uu.seUppsala University Publications
Change search
CiteExportLink to record
Permanent link

Direct link
Cite
Citation style
  • apa
  • ieee
  • modern-language-association
  • vancouver
  • Other style
More styles
Language
  • de-DE
  • en-GB
  • en-US
  • fi-FI
  • nn-NO
  • nn-NB
  • sv-SE
  • Other locale
More languages
Output format
  • html
  • text
  • asciidoc
  • rtf
Intratumoural Heterogeneity of TERT Promoter Mutations in Adrenocortical Carcinoma
Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences. Uppsala University. (Experimental Surgery Group)
Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences.
Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences.
Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences. (Experimental Surgery Group)
Show others and affiliations
(English)Manuscript (preprint) (Other (popular science, discussion, etc.))
Keyword [en]
TERT, Adrenocortical Carcinoma, Mutation, Heterogeneity.
National Category
Cell and Molecular Biology Cancer and Oncology
Research subject
Molecular Genetics; Endocrinology and Diabetology
Identifiers
URN: urn:nbn:se:uu:diva-325979OAI: oai:DiVA.org:uu-325979DiVA: diva2:1119026
Funder
Swedish Cancer Society
Available from: 2017-07-03 Created: 2017-07-03 Last updated: 2017-07-05
In thesis
1. New Insights in Adrenal Tumourigenesis.
Open this publication in new window or tab >>New Insights in Adrenal Tumourigenesis.
2017 (English)Doctoral thesis, comprehensive summary (Other academic)
Abstract [en]

Unilateral cortisol producing adenoma (CPA) is the most common cause of ACTH-independent Cushing’s syndrome and is surgically curable. On the other hand, adrenocortical carcinomas (ACCs) are rare and aggressive tumours. Although the overall survival of the patients with ACC is very poor, the outcome can be heterogeneous and vary significantly between the patients. This thesis comprises studies showing genetic and genomic events occurring in CPAs and ACCs, their functional impact and clinical correlations.

The Wnt/β-catenin and cAMP/PKA signalling pathways are crucial in adrenal homeostasis and frequent mutations in members of these pathways (CTNNB1, GNAS, and PRKACA) are found in CPAs. Mutational analysis revealed that ~60% of the CPAs harboured mutations in either of these genes. Transcriptome signature exhibited increased expression of genes involved in steroidogenesis in PRKACA/GNAS mutated (Cluster1) tumours in comparison to CTNNB1 mutated /wildtype (Cluster2) tumours. In addition we have also observed that gain of chromosome arm 9q was the most frequent arm level copy number variation (CNV) occurring in CPAs and were exclusively present in Cluster2 tumours. We also discovered novel PRKACA mutations occurring in ACCs, causing activation of cAMP/signalling pathway.   

Comprehensive analysis of Wnt/β-catenin signalling pathway in ACCs revealed novel interstitial deletions occurring in CTNNB1 leading to deletion of the N-terminus of β-catenin. This is a novel and yet another frequent event leading to activated Wnt/β-catenin signalling and downstream targets in ACCs. Both, mutations occurring in CTNNB1 and nuclear expression of its protein were associated with poor overall survival. Through multiregional sampling approach we discovered intra-tumour heterogeneity in ACC tumours. Although all the multiregions within a tumour showed presence of shared basal CNVs, they encompassed private CNVs, different ploidy levels and private mutations in known driver genes. We found intra-tumour heterogeneity in CTNNB1, PRKACA, TERT promoter and TP53 mutations as well as ZNRF3 and CDKN2A/2B homozygous deletions.

Place, publisher, year, edition, pages
Uppsala: Acta Universitatis Upsaliensis, 2017. 54 p.
Series
Digital Comprehensive Summaries of Uppsala Dissertations from the Faculty of Medicine, ISSN 1651-6206 ; 1345
Keyword
cortisol producing adenomas, adrenocortical carcinomas, mutation, heterogeneity, PRKACA, TERT, CTNNB1
National Category
Cell and Molecular Biology Cancer and Oncology Endocrinology and Diabetes
Research subject
Molecular Genetics
Identifiers
urn:nbn:se:uu:diva-326149 (URN)978-91-513-0009-2 (ISBN)
Public defence
2017-09-16, Fåhraeussalen, Rudbecklaboratoriet Hus 5, Dag Hammarskjölds väg 20, Uppsala, 13:15 (English)
Opponent
Supervisors
Funder
Swedish Cancer Society
Available from: 2017-08-22 Created: 2017-07-05 Last updated: 2017-09-08

Open Access in DiVA

No full text

By organisation
Department of Surgical Sciences
Cell and Molecular BiologyCancer and Oncology

Search outside of DiVA

GoogleGoogle Scholar

urn-nbn

Altmetric score

urn-nbn
Total: 123 hits
CiteExportLink to record
Permanent link

Direct link
Cite
Citation style
  • apa
  • ieee
  • modern-language-association
  • vancouver
  • Other style
More styles
Language
  • de-DE
  • en-GB
  • en-US
  • fi-FI
  • nn-NO
  • nn-NB
  • sv-SE
  • Other locale
More languages
Output format
  • html
  • text
  • asciidoc
  • rtf