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Molecular markers of pituitary tumor development, progression and therapy response



Project Title: „Molecular markers of pituitary tumor development, progression and therapy response” 

Funding:  European Regional Development Fund (ERDF), Measure “Industry-Driven Research”

Project Nr.:

Period: 1st January 2017 – 31 st December 2019

Project costs: 648 600,28 EUR

Principle Investigator: Dr. biol., Assoc. Prof. J. Kloviņš 


 Pituitary adenomas are rare benign tumors that are responsible for serious health complications with increased morbidity and mortality. Despite the extensive studies the primary genetic defects determining the tumorigenesis of pituitary adenomas is still unclear and very heterogeneous. Another problem is the inaccessibility of the pituitary gland that hampers the use of molecular biomarkers for observation or differential treatment purpose. Accordingly, to successfully treat pituitary adenomas more rigorous diagnostic approaches are needed that would allow for detailed tumor subtype classification to enable personalized treatments. The project is aimed to help in solving these issues. The main objective of this project is to investigate molecular determinants of pituitary adenoma development and progression and to identify the crucial factors linked to variability in clinical outcome that could further be applied as biomarkers for improvement of pituitary tumor treatment therapies. Specifically we aim (1) to identify disease specific somatic genetic variations in different types of pituitary adenoma and use this information to characterize the separate cell populations in adenoma resections as well as markers for non-invasive monitoring of adenomas, (2) to identify vesicle associated based RNA markers that differentiate between healthy subjects and pituitary adenoma patients, as well as different clinical outcomes and treatment efficiency, (3) to estimate the best combination of variable biomarkers that can predict PA growth dynamics and recurrence probability. Presented project will perform original and innovative experiments including the genetic characterization of the tumor specific cell populations, estimation of tumor specific cell free DNA and identification of vesicle associated RNA as liquid biopsy based biomarkers that has not been done in case of pituitary adenoma studies.

Information published: 02.01.2017.

Progress of the project

1 January 2017 - 31 March 2017

During this period intensive preparation for project implementation has been carried out, criteria have been selected for patient identification from Genome Database of Latvian Population collection, the characterization have been started of the patients to be included in the research. These actions have facilitated collection establishment of samples and associated data for project implementation.  Additionally, the collection of supplementary clinical data has begun, as well as recruitment of new patients. The experimental approaches have been developed for massive parallel sequencing and cell free DNA studies, the experimental protocols and methodology have been developed. Also procedures for cell sorting have been created.

Information published: 31.03.2017.

Progress of the project

1 April 2017 - 31 June 2017

Project specific database of pituitary adenoma patients has been developed based on Genome Database of Latvian population, including clinical information about the patients, this database will be updated during the course of the project. Four exoms of pituitary adenoma have been sequenced and primary analysis undertaken to compare presence of somatic mutations in primary and regrown tumors. Following the developed protocol cells from two pituitary adenoma biopsies have been sorted and isolation of tumor specific RNA have started. Isolation method for cell free DNA from patients’ plasma have been optimized and cell free DNA isolated from five patients’ plasma. The protocol development for exosome and miRNA isolation from plasma has been started.

Information published: 30.06.2017.


Progress of the project

1 July 2017 - 30 September 2017

The designed project specific database cross-checked and arranged according to project’s needs, additional clinical data and new pituitary adenoma samples have been collected. DNA exome sequencing have been continued, including library preparation, quality control and sequencing. Results have been anaysed comparing patients genomic, primary and recurrent tumor somatic DNA. Genomic rearrangements have been studied and discrimination in different types of mutations (insertions, deletions, translocations etc.). Cell sorting experiments have been further conducted, as well as RNA extraction from pituitary adenoma tumor cell types.  Cell free circulating DNA isolation have been performed for six samples and first exosome and miRNA isolation experiments executed.

Information published: 29.09.2017.


Progress of the project

1 October 2017 - 31 December 2017

In this implementation period of the project additional clinical data and new pituitary adenoma samples have been collected, therefore, supplementing the established collection. Additionally, processing of five new adenoma tumor tissue samples have been carried out, in the sorted populations presence of GNAS genetic markers have been analysed, RNA has been extracted and quality control performed. With the combination of castPCR and other molecular methods GNAS mutation detection have been optimized in pituitary adenoma patients’ plasma samples as well. Work on miRNA analysis optimization is ongoing.

Information published: 02.01.2018.


Progress of the project

1 January 2018 - 31 March 2018

 During this implementation period additional biological samples and clinical data have been collected, this have been included in projectspecific database. Large scale GNAS mutation detection have been undertaken in patients’ plasma, the correlation analysis has been started. The work has been continued with next generation sequencing data analysis and validation. The first plasma free miRNA analysis and RNA profiling have been undertaken. The cell sorting experiments have been continued with detection of GNAS mutation presence in different adenoma cell population.

Information published: 29.03.2018.


Progress of the project

1 April 2018 – 30 June 2018

In this project implementation period enrolment of additional patients have been carried out and clinical information gathered for further project implementation. Tumor somatic DNA sequencing and validation studies continued. Data analysis for information in literature carried out to investigate the role of genetic variation on potential pituitary adenoma pathogenesis. The cell line culturing and sorting have been continued. In parallel with GNAS mutation identification experiments in patients’ plasma cell free DNA this have been carried out also in control group. The experimental work on RNA profiling have been continued.

Information published: 29.06.2018.


Progress of the project:

1 July 2018 – 30 September 2018

In this project implementation period enrolment of additional patients have been carried out and clinical information gathered for further project implementation. The detailed exome sequencing data analysis have been performed and design have been developed for the investigation of functional role of the discovered mutations. The comparative analysis of primary and recurrent tumour sequencing data has been completed and publication preparation have been started. Genetic and molecular markers have been identified in spheres derived from pituitary adenoma operation material and characterization of sphere profiles performed. The plasma derived cell free DNA have been analysed in relation to pituitary adenoma clinical parameters. The experimental work on RNA profiling have been continued.

Information published: 28.09.2018.


Progress of the project:

1 October 2018 – 31 December 2018

In this project implementation period enrolment of additional patients have been carried out and clinical information gathered for further project implementation. The cell cultures from newly obtained tumour tissue samples were harvested and sphere and mesenhymal cells were sorted according to expression of specific markers. Sequencing and profiling experiments with sorted cell types were carried out. The analysis of cell free DNA profiles in correlation with disease related clinical factors has been started. Experiments of miRNA analysis and total mRNA profiling has been continued. 

Information published 28.12.2018.

Mājas lapas izstrādi finansēja ERAF aktivitātes projekts Nr. 2010/0196/2DP/ "Latvijas biomedicīnas pētījumu integrācija Eiropas zinātnes telpā".