gynecology and Obstetrics, Johns Hopkins School of Medicine, Baltimore, MD, USA.
⁸ Department of Obstetrics & Gynaecology, Faculty of Medicine, University of British Columbia, Vancouver, BC, Canada. Electronic address: mark.carey@ubc.ca.
⁹ Ovarian Cancer Research Center, Division of Gynecologic Oncology, Department of Obstetrics & Gynecology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA. Electronic address: Fiona.simpkins@pennmedicine.upenn.edu.

PMID: 37657193
DOI: 10.1016/j.ygyno.2023.08.007

Abstract

Objective: To investigate the incidence of MAPK/ERK pathway genomic alterations among patients with gynecologic malignancies.

Methods: We accessed the American Association of Cancer Research Genomics Evidence of Neoplasia Information Exchange publicly available dataset (v13.0). Patients with malignant tumors of the ovary, uterus, and cervix were identified. Following stratification by tumor site and histology, we examined the prevalence of MAPK/ERK pathway gene alterations (somatic mutation, and/or structural chromosome alterations). We included the following RAS-MAPK pathway genes known to be implicated in the dysregulation of the pathway; KRAS, NRAS, BRAF, HRAS, MAP2K1, RAF1, PTPN11, NF1, and ARAF. Data from the OncoKB database, as provided by cBioPortal, were utilized to determine pathogenic gene alterations.

Results: We identified a total of 10,233 patients with gynecologic malignancies; 48.2% (n = 4937) with ovarian, 45.2% (n = 4621) with uterine and 6.6% (n = 675) with cervical cancer respectively. The overall incidence of MAPK pathway gene alterations was 21%; the most commonly altered gene was KRAS (13%), followed by NF1 (7%), NRAS (1.3%), and BRAF (1.2%). The highest incidence was observed among patients with mucinous ovarian (71%), low-grade serous ovarian (48%), endometrioid ovarian (37%), and endometrioid endometrial carcinoma (34%).

Conclusions: Approximately 1 in 5 patients with a gynecologic tumor harbor a MAPK/ERK pathway genomic alteration. Novel treatment strategies capitalizing on these alterations are warranted.

Keywords: Genomics; Ovarian cancer; Therapeutics; Uterine cancer.