Involvement of chromatin remodeling genes and the Rho GTPases RhoB and CDC42 in ovarian clear cell carcinoma

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Arildsen, Nicolai SkovbjergLund University,Lunds universitet,Bröstcancer-genetik,Sektion I,Institutionen för kliniska vetenskaper, Lund,Medicinska fakulteten,Bröst- och ovarialcancer,Forskargrupper vid Lunds universitet,Breastcancer-genetics,Section I,Department of Clinical Sciences, Lund,Faculty of Medicine,Breast and Ovarian Cancer Genomics,Lund University Research Groups,Skåne University Hospital (author)

Involvement of chromatin remodeling genes and the Rho GTPases RhoB and CDC42 in ovarian clear cell carcinoma

Article/chapterEnglish2017

Publisher, publication year, extent ...

2017-05-29
Frontiers Media SA,2017

Numbers

LIBRIS-ID:oai:lup.lub.lu.se:c51a2315-dfd4-4858-bd5b-eb8b3a4115a4
https://lup.lub.lu.se/record/c51a2315-dfd4-4858-bd5b-eb8b3a4115a4URI
https://doi.org/10.3389/fonc.2017.00109DOI
http://kipublications.ki.se/Default.aspx?queryparsed=id:139318813URI

Supplementary language notes

Language:English
Summary in:English

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SwePubSwePub

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Subject category:art swepub-publicationtype
Subject category:ref swepub-contenttype

Notes

Objective: Ovarian clear cell carcinomas (OCCCs) constitute a rare ovarian cancer subtype with distinct clinical features, but may nonetheless be difficult to distinguish morphologically from other subtypes. There is limited knowledge of genetic events driving OCCC tumorigenesis beyond ARID1A, which is reportedly mutated in 30-50% of OCCCs. We aimed to further characterize OCCCs by combined global transcriptional profiling and targeted deep sequencing of a panel of well-established cancer genes. Increased knowledge of OCCC-specific genetic aberrations may help in guiding development of targeted treatments and ultimately improve patient outcome. Methods: Gene expression profiling of formalin-fixed, paraffin-embedded (FFPE) tissue from a cohort of the major ovarian cancer subtypes (cohort 1; n = 67) was performed using whole-genome cDNA-mediated Annealing, Selection, extension and Ligation (WG-DASL) bead arrays, followed by pathway, gene module score, and gene ontology analyses, respectively. A second FFPE cohort of 10 primary OCCCs was analyzed by targeted DNA sequencing of a panel of 60 cancer-related genes (cohort 2). Non-synonymous and non-sense variants affecting single-nucleotide variations and insertions or deletions were further analyzed. A tissue microarray of 43 OCCCs (cohort 3) was used for validation by immunohistochemistry and chromogenic in situ hybridization. Results: Gene expression analyses revealed a distinct OCCC profile compared to other histological subtypes, with, e.g., ERBB2, TFAP2A, and genes related to cytoskeletal actin regulation being overexpressed in OCCC. ERBB2 was, however, not overexpressed on the protein level and ERBB2 amplification was rare in the validation cohort. Targeted deep sequencing revealed non-synonymous variants or insertions/deletions in 11/60 cancer-related genes. Genes involved in chromatin remodeling, including ARID1A, SPOP, and KMT2D were frequently mutated across OCCC tumors. Conclusion: OCCCs appear genetically heterogeneous, but harbor frequent alterations in chromatin remodeling genes. Overexpression of TFAP2A and ERBB2 was observed on the mRNA level in relation to other ovarian cancer subtypes. However, overexpression of ERBB2 was not reflected by HER2 amplification or protein overexpression in the OCCC validation cohort. In addition, Rho GTPase-dependent actin organization may also play a role in OCCC pathogenesis and warrants further investigation. The distinct biological features of OCCC discovered here may provide a basis for novel targeted treatment strategies.

Subject headings and genre

MEDICIN OCH HÄLSOVETENSKAP Klinisk medicin Cancer och onkologi hsv//swe
MEDICAL AND HEALTH SCIENCES Clinical Medicine Cancer and Oncology hsv//eng
Chromatin modification
Clear cell ovarian cancer
Deep sequencing
ERBB2
Gene expression profiling
Inter-tumor heterogeneity
Rho GTPase

Added entries (persons, corporate bodies, meetings, titles ...)

Jönsson, Jenny MariaLund University,Lunds universitet,Bröstcancer-genetik,Sektion I,Institutionen för kliniska vetenskaper, Lund,Medicinska fakulteten,Bröst- och ovarialcancer,Forskargrupper vid Lunds universitet,Breastcancer-genetics,Section I,Department of Clinical Sciences, Lund,Faculty of Medicine,Breast and Ovarian Cancer Genomics,Lund University Research Groups,Skåne University Hospital(Swepub:lu)med-j-j (author)
Bartuma, KatarinaLund University,Lunds universitet,Bröstcancer-genetik,Sektion I,Institutionen för kliniska vetenskaper, Lund,Medicinska fakulteten,Breastcancer-genetics,Section I,Department of Clinical Sciences, Lund,Faculty of Medicine,St Erik Eye Hospital,Skåne University Hospital(Swepub:lu)med-krd (author)
Ebbesson, AnnaLund University,Lunds universitet,Create Health,Annan verksamhet, LTH,Lunds Tekniska Högskola,Bröstcancer-genetik,Sektion I,Institutionen för kliniska vetenskaper, Lund,Medicinska fakulteten,Bröst- och ovarialcancer,Forskargrupper vid Lunds universitet,Other operations, LTH,Faculty of Engineering, LTH,Breastcancer-genetics,Section I,Department of Clinical Sciences, Lund,Faculty of Medicine,Breast and Ovarian Cancer Genomics,Lund University Research Groups(Swepub:lu)med-aee (author)
Westbom-Fremer, SofiaSkåne University Hospital (author)
Måsbäck, AnnaLund University,Lunds universitet,Tumörmikromiljö,Sektion I,Institutionen för kliniska vetenskaper, Lund,Medicinska fakulteten,Tumor microenvironment,Section I,Department of Clinical Sciences, Lund,Faculty of Medicine,Skåne University Hospital(Swepub:lu)an4214ma (author)
Malander, SusanneLund University,Lunds universitet,Tumörmikromiljö,Sektion I,Institutionen för kliniska vetenskaper, Lund,Medicinska fakulteten,Tumor microenvironment,Section I,Department of Clinical Sciences, Lund,Faculty of Medicine,Skåne University Hospital(Swepub:lu)onk-sma (author)
Nilbert, MefLund University,Lunds universitet,Bröstcancer-genetik,Sektion I,Institutionen för kliniska vetenskaper, Lund,Medicinska fakulteten,Breastcancer-genetics,Section I,Department of Clinical Sciences, Lund,Faculty of Medicine,Hvidovre Hospital(Swepub:lu)onk-mni (author)
Hedenfalk, Ingrid A.Lund University,Lunds universitet,Create Health,Annan verksamhet, LTH,Lunds Tekniska Högskola,Bröstcancer-genetik,Sektion I,Institutionen för kliniska vetenskaper, Lund,Medicinska fakulteten,Bröst- och ovarialcancer,Forskargrupper vid Lunds universitet,Other operations, LTH,Faculty of Engineering, LTH,Breastcancer-genetics,Section I,Department of Clinical Sciences, Lund,Faculty of Medicine,Breast and Ovarian Cancer Genomics,Lund University Research Groups(Swepub:lu)onk-ifa (author)
Bröstcancer-genetikSektion I (creator_code:org_t)

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