Targeted deep sequencing of mucinous ovarian tumors reveals multiple overlapping RAS-pathway activating mutations in borderline and cancerous neoplasms

BMC Cancer

Research Article

Magnus Von Knebel Doeberitz¹  Miriam Reuschenbach¹  Elena-Sophie Prigge¹  Jessica N. McAlpine²  Jamie Bakkum-Gamez³  Kevin Halling⁴  Boris J. Winterhoff⁴  Jesse Voss⁴  Benjamin R. Kipp⁴  Joaquin J. Garcia⁴  Winnie Yang⁵  Robertson Mackenzie⁵  Blake C. Gilks⁶  Janine Senz⁶  Anthony Karnezis⁶  Michael S. Anglesio⁷  David G. Huntsman⁸  Stefan Kommoss⁹ 

[1] Applied Tumor Biology, Institute of Pathology, University of Heidelberg, Heidelberg, Germany;Gynecology and Obstetrics, Division of Gynecologic Oncology, University of British Columbia, Vancouver, Canada;Gynecology and Obstetrics, Mayo Clinic, Rochester, USA;Laboratory Medicine and Pathology, Mayo Clinic, Rochester, USA;Molecular Oncology, BC Cancer Agency Research Centre, Vancouver, Canada;Pathology and Laboratory Medicine, University of British Columbia, Vancouver, Canada;Pathology and Laboratory Medicine, University of British Columbia, Vancouver, Canada;Department of Pathology and Laboratory Medicine, University of British Columbia, Vancouver, Canada;Pathology and Laboratory Medicine, University of British Columbia, Vancouver, Canada;Gynecology and Obstetrics, Division of Gynecologic Oncology, University of British Columbia, Vancouver, Canada;Pathology and Laboratory Medicine, University of British Columbia, Vancouver, Canada;Gynecology and Obstetrics, Tuebingen University Hospital, Tuebingen, Germany;

关键词: Next-generation sequencing;    Mucinous;    Ovarian;    BRAF;    KRAS;    TP53;    Heterogeneity;   

DOI  :  10.1186/s12885-015-1421-8

 received in 2014-12-05, accepted in 2015-05-06,  发布年份 2015

来源: Springer

【 摘 要 】

BackgroundMucinous ovarian tumors represent a distinct histotype of epithelial ovarian cancer. The rarest (2-4 % of ovarian carcinomas) of the five major histotypes, their genomic landscape remains poorly described. We undertook hotspot sequencing of 50 genes commonly mutated in human cancer across 69 mucinous ovarian tumors. Our goals were to establish the overall frequency of cancer-hotspot mutations across a large cohort, especially those tumors previously thought to be “RAS-pathway alteration negative”, using highly-sensitive next-generation sequencing as well as further explore a small number of cases with apparent heterogeneity in RAS-pathway activating alterations.MethodsUsing the Ion Torrent PGM platform, we performed next generation sequencing analysis using the v2 Cancer Hotspot Panel. Regions of disparate ERBB2-amplification status were sequenced independently for two mucinous carcinoma (MC) cases, previously established as showing ERBB2 amplification/overexpression heterogeneity, to assess the hypothesis of subclonal populations containing either KRAS mutation or ERBB2 amplification independently or simultaneously.ResultsWe detected mutations in KRAS, TP53, CDKN2A, PIK3CA, PTEN, BRAF, FGFR2, STK11, CTNNB1, SRC, SMAD4, GNA11 and ERBB2. KRAS mutations remain the most frequently observed alteration among MC (64.9 %) and mucinous borderline tumors (MBOT) (92.3 %). TP53 mutation occurred more frequently in carcinomas than borderline tumors (56.8 % and 11.5 %, respectively), and combined IHC and mutation data suggest alterations occur in approximately 68 % of MC and as many as 20 % of MBOT. Proven and potential RAS-pathway activating changes were observed in all but one MC. Concurrent ERBB2 amplification and KRAS mutation were observed in a substantial number of cases (7/63 total), as was co-occurrence of KRAS and BRAF mutations (one case). Microdissection of ERBB2-amplified regions of tumors harboring KRAS mutation suggests these alterations are occurring in the same cell populations, while consistency of KRAS allelic frequency in both ERBB2 amplified and non-amplified regions suggests this mutation occurred in advance of the amplification event.ConclusionsOverall, the prevalence of RAS-alteration and striking co-occurrence of pathway “double-hits” supports a critical role for tumor progression in this ovarian malignancy. Given the spectrum of RAS-activating mutations, it is clear that targeting this pathway may be a viable therapeutic option for patients with recurrent or advanced stage mucinous ovarian carcinoma, however caution should be exercised in selecting one or more personalized therapeutics given the frequency of non-redundant RAS-activating alterations.

【 授权许可】

Unknown   
© Mackenzie et al.; licensee BioMed Central. 2015. This article is published under license to BioMed Central Ltd. This is an Open Access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/4.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly credited. The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated.