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BMC Cancer
Published in: BMC Cancer 1/2014

Open Access 01-12-2014 | Research article

Intratumoral heterogeneity in a minority of ovarian low-grade serous carcinomas

Authors: Alicia A Tone, Melissa K McConechy, Winnie Yang, Jiarui Ding, Stephen Yip, Esther Kong, Kwong-Kwok Wong, David M Gershenson, Helen Mackay, Sohrab Shah, Blake Gilks, Anna V Tinker, Blaise Clarke, Jessica N McAlpine, David Huntsman

Published in: BMC Cancer | Issue 1/2014

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Abstract

Background

Ovarian low-grade serous carcinoma (LGSC) has fewer mutations than ovarian high-grade serous carcinoma (HGSC) and a less aggressive clinical course. However, an overwhelming majority of LGSC patients do not respond to conventional chemotherapy resulting in a poor long-term prognosis comparable to women diagnosed with HGSC. KRAS and BRAF mutations are common in LGSC, leading to clinical trials targeting the MAPK pathway. We assessed the stability of targetable somatic mutations over space and/or time in LGSC, with a view to inform stratified treatment strategies and clinical trial design.

Methods

Eleven LGSC cases with primary and recurrent paired samples were identified (stage IIB-IV). Tumor DNA was isolated from 1–4 formalin-fixed paraffin-embedded tumor blocks from both the primary and recurrence (n = 37 tumor and n = 7 normal samples). Mutational analysis was performed using the Ion Torrent AmpliSeqTM Cancer Panel, with targeted validation using Fluidigm-MiSeq, Sanger sequencing and/or Raindance Raindrop digital PCR.

Results

KRAS (3/11), BRAF (2/11) and/or NRAS (1/11) mutations were identified in five unique cases. A novel, non-synonymous mutation in SMAD4 was observed in one case. No somatic mutations were detected in the remaining six cases. In two cases with a single matched primary and recurrent sample, two KRAS hotspot mutations (G12V, G12R) were both stable over time. In three cases with multiple samplings from both the primary and recurrent surgery some mutations (NRAS Q61R, BRAF V600E, SMAD4 R361G) were stable across all samples, while others (KRAS G12V, BRAF G469V) were unstable.

Conclusions

Overall, the majority of cases with detectable somatic mutations showed mutational stability over space and time while one of five cases showed both temporal and spatial mutational instability in presumed drivers of disease. Investigation of additional cases is required to confirm whether mutational heterogeneity in a minority of LGSC is a general phenomenon that should be factored into the design of clinical trials and stratified treatment for this patient population.
Appendix
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Metadata
Title
Intratumoral heterogeneity in a minority of ovarian low-grade serous carcinomas
Authors
Alicia A Tone
Melissa K McConechy
Winnie Yang
Jiarui Ding
Stephen Yip
Esther Kong
Kwong-Kwok Wong
David M Gershenson
Helen Mackay
Sohrab Shah
Blake Gilks
Anna V Tinker
Blaise Clarke
Jessica N McAlpine
David Huntsman
Publication date
01-12-2014
Publisher
BioMed Central
Published in
BMC Cancer / Issue 1/2014
Electronic ISSN: 1471-2407
DOI
https://doi.org/10.1186/1471-2407-14-982

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