Highlights
- •17 cases of FIGO stage III low-grade serous carcinoma/serous borderline tumors underwent molecular profiling.
- •Tumor mutational burdens were generally low (range 3–10 mutations/Mb in 14 cases assessed).
- •Microsatellites were assessed to be stable in 12/12 cases.
- •The majority of tumors (11/17) harbored a clear driver mutation in forms of RTK/RAS/MAPK pathway gene mutations.
- •While BRCA2 variants were seen in 5/17 cases, further analyses suggest they are unlikely to be clinically significant.
Abstract
Objective
The mutational spectra of low-grade serous carcinomas (LGSCs) and serous borderline
tumors (SBTs) of the ovary are poorly characterized. We present 17 cases of advanced
or recurrent LGSC/SBT patients who underwent molecular profiling.
Methods
Thirteen LGSCs and four SBTs underwent targeted gene panel testing by massively parallel
sequencing. Microsatellite stability and tumor mutation burdens (TMBs) were determined
based on panel sequencing data.
Results
The mean TMB was 5.2 mutations/megabase (range 3–10) in 14 cases. Twelve of twelve
(12/12) cases were microsatellite stable. Clear driver mutations were identified in
11 cases, namely KRAS (5/17), BRAF (2/17), NRAS (2/17) and ERBB2 (2/17). Five cases harbored BRCA2 alterations (allele fractions: 44–51%), including two classified as likely benign/benign
variants, and three classified as variants of uncertain significance (VUSs), with
two variants being confirmed to be germline. The three BRCA2 VUSs were missense variants that were assessed to be of unlikely clinical significance,
based on family cancer history and expected impact on protein function. Two patients
received PARP inhibitors during their disease course, with neither of the patients
demonstrating appreciable response.
Conclusions
The mutational spectra in 17 clinically aggressive SBT/LGSC cases demonstrate genomically
stable tumors, frequently driven by the RTK/RAS/MAPK pathway. While BRCA2 variants were identified, our data demonstrate BRCA2 gene variants are at most VUSs and of dubious clinical significance, in contrast
to disease-associated BRCA1/2 variants that may be identified in high-grade serous carcinoma. Germline testing
and PARP inhibitors are thus expected to provide limited benefit to patients with
LGSC/SBTs.
Keywords
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Article info
Publication history
Published online: March 24, 2021
Accepted:
March 15,
2021
Received:
January 21,
2021
Identification
Copyright
© 2021 Elsevier Inc. All rights reserved.
