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Published on: July 25, 2020
Molecular profiling of low grade serous ovarian tumours identifies novel candidate driver genes
Sally M Hunter1, Michael S Anglesio2, Georgina L Ryland1
1Centre for Cancer Genomics and Predictive Medicine, Peter MacCallum Cancer Centre, East Melbourne, Australia.
Abstract:
Low grade serous ovarian tumours are a rare and under-characterised histological subtype of epithelial ovarian tumours, with little known of the molecular drivers and facilitators of tumorigenesis beyond classic oncogenic RAS/RAF mutations. With a move towards targeted therapies due to the chemoresistant nature of this subtype, it is pertinent to more fully characterise the genetic events driving this tumour type, some of which may influence response to therapy and/or development of drug resistance. We performed genome-wide high-resolution genomic copy number analysis (Affymetrix SNP6.0) and mutation hotspot screening (KRAS, BRAF, NRAS, HRAS, ERBB2 and TP53) to compare a large cohort of ovarian serous borderline tumours (SBTs, n = 57) with low grade serous carcinomas (LGSCs, n = 19). Whole exome sequencing was performed for 13 SBTs, nine LGSCs and one mixed low/high grade carcinoma. Copy number aberrations were detected in 61% (35/57) of SBTs, compared to 100% (19/19) of LGSCs. Oncogenic RAS/RAF/ERBB2 mutations were detected in 82.5% (47/57) of SBTs compared to 63% (12/19) of LGSCs, with NRAS mutations detected only in LGSC. Some copy number aberrations appeared to be enriched in LGSC, most significantly loss of 9p and homozygous deletions of the CDKN2A/2B locus. Exome sequencing identified BRAF, KRAS, NRAS, USP9X and EIF1AX as the most frequently mutated genes. We have identified markers of progression from borderline to LGSC and novel drivers of LGSC. USP9X and EIF1AX have both been linked to regulation of mTOR, suggesting that mTOR inhibitors may be a key companion treatment for targeted therapy trials of MEK and RAF inhibitors.
Insights
This study reveals key genetic drivers in low-grade serous ovarian tumors, identifying USP9X and EIF1AX mutations. These findings suggest mTOR inhibitors could enhance targeted therapies for this rare cancer.
Area of Science:
- Oncology
- Genomics
- Molecular Biology
Background:
- Low-grade serous ovarian tumors (LGSC) are rare epithelial ovarian tumors with poorly understood molecular drivers.
- The chemoresistant nature of LGSC necessitates the development of targeted therapies.
- Identifying genetic events is crucial for understanding LGSC progression and therapeutic response.
Purpose of the Study:
- To comprehensively characterize the genetic landscape of ovarian serous borderline tumors (SBTs) and low-grade serous carcinomas (LGSCs).
- To identify molecular markers distinguishing SBTs from LGSCs and novel drivers of LGSC.
- To explore potential therapeutic targets based on identified genetic alterations.
Main Methods:
- Genome-wide high-resolution genomic copy number analysis (Affymetrix SNP6.0).
- Mutation hotspot screening for key oncogenes (KRAS, BRAF, NRAS, HRAS, ERBB2, TP53).
- Whole exome sequencing of selected SBTs, LGSCs, and a mixed-grade carcinoma.
Main Results:
- Copy number aberrations were present in 61% of SBTs and 100% of LGSCs.
- RAS/RAF/ERBB2 mutations were common in both subtypes, with NRAS mutations exclusive to LGSC.
- Significant copy number alterations in LGSC included 9p loss and CDKN2A/2B locus homozygous deletions; USP9X and EIF1AX were frequently mutated.
Conclusions:
- Genetic alterations, particularly copy number aberrations and mutations in USP9X and EIF1AX, mark the progression from SBT to LGSC.
- USP9X and EIF1AX mutations implicate the mTOR pathway in LGSC tumorigenesis.
- mTOR inhibitors may represent a promising companion therapy for MEK and RAF inhibitors in LGSC treatment.
