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Subtype-specific mutation of PPP2R1A in endometrial and ovarian carcinomas
Melissa K McConechy1, Michael S Anglesio, Steve E Kalloger
1Department of Pathology and Laboratory Medicine, University of British Columbia, British Columbia Cancer Agency, 3427-600 West 10th Avenue, Vancouver, BC, Canada.
Abstract:
PPP2R1A mutations have recently been described in 3/42 (7%) of clear cell carcinomas of the ovary. PPP2R1A encodes the α-isoform of the scaffolding subunit of the serine/threonine protein phosphatase 2A (PP2A) holoenzyme. This putative tumour suppressor complex is involved in growth and survival pathways. Through targeted sequencing of PPP2R1A, we identified somatic missense mutations in 40.8% (20/49) of high-grade serous endometrial tumours, and 5.0% (3/60) of endometrial endometrioid carcinomas. Mutations were also identified in ovarian tumours at lower frequencies: 12.2% (5/41) of endometrioid and 4.1% (2/49) of clear cell carcinomas. No mutations were found in 50 high-grade and 12 low-grade serous carcinomas. Amino acid residues affected by these mutations are highly conserved across species and are involved in direct interactions with regulatory B-subunits of the PP2A holoenzyme. PPP2R1A mutations in endometrial high-grade serous carcinomas are a frequent and potentially targetable feature of this disease. The finding of frequent PPP2R1A mutations in high-grade serous carcinoma of the endometrium but not in high-grade serous carcinoma of the ovary provides clear genetic evidence that these are distinct diseases.
Insights
Mutations in the PPP2R1A gene, which encodes a subunit of protein phosphatase 2A (PP2A), are common in high-grade serous endometrial tumors. This discovery highlights genetic differences between endometrial and ovarian high-grade serous carcinomas.
Area of Science:
- Oncology
- Molecular Biology
- Genetics
Background:
- The PPP2R1A gene encodes a scaffolding subunit of the protein phosphatase 2A (PP2A) holoenzyme, a complex implicated in tumor suppression.
- Previous studies identified PPP2R1A mutations in a small subset of ovarian clear cell carcinomas.
Purpose of the Study:
- To investigate the frequency and spectrum of PPP2R1A mutations in endometrial and ovarian carcinomas.
- To determine if PPP2R1A mutations can serve as a genetic marker to distinguish between endometrial and ovarian high-grade serous carcinomas.
Main Methods:
- Targeted sequencing of the PPP2R1A gene in a cohort of endometrial and ovarian tumors.
- Analysis of mutation frequencies across different histological subtypes and grades.
Main Results:
- Somatic missense mutations in PPP2R1A were identified in 40.8% of high-grade serous endometrial tumors and 5.0% of endometrial endometrioid carcinomas.
- Mutations were found at lower frequencies in ovarian endometrioid (12.2%) and clear cell (4.1%) carcinomas.
- No PPP2R1A mutations were detected in high-grade or low-grade serous ovarian carcinomas.
Conclusions:
- PPP2R1A mutations represent a frequent and potentially targetable genetic alteration in high-grade serous endometrial carcinoma.
- The distinct prevalence of PPP2R1A mutations in endometrial versus ovarian high-grade serous carcinoma provides genetic evidence that these are distinct disease entities.
