Whole exome sequencing of low grade serous ovarian carcinoma identifies genomic events associated with clinical outcome.
Gynecol Oncol
; 174: 157-166, 2023 07.
Article
em En
| MEDLINE
| ID: mdl-37207500
ABSTRACT
OBJECTIVES:
Low-grade serous ovarian carcinoma (LGSOC) is a distinct, rare, ovarian cancer type characterised by younger patient age and intrinsic chemoresistance. Understanding the molecular landscape is crucial for optimising targeted therapy.METHODS:
Genomic data from whole exome sequencing of tumour tissue was analysed in a LGSOC cohort with detailed clinical annotation.RESULTS:
63 cases were analysed and three subgroups identified based on single nucleotide variants canonical MAPK mutant (cMAPKm 52%, KRAS/BRAF/NRAS), MAPK-associated gene mutation (MAPK-assoc 27%) and MAPK wild-type (MAPKwt 21%). NOTCH pathway disruption occurred across all subgroups. Tumour mutational burden (TMB), mutational signatures and recurrent copy number (CN) changes varied across the cohort with co-occurrence of chromosome 1p loss and 1q gain (CN Chr1pq) a recurrent feature. Low TMB and CN Chr1pq were associated with inferior disease-specific survival (HR 6.43; p < 0.001 and HR 3.29, p = 0.011 respectively). Stepwise genomic classification in relation to outcome resulted in four groups (TMB low; CN Chr1pq; MAPKwt/MAPKassoc; cMAPKm). 5 year disease-specific survival was 46%, 55%, 79% and 100% respectively for these groups. The two most favourable genomic subgroups were enriched for the SBS10b mutational signature, particularly the cMAPKm subgroup.CONCLUSIONS:
LGSOC comprises multiple genomic subgroups with distinct clinical and molecular features. Chr1pq CN arm disruption and TMB represent promising methods to identify individuals with poorer prognosis. Further investigation of the molecular basis for these observations is required. MAPKwt cases represent around a fifth of patients. NOTCH inhibitors represent a candidate therapeutic strategy worthy of exploration across these cases.Palavras-chave
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Base de dados:
MEDLINE
Assunto principal:
Neoplasias Ovarianas
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Cistadenocarcinoma Seroso
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Cistadenocarcinoma Papilar
Idioma:
En
Ano de publicação:
2023
Tipo de documento:
Article