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Translational relevance of RET gene alterations in breast cancer

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TitleInfo
Title
Translational relevance of RET gene alterations in breast cancer
Name (type = personal)
NamePart (type = family)
Paratala
NamePart (type = given)
Bhavna S
NamePart (type = date)
1987-
DisplayForm
Bhavna S Paratala
Role
RoleTerm (authority = RULIB)
author
Name (type = personal)
NamePart (type = family)
Hirshfield
NamePart (type = given)
Kim M
DisplayForm
Kim M Hirshfield
Affiliation
Advisory Committee
Role
RoleTerm (authority = RULIB)
chair
Name (type = corporate)
NamePart
Rutgers University
Role
RoleTerm (authority = RULIB)
degree grantor
Name (type = corporate)
NamePart
School of Graduate Studies
Role
RoleTerm (authority = RULIB)
school
TypeOfResource
Text
Genre (authority = marcgt)
theses
OriginInfo
DateCreated (qualifier = exact)
2019
DateOther (qualifier = exact); (type = degree)
2019-01
CopyrightDate (encoding = w3cdtf)
2019
Place
PlaceTerm (type = code)
xx
Language
LanguageTerm (authority = ISO639-2b); (type = code)
eng
Abstract (type = abstract)
RET is a receptor tyrosine kinase that is crucial for normal tissue development and maintenance, but deregulation of its activity is a known contributor to oncogenesis in several cancers. Gain-of-function alterations in thyroid and lung cancers, causally-associated mutations in hereditary forms of endocrine disorders combined with the observed tumor responses to tyrosine kinase inhibitors with anti-RET activity underscore the potential use of RET as a therapeutic target in breast cancer. In breast cancer, correlations of RET overexpression with endocrine resistance and reduced expression with improved overall survival in estrogen receptor positive cases are driving clinical investigations of using RET-targeting kinase inhibitors for treatment of this disease. In efforts to identify clinically relevant biomarkers that may help direct individualized patient treatment, our initial finding of RET gene rearrangements in two independent breast cancers initiated our inquiry into the frequency and therapeutic relevance of RET gene alterations in breast cancer. Upon analyzing ~9,700 breast cancers that were deep-sequenced using a targeted, hybrid capture assay, which includes relevant intronic details of RET, we discovered a spectrum of RET structural alterations in 121 cases (1.25%), of which, a majority were triple negative breast cancers that are known to have poorer prognosis and limited targeted treatment options. RET alterations were also identified in a subset of HER2-amplified breast cancers, primarily as RET amplification. We further characterized the functional consequence of RET amplification, the most frequent alteration, and the two initially identified RET rearrangements, NCOA4-RET and RASGEF1A-RET, by generating cell line and xenograft models. Comparison with an inactive RET kinase mutant and a known active RET kinase mutant by ectopic expression revealed constitutive kinase activation and downstream signaling of oncogenic pathways by both RET amplification and rearrangements. Results revealed that RET rearrangements induce transformation of non-tumorigenic cells, support xenograft tumor formation, and render cells carrying these alterations sensitive to RET inhibition in vitro and in vivo. Moreover, detection of the NCOA4-RET fusion in an index case of metastatic breast cancer that progressed on HER2-targeted therapy led to subsequent patient treatment with the RET inhibitor, cabozantinib, resulting in a rapid clinical and radiographic response. In another index case of advanced breast cancer, a RET amplification was detected and noted to be acquired in the setting of resistance to HER2-targeted therapy. RET expression was confirmed in a patient-derived cell line and xenograft model generated from this resistant tumor. Our xenograft model revealed tumor growth inhibition with cabozantinib and tested the applicability of its combination with HER2-targeting agents. Overall, this work presents a comprehensive, mutational analysis of RET in breast cancer and by using cell line models, patient-derived models, and index case reports, signifies the functional role of RET alterations as well as the therapeutic relevance of targeting RET in this selected subset of breast cancers.
Subject (authority = RUETD)
Topic
Pharmacology, Cellular and Molecular
Subject (authority = ETD-LCSH)
Topic
Cancer--Genetic aspects
RelatedItem (type = host)
TitleInfo
Title
Rutgers University Electronic Theses and Dissertations
Identifier (type = RULIB)
ETD
Identifier
ETD_9357
PhysicalDescription
Form (authority = gmd)
electronic resource
InternetMediaType
application/pdf
InternetMediaType
text/xml
Extent
1 online resource (115 pages) : illustrations
Note (type = degree)
Ph.D.
Note (type = bibliography)
Includes bibliographical references
Note (type = statement of responsibility)
by Bhavna S. Paratala
RelatedItem (type = host)
TitleInfo
Title
School of Graduate Studies Electronic Theses and Dissertations
Identifier (type = local)
rucore10001600001
Location
PhysicalLocation (authority = marcorg); (displayLabel = Rutgers, The State University of New Jersey)
NjNbRU
Identifier (type = doi)
doi:10.7282/t3-rsdk-av61
Genre (authority = ExL-Esploro)
ETD doctoral
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Rights

RightsDeclaration (ID = rulibRdec0006)
The author owns the copyright to this work.
RightsHolder (type = personal)
Name
FamilyName
Paratala
GivenName
Bhavna S
Role
Copyright Holder
RightsEvent
Type
Permission or license
DateTime (encoding = w3cdtf); (qualifier = exact); (point = start)
2018-11-04 20:42:20
AssociatedEntity
Name
Bhavna S Paratala
Role
Copyright holder
Affiliation
Rutgers University. School of Graduate Studies
AssociatedObject
Type
License
Name
Author Agreement License
Detail
I hereby grant to the Rutgers University Libraries and to my school the non-exclusive right to archive, reproduce and distribute my thesis or dissertation, in whole or in part, and/or my abstract, in whole or in part, in and from an electronic format, subject to the release date subsequently stipulated in this submittal form and approved by my school. I represent and stipulate that the thesis or dissertation and its abstract are my original work, that they do not infringe or violate any rights of others, and that I make these grants as the sole owner of the rights to my thesis or dissertation and its abstract. I represent that I have obtained written permissions, when necessary, from the owner(s) of each third party copyrighted matter to be included in my thesis or dissertation and will supply copies of such upon request by my school. I acknowledge that RU ETD and my school will not distribute my thesis or dissertation or its abstract if, in their reasonable judgment, they believe all such rights have not been secured. I acknowledge that I retain ownership rights to the copyright of my work. I also retain the right to use all or part of this thesis or dissertation in future works, such as articles or books.
RightsEvent
Type
Embargo
DateTime (encoding = w3cdtf); (qualifier = exact); (point = start)
2019-01-31
DateTime (encoding = w3cdtf); (qualifier = exact); (point = end)
2020-01-31
Detail
Access to this PDF has been restricted at the author's request. It will be publicly available after January 31st, 2020.
Copyright
Status
Copyright protected
Availability
Status
Open
Reason
Permission or license
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windows xp
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DateCreated (point = end); (encoding = w3cdtf); (qualifier = exact)
2018-11-05T01:29:37
DateCreated (point = end); (encoding = w3cdtf); (qualifier = exact)
2018-11-05T01:29:37
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