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Published on: April 11, 2016
Targeted and Shallow Whole-Genome Sequencing Identifies Therapeutic Opportunities in p53abn Endometrial Cancers
Amy Jamieson1, Juliana Sobral de Barros2, Dawn R Cochrane2
1Division of Gynecologic Oncology, Department of Gynecology and Obstetrics, University of British Columbia, Vancouver, Canada.
Purpose:
Shallow whole-genome sequencing (sWGS) can detect copy-number (CN) aberrations. In high-grade serous ovarian cancer (HGSOC) sWGS identified CN signatures such as homologous recombination deficiency (HRD) to direct therapy. We applied sWGS with targeted sequencing to p53abn endometrial cancers to identify additional prognostic stratification and therapeutic opportunities.
Experimental Design:
sWGS and targeted panel sequencing was performed on formalin-fixed, paraffin-embedded p53abn endometrial cancers. CN alterations, mutational data and CN signatures were derived, and associations to clinicopathologic and outcomes data were assessed.
Results:
In 187 p53abn endometrial cancers, 5 distinct CN signatures were identified. Signature 5 was associated with BRCA1/2 CN loss with features similar to HGSOC HRD signature. Twenty-two percent of potential HRD cases were identified, 35 patients with signature 5, and 8 patients with BRCA1/2 somatic mutations. Signatures 3 and 4 were associated with a high ploidy state, and CCNE1, ERBB2, and MYC amplifications, with mutations in PIK3CA enriched in signature 3. We observed improved overall survival (OS) for patients with signature 2 and worse OS for signatures 1 and 3. Twenty-eight percent of patients had CCNE1 amplification and this subset was enriched with carcinosarcoma histotype. Thirty-four percent of patients, across all histotypes, had ERBB2 amplification and/or HER2 overexpression on IHC, which was associated with worse outcomes. Mutations in PPP2R1A (29%) and FBXW7 (16%) were among the top 5 most common mutations.
Conclusions:
sWGS and targeted sequencing identified therapeutic opportunities in 75% of patients with p53abn endometrial cancer. Further research is needed to determine the efficacy of treatments targeting these identified pathways within p53abn endometrial cancers.
Insights
Shallow whole-genome sequencing identified copy-number signatures in p53abn endometrial cancers, revealing new prognostic markers and therapeutic targets. These findings offer potential for improved patient stratification and treatment strategies.
Area of Science:
- Genomics
- Oncology
- Cancer Research
Background:
- Shallow whole-genome sequencing (sWGS) detects copy-number (CN) aberrations.
- In high-grade serous ovarian cancer (HGSOC), sWGS identified CN signatures like homologous recombination deficiency (HRD) for therapy guidance.
Purpose of the Study:
- Apply sWGS and targeted sequencing to p53abn endometrial cancers.
- Identify prognostic stratification and therapeutic opportunities.
Main Methods:
- Performed sWGS and targeted panel sequencing on p53abn endometrial cancers.
- Derived CN alterations, mutational data, and CN signatures.
- Assessed associations with clinicopathologic and outcomes data.
Main Results:
- Identified 5 distinct CN signatures in 187 p53abn endometrial cancers.
- Signature 5 associated with BRCA1/2 CN loss, similar to HGSOC HRD.
- Found CCNE1, ERBB2, MYC amplifications, and common mutations (PPP2R1A, FBXW7).
- Observed differential overall survival (OS) based on CN signatures.
- CCNE1 amplification enriched in carcinosarcoma; ERBB2 amplification/HER2 overexpression associated with worse outcomes.
Conclusions:
- sWGS and targeted sequencing identified therapeutic opportunities in 75% of p53abn endometrial cancers.
- Further research is needed to validate treatment efficacy for identified pathways.
