MERMAID NEWSLETTER – Christmas 2018

 

Dear donors and friends of MERMAID

At the MERMAID Project we would like to wish you a Merry Christmas and provide you with an update of what has happened in the project in 2018.

Grace to generous donations – also through 2018 – the research in “MERMAID III – The challenge of ovarian cancer: Screening, early diagnosis and the identification of women at high risk” is progressing according to schedule.

The research in MERMAID III is divided into three sub-projects. The goal of the research is to identify one or more methods of diagnosing ovarian cancer at an early stage.

Only around 40% of women diagnosed survive. However, 90% of women diagnosed at an early stage survive, whereas a mere 5-10% survives when diagnosed at late stage. Hypothetically, via identifying all women at the earliest stage, the survival rate could increase to 90%.

The research is carried out by three professors: Susanne Krüger Kjær, Claus Høgdall and Jan Blaakær, all very dedicated and with great competence within gynecological research.

In MERMAID we are proud to announce that Susanne Krüger Kjær recently has been named as one of the worlds most cited researchers.

In the following the professors of the projects describe the development in the research during 2018.

 

Early detection and long-term survival

Head of research: Professor Susanne Krüger Kjær, The Dansih Cancer Society (Kræftens Bekæmpelse)/Copenhagen University Hospital, DK.

In this part of the Mermaid III project we are collecting cervical cell samples from women participating in routine cervical cancer screening in Denmark (the region of Southern Denmark) to obtain biological material as a source of DNA/RNA. These samples – from women who subsequently develop ovarian cancer – will be tested for different biomarkers that potentially makes it possible to diagnose the cancer in an early stage. The testing of the samples will be done in collaboration with researchers at Johns Hopkins University, USA.

We have established a collaboration with the Department of Clinical Pathology at Vejle hospital, and have started the collection of samples. The procedure of the biobanking has now finally fallen into place and the procurement of the Tecan robot, financed by a specific donation – DKK 1.217.290 million –  from The John and Birthe Meyer Foundation, and the Labware software has been finalized in January 2018. The arrival of robot and the training of the staff took place in the early spring of 2018. At the end of 2018, we have collected around 75,000 samples.
The establishment of this method of collecting and storing biological material has been presented at an international conference in Sydney in October 2018.

Another aim of this part of Mermaid III is to assess long-term survival (>10 years) of women diagnosed with ovarian in Denmark, and to identify characteristics associated with being a long-term survivor of ovarian including clinical factors lifestyle factors, histopathologic factors, and socioeconomic factors.

In Denmark, we have exceptionally good conditions for doing long-term follow-up studies due to the existence of the unique personal identification numbers and the high-quality, nationwide registers.

From the Danish Cancer Registry, we have identified all women diagnosed with ovarian cancer in Denmark 1978 and onwards. Using the personal identification number as key identifier we have performed an accurate linkage of information between the different public registries and the women in our cohort. In addition, registration of the personal identification number enables us to follow the women with virtually no loss to follow-up. By linkage with the Danish Civil Registration System, we have identified the date of death on all women with ovarian cancer who died during follow-up. We will also link with Danish Causes of Death Registry to obtained information on causes of death for those women diagnosed with ovarian cancer who died during follow-up.

To obtain information on different characteristics potentially related to survival of women diagnosed with ovarian cancer, we will link our study cohort with a variety of nationwide registries such as the Medical Birth Registry, the In Vitro Fertilization Registry, the Prescription Database, the Danish National Patient Registry, and the Danish Pathology Data Bank. We will retrieve the tumor tissue slides and the blocks from the relevant pathology department in the respective hospitals. All tumor tissue slides and blocks will be sent to the laboratory at the Johns Hopkins University Hospital, where expert gynecologic pathologists will review the tumor tissue slides and select relevant tumor blocks the purpose of molecular analysis of different tumor markers to identify potential markers of long-term survival. This comprehensive project is running as planned.

The project Biomarkers and / or prognostic markers

Head of research:  Professor Claus Høgdall, Copenhagen University Hospital, Rigshospitalet,DK

For this part of the MERMAID research, blood and tissue from women with ovarian cancer are collected in order to identify biochemical and molecular biologic markers that characterize the disease.

A biomarker or a combination of biomarkers may detect cancer in the early stage so that the patient can be cured, or even better, designate patients at high risk of developing ovarian cancer and thus prevent the development of the cancer by prophylactic treatments. Biomarkers can also contribute to predicting treatment effects, and thus provide the basis for patients to be offered a personally more effective treatment such as biological treatment.

The project is divided into 3 sub-studies including a large number of planned analyzes. All studies follow the schedule. The first sub-study deals with MicroRNA, which are small molecules that play a very important role in regulating the genes in the cell. One microRNA may regulate more than one gene. This work has resulted in 4 scientific articles published (2016 one article, 2017 two articles, 2018 one article) and furthermore 1 article is submitted. In addition, the results were presented as oral presentations and posters, respectively.

Analysis of all messenger RNA (mRNA), which is a type of RNA translated into proteins, was completed in 2018 and the first scientific article is under preparation. Several will follow. MicroRNA and parts of the mRNA studies will form the basis of a Ph.D. dissertation by doctor Kira Phram, who has been Ph.D. MERMAID student for the last 3 years.

The PhD thesis is scheduled for February 2019. More microRNA studies in blood are now being planned by molecular biologist post doc. Douglas Oliveira employed 2018 (November). The analyzes are already expected to result in submission of the first article by the end of the year.

Sub-study 2 deals with DNA methylation also called epigenetic, that is important for the regulation of the genes. The project is planned with the aims to find DNA methylation markers both for the prediction of chemo resistance as well as for diagnostics and screening. As planned, according to schedule, molecular biologist postdoc Julie Lilith Hentze has been employed.

Julie has already published the first MERMAID article, has one article expected to be published late this year and is completing a new article for submission within the next couple of months. Julie is also finishing DNA preparation for the further planned methylation analyzes. The methylation study comprises three work packages all ensuring optimal use of both biological material and data. The study program thus proceeds positively according to the plan.

For the third sub-study Next-Generation Sequencing (NGS), Michael Kronborg was employed April 2018.  He is a post doc in molecular biology with special expertise in NGS. The overall goal is to find changes (mutations) in DNA that explain the etiology and / or prognosis, and which may establish the basis for new biomarkers with future possible treatment consequences. The patient group for these studies, based on histology, stage of disease, age and survival, has been selected and DNA extraction are planned in December 2018. Exome sequencing will be performed on this DNA.

The statistical analyzes will be initiated in 2019.  In connection with the planning, Michael has reviewed the literature of all known genetic variants (mutations), resulting in a review article that is now submitted to publication. This sub-study also follows the plan.

The Mermaid III research study  ”The Infection Theory”

Head of research:  Professor Jan Blaakær, University of Southern Denmark (SDU) and the University Hospital, Odense, DK

In this study, which is currently being reviewed for publication in Infectious Agents and Cancer, we examined the possible role of Cytomegalo-virus (CMV) and Epstein-Barr Virus (EBV) in ovarian carcinogenesis. We didn’t demonstrate a correlation to CMV but we found EBV in 5% of the ovarian cancer cases. We compared this observation to a healthy control group and found a significant difference, indicating that EBV might influence the development of some ovarian cancer cases. This is a very interesting observation as this is the first study to demonstrate EBV in ovarian cancer tissue samples. Moreover, EBV infects epithelial cells and is an established etiological factor in the development of nasopharyngeal and gastric carcinomas. It is also implicated in a range of B- and T- celllymphoproliferative disorders including Burkitt’s lymphoma and angioimmunoblastic T-cell lymphoma.

Ovarian cancer is made up of different histological subtypes and EBV might be an etiological factor in one or more of these subtypes

The next step in our research project in the infection theory project is applying next generation sequencing (NGS) technique to ovarian cancer. The time and the technological development have made NGS affordable. This technique demonstrates the base sequences of DNA and by using this technique, we can demonstrate genetic material, or traces of microbes in ovarian cancer tissue. The NGS study is currently carried out at Herlev Hospital. After sequencing the first 44 patients we have generated an enormous quantity of data, which is being interpreted at the moment consulting large databases with known bacterial DNA sequences.

Professor Robert Kurman, John Hopkins Hospital, Baltimore published a possible change in the Fallopian tubes named as ‘carcinoma in situ’ (STIC) and corresponding to the changes preceding cervical cancer (Kurman  & Shih ’The Origin and Pathogenesis of Epithelial Ovarian Cancer: A Proposed Unifying Theory’, Am J Surg Pathol 2010;34:433–443).

In the light of these observations we have decided to examine Danish women with STIC lesions applying our results from the infection theory so far. We have identified the ‘STIC-women’ in the national patient registry and permissions from relevant authorities have been obtained. We await the results from the NGS study before initiating the STIC study in order to qualify our search for microbiological DNA.

The research

The research, which is expected to span over the next five years, is coordinated by professor Bent Ottesen, Project director Rigshospitalet, Copenhagen University Hospital.

During the year a number of research articles has been published by all sub-projects. Please refer to Birgitte Blix Treschow, project coordinator, for access to the publications.

Donations and duration

MERMAID III is the MERMAID Project’s largest research project to date with a budget of DKK40 million of which DKK 34.9 has been received in funds and commitments.

MERMAID is focused on a minimal of administrative expenses and for 2018 it amounts to approx. 1 %.

The research expenses in 2018 amounts to approx. DKK 4.3 million which means that DKK 15.1 million has been spent of the budget.

In MERMAID we wish you and your families a Merry Christmas and a Happy New Year

We thank you for all support and interest and look forward to keeping you informed of the progresses of the research.

Kind Regards,

On behalf of the MERMAID Project

Birgitte Blix Treschow,

Project Coordinator, MERMAID

www.mermaidprojektet.dk