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

BACKGROUND: Mucinous 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 acros...

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Autores principales: Mackenzie, Robertson, Kommoss, Stefan, Winterhoff, Boris J., Kipp, Benjamin R., Garcia, Joaquin J., Voss, Jesse, Halling, Kevin, Karnezis, Anthony, Senz, Janine, Yang, Winnie, Prigge, Elena-Sophie, Reuschenbach, Miriam, Doeberitz, Magnus Von Knebel, Gilks, Blake C., Huntsman, David G., Bakkum-Gamez, Jamie, McAlpine, Jessica N., Anglesio, Michael S.
Formato: Online Artículo Texto
Lenguaje:English
Publicado: BioMed Central 2015
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4494777/
https://www.ncbi.nlm.nih.gov/pubmed/25986173
http://dx.doi.org/10.1186/s12885-015-1421-8
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author Mackenzie, Robertson
Kommoss, Stefan
Winterhoff, Boris J.
Kipp, Benjamin R.
Garcia, Joaquin J.
Voss, Jesse
Halling, Kevin
Karnezis, Anthony
Senz, Janine
Yang, Winnie
Prigge, Elena-Sophie
Reuschenbach, Miriam
Doeberitz, Magnus Von Knebel
Gilks, Blake C.
Huntsman, David G.
Bakkum-Gamez, Jamie
McAlpine, Jessica N.
Anglesio, Michael S.
author_facet Mackenzie, Robertson
Kommoss, Stefan
Winterhoff, Boris J.
Kipp, Benjamin R.
Garcia, Joaquin J.
Voss, Jesse
Halling, Kevin
Karnezis, Anthony
Senz, Janine
Yang, Winnie
Prigge, Elena-Sophie
Reuschenbach, Miriam
Doeberitz, Magnus Von Knebel
Gilks, Blake C.
Huntsman, David G.
Bakkum-Gamez, Jamie
McAlpine, Jessica N.
Anglesio, Michael S.
author_sort Mackenzie, Robertson
collection PubMed
description BACKGROUND: Mucinous 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. METHODS: Using 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. RESULTS: We 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. CONCLUSIONS: Overall, 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. ELECTRONIC SUPPLEMENTARY MATERIAL: The online version of this article (doi:10.1186/s12885-015-1421-8) contains supplementary material, which is available to authorized users.
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spelling pubmed-44947772015-07-08 Targeted deep sequencing of mucinous ovarian tumors reveals multiple overlapping RAS-pathway activating mutations in borderline and cancerous neoplasms Mackenzie, Robertson Kommoss, Stefan Winterhoff, Boris J. Kipp, Benjamin R. Garcia, Joaquin J. Voss, Jesse Halling, Kevin Karnezis, Anthony Senz, Janine Yang, Winnie Prigge, Elena-Sophie Reuschenbach, Miriam Doeberitz, Magnus Von Knebel Gilks, Blake C. Huntsman, David G. Bakkum-Gamez, Jamie McAlpine, Jessica N. Anglesio, Michael S. BMC Cancer Research Article BACKGROUND: Mucinous 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. METHODS: Using 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. RESULTS: We 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. CONCLUSIONS: Overall, 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. ELECTRONIC SUPPLEMENTARY MATERIAL: The online version of this article (doi:10.1186/s12885-015-1421-8) contains supplementary material, which is available to authorized users. BioMed Central 2015-05-19 /pmc/articles/PMC4494777/ /pubmed/25986173 http://dx.doi.org/10.1186/s12885-015-1421-8 Text en © 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.
spellingShingle Research Article
Mackenzie, Robertson
Kommoss, Stefan
Winterhoff, Boris J.
Kipp, Benjamin R.
Garcia, Joaquin J.
Voss, Jesse
Halling, Kevin
Karnezis, Anthony
Senz, Janine
Yang, Winnie
Prigge, Elena-Sophie
Reuschenbach, Miriam
Doeberitz, Magnus Von Knebel
Gilks, Blake C.
Huntsman, David G.
Bakkum-Gamez, Jamie
McAlpine, Jessica N.
Anglesio, Michael S.
Targeted deep sequencing of mucinous ovarian tumors reveals multiple overlapping RAS-pathway activating mutations in borderline and cancerous neoplasms
title Targeted deep sequencing of mucinous ovarian tumors reveals multiple overlapping RAS-pathway activating mutations in borderline and cancerous neoplasms
title_full Targeted deep sequencing of mucinous ovarian tumors reveals multiple overlapping RAS-pathway activating mutations in borderline and cancerous neoplasms
title_fullStr Targeted deep sequencing of mucinous ovarian tumors reveals multiple overlapping RAS-pathway activating mutations in borderline and cancerous neoplasms
title_full_unstemmed Targeted deep sequencing of mucinous ovarian tumors reveals multiple overlapping RAS-pathway activating mutations in borderline and cancerous neoplasms
title_short Targeted deep sequencing of mucinous ovarian tumors reveals multiple overlapping RAS-pathway activating mutations in borderline and cancerous neoplasms
title_sort targeted deep sequencing of mucinous ovarian tumors reveals multiple overlapping ras-pathway activating mutations in borderline and cancerous neoplasms
topic Research Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4494777/
https://www.ncbi.nlm.nih.gov/pubmed/25986173
http://dx.doi.org/10.1186/s12885-015-1421-8
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