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Published on: March 21, 2018
Profiling cancer gene mutations in longitudinal epithelial ovarian cancer biopsies by targeted next-generation
L Beltrame1, M Di Marino1, R Fruscio2
1Department of Oncology, Centro di Ricerche Cliniche per le Malattie Rare 'ALDO e CELE DACCO'', IRCCS 'Mario Negri' Institute for Pharmacological Research, Milano.
Background:
The majority of patients with stage III-IV epithelial ovarian cancer (EOC) relapse after initially responding to platinum-based chemotherapy, and develop resistance. The genomic features involved in drug resistance are unknown. To unravel some of these features, we investigated the mutational profile of genes involved in pathways related to drug sensitivity in a cohort of matched tumors obtained at first surgery (Ft-S) and second surgery (Sd-S).
Patients And Methods:
Matched biopsies (33) taken at Ft-S and Sd-S were selected from the 'Pandora' tumor tissue collection. DNA libraries for 65 genes were generated using the TruSeq Custom Amplicon kit and sequenced on MiSeq (Illumina). Data were analyzed using a high-performance cluster computing platform (Cloud4CARE project) and independently validated.
Results:
A total of 2270 somatic mutations were identified (89.85% base substitutions 8.19% indels, and 1.92% unknown). Homologous recombination (HR) genes and TP53 were mutated in the majority of Ft-S, while ATM, ATR, TOP2A and TOP2B were mutated in the entire dataset. Only 2% of mutations were conserved between matched Ft-S and Sd-S. Mutations detected at second surgery clustered patients in two groups characterized by different mutational profiles in genes associated with HR, PI3K, miRNA biogenesis and signal transduction.
Conclusions:
There was a low level of concordance between Ft-S and Sd-S in terms of mutations in genes involved in key processes of tumor growth and drug resistance. This result suggests the importance of future longitudinal analyses to improve the clinical management of relapsed EOC.
Insights
Genomic analysis of ovarian cancer tumors before and after relapse reveals few conserved mutations, highlighting the need for longitudinal studies to guide treatment for recurrent disease.
Area of Science:
- Genomic Medicine
- Oncology
- Molecular Biology
Background:
- Epithelial ovarian cancer (EOC) frequently relapses after chemotherapy.
- Drug resistance in advanced EOC is a major clinical challenge.
- Genomic underpinnings of EOC drug resistance remain largely unknown.
Purpose of the Study:
- To investigate the mutational profiles of genes related to drug sensitivity in EOC.
- To compare genomic features between tumors at first and second surgery.
- To identify genomic alterations associated with platinum-based chemotherapy resistance.
Main Methods:
- Analysis of 33 matched tumor biopsies from first (Ft-S) and second (Sd-S) surgeries.
- Targeted sequencing of 65 genes involved in drug sensitivity pathways.
- High-performance computing for data analysis and independent validation.
Main Results:
- Identified 2270 somatic mutations, predominantly base substitutions.
- Homologous recombination (HR) genes and TP53 mutations were common in Ft-S.
- Only 2% of mutations were shared between Ft-S and Sd-S.
- Second surgery mutations defined patient groups with distinct profiles in HR, PI3K, and miRNA pathways.
Conclusions:
- Low concordance of mutations between Ft-S and Sd-S suggests significant genomic evolution.
- Genomic landscape changes impact tumor growth and drug resistance mechanisms.
- Longitudinal genomic analysis is crucial for optimizing clinical management of relapsed EOC.
