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

Overview of attention for article published in BMC Cancer, May 2015
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Title
Targeted deep sequencing of mucinous ovarian tumors reveals multiple overlapping RAS-pathway activating mutations in borderline and cancerous neoplasms
Published in
BMC Cancer, May 2015
DOI 10.1186/s12885-015-1421-8
Pubmed ID
Authors

Robertson Mackenzie, Stefan Kommoss, Boris J. Winterhoff, Benjamin R. Kipp, Joaquin J. Garcia, Jesse Voss, Kevin Halling, Anthony Karnezis, Janine Senz, Winnie Yang, Elena-Sophie Prigge, Miriam Reuschenbach, Magnus Von Knebel Doeberitz, Blake C. Gilks, David G. Huntsman, Jamie Bakkum-Gamez, Jessica N. McAlpine, Michael S. Anglesio

Abstract

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. 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. 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. 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.

Twitter Demographics

The data shown below were collected from the profile of 1 tweeter who shared this research output. Click here to find out more about how the information was compiled.

Mendeley readers

The data shown below were compiled from readership statistics for 61 Mendeley readers of this research output. Click here to see the associated Mendeley record.

Geographical breakdown

Country Count As %
Unknown 61 100%

Demographic breakdown

Readers by professional status Count As %
Student > Ph. D. Student 10 16%
Researcher 8 13%
Student > Bachelor 6 10%
Other 5 8%
Student > Doctoral Student 4 7%
Other 12 20%
Unknown 16 26%
Readers by discipline Count As %
Medicine and Dentistry 27 44%
Biochemistry, Genetics and Molecular Biology 9 15%
Agricultural and Biological Sciences 2 3%
Nursing and Health Professions 1 2%
Immunology and Microbiology 1 2%
Other 3 5%
Unknown 18 30%

Attention Score in Context

This research output has an Altmetric Attention Score of 1. This is our high-level measure of the quality and quantity of online attention that it has received. This Attention Score, as well as the ranking and number of research outputs shown below, was calculated when the research output was last mentioned on 20 May 2015.
All research outputs
#2,705,903
of 5,124,740 outputs
Outputs from BMC Cancer
#1,196
of 2,833 outputs
Outputs of similar age
#97,558
of 171,253 outputs
Outputs of similar age from BMC Cancer
#109
of 199 outputs
Altmetric has tracked 5,124,740 research outputs across all sources so far. This one is in the 34th percentile – i.e., 34% of other outputs scored the same or lower than it.
So far Altmetric has tracked 2,833 research outputs from this source. They receive a mean Attention Score of 2.6. This one is in the 45th percentile – i.e., 45% of its peers scored the same or lower than it.
Older research outputs will score higher simply because they've had more time to accumulate mentions. To account for age we can compare this Altmetric Attention Score to the 171,253 tracked outputs that were published within six weeks on either side of this one in any source. This one is in the 33rd percentile – i.e., 33% of its contemporaries scored the same or lower than it.
We're also able to compare this research output to 199 others from the same source and published within six weeks on either side of this one. This one is in the 36th percentile – i.e., 36% of its contemporaries scored the same or lower than it.