Welcome to our first issue of the CIRCULAR VISION newsletter

Despite many years of research, we still have problems diagnosing many cancers and Inflammatory Bowel Disease (IBD) at an early stage.

Birgitte Regenberg - University of Copenhagen

Many human diseases have a genetic component. Over the past years, it has become clear that DNA can be deleted from the chromosomes, and becomes circular. Circular DNA can be an important player in tumour progression in all types of cancers, but circular DNA is also released into the blood from where it can be sampled and recorded. Therefore, this makes circular DNA in blood plasma a potential biomarker for both cancers and IBD.

In CIRCULAR VISION, we aim to develop and combine novel methods in molecular biology, microfluidics, DNA sequencing and bioinformatics in order to develop circular DNA as diagnostic markers. Such markers for IBD and lung cancer will then be adapted to clinical diagnosis and prognosis using advanced image analysis and cytometry methods.

Our work is important because these diseases affect so many early in their life’s, their families and everyone near the patient, for example, Lars who lost his mother to pancreatic cancer ten years ago. He tells in our newsletter his story about how hard the disease is and how he experienced a combination of shock, sadness, and powerlessness.

On top of that, cancer and IBD diseases also have a financial and economic impact and it places a massive burden on our health systems.

CIRCULAR VISION is a highly innovative EU Horizon 2020 funded project (FET-Open) that aims to explore the new opportunities circular DNA creates in early diagnosis, screening and monitoring of disease. While many human diseases such as cancers and inflammatory disorders are associated with the production of 'circular DNA' from chromosomes, the technology for detecting circular DNA and for creating disease models is lacking.

To achieve these objectives, Circular Vision gathers key pioneers in the emerging field of circular DNA with leading clinical experts, bioinformaticians, and key commercial players in cytometry and genomics.

The biggest goal in CIRCULAR DNA is to develop technologies for detection of cancer and IBD in blood and plasma. Our hope is to develop a method that can help a patient with IBD to diagnose his/her disease using noninvasive methods, such as simple blood tests, which provide quick diagnostic and less use of immunosuppressant drugs.

During the past year, we have collected hundreds of tumour and blood plasma samples of lung and pancreatic cancer, the most deadly cancer in Denmark and Europe, from the Danish biobanks at Odense Hospital, Herlev and Gentofte hospital. We have also collected tissues samples from IBD patients at the Gemelli Hospital in Rome. Now we are in the stage of analysing the data for circular DNA with our partner BHRI (Biodonostia Health Research Institute) in Spain. By using our unique techniques and methods for data analysis, we look for patterns of circular DNA in plasma that indicate cancer or IBD – and thereby patterns that can eventually be used in routine tests in the clinic. .

An essential part of our work is to disseminate it to other scientists through scientific analysis circular DNA with long-read sequencing long pieces of DNA published at Molecular Cell and in several scientific papers.

We have consortium meetings every six months for scientific discussion and the progression of our research. The first consortium meeting was held via Zoom due to COVID travel restrictions and the second consortium meeting was held in Rome last September. Our next meeting is in Zurich in April and I am looking forward to continuing the fruitful discussion with all our partners.

Stay Tuned!

Lars shares his story after his mother Kirsten was diagnosed with pancreatic cancer

It all happened very quickly back in the summer of 2008 when my mother started to have some symptoms such as indigestion issues and a bit of pain in her stomach that would not go away. She was a nurse herself and found that the symptoms were hard to assess. Around Christmas the same year she experienced yellowing of the eyes and skin.

She phoned her general practitioner for an appointment and she was quickly referred to the Aalborg hospital for some blood tests. Quickly after the doctor received the results of the blood test she was referred to a scanning session at the hospital. My father and I were present in the meeting with the doctor to get the results of the scans. The doctor confirmed what we all feared namely that it was pancreatic cancer and that unfortunately, it was diagnosed in the late stages of the disease. My mother was diagnosed with pancreatic cancer stage 3 and the doctor explained to the family that there were no treatment options.

I still remember the words of the doctor saying that the cancer has spread and that there were no possible treatment options plus in addition to this that the chance of survival after 12 months was very low. Needless to say, this was shocking news. I would have liked a different communication with the doctor. He was basically giving my mother a death sentence. I remember experiencing a combination of shock, sadness, worriedness, and powerlessness.

 Soon after that, we began to look into alternatives to conventional treatment to give some hope of survival for my mother’s deadly disease. In addition, as the tests showed that the cancer was too widespread to be removed completely, a palliative surgery was done to relieve symptoms and to prevent complications like a blocked bile duct or intestine, at the Herlev Hospital in Copenhagen.

Before my mother’s diagnosis, I had limited knowledge about the important function of the pancreas and it surprised me that even though pancreatic cancer is the most lethal, deadliest cancer there was no efficient way to detect this cancer early so it can be removed surgically before it spread.

Abby, my mother’s nickname given to her by her grandchildren, died from pancreatic cancer at the hospice in Aalborg in February 2009 at age 68.

Pancreatic cancer is the most horrendous illness that I have ever witnessed. To see your strong and healthy loved one struggle and suffer through this disease is heartbreaking. It surprises me that after more than 10 years there are not significantly better ways to early detect this cancer. I have the biggest respect for researchers that work in this area to seek out signs of pancreatic tumours in the blood that may help to detect this disease before it has spread.

Kirsten was the mother in law of Sonia Diaz who is the project manager for the CIRCULAR VISION project. From CIRCULAR VISION we want to give voice to patients and families in Europe and other parts of the world who would like to share their stories to give more awareness of diseases such as cancer and IBD. If you are a patient or a family who is living with a patient with cancer or IBD and would like to participate in this sections stories please contact us. 

About Pancreatic cancer 

Pancreatic cancer is often difficult to diagnose. This is because there are no validated, specific screening tests that can easily find early-stage pancreatic cancer in people who do not show symptoms. Furthermore, people with pancreatic cancer often do not have identified symptoms in the early stages of the disease. 

Pancreatic and lung cancer are among the most common causes of cancer deaths in Denmark and worldwide due to late diagnosis and lack of methods for specific treatment and tests for relapse of the disease.

The development of biomarkers for early detection, diagnosis and relapse as pursued in CIRCULAR VISION will dramatically change the health outcome of patients with pancreas and lung cancer since more patients will operate and have a possibility for a long time survival.

To achieve these objectives, CIRCULAR VISION gathers key pioneers in the emerging field of circular DNA with leading clinical experts, bioinformaticians and key commercial players in cytometry and genomics.

Read more about the project of the CIRCULAR VISION research in Birgitte Regenberg’s article. 

Statistics in Europe
Source: ECIS - European Cancer Information System
Glossary: Crude rate – ASR (Age-Standardized Rate) and Cumulative risk

Source: ECIS - European Cancer Information System
From https://ecis.jrc.ec.europa.eu, accessed on 06/10/2021
© European Union, 2021

THE INTERNATIONAL CIRCULAR DNA RESEARCH CONSORTIUM (ICDC)

The interest in extrachromosomal circular DNA (eccDNA) has increased exponentially in the scientific community across the globe.

Yonglun Luo - Aarhus University
Birgitte Regenberg - University of Copenhagen

Circular DNA arises from chromosomes and exists in a circular structure in the nucleus, and over the past few years it has been recognized as a form of DNA commonly existing in different cells, tissues and organ in eukaryotic organisms from yeast to human.

Large circular DNA in tumors (also known as ecDNA) are associated with oncogene amplification, development of drug resistance and dysregulation of gene expression. This makes circular DNA an attractive target for therapy and a potential biomarker for cancer diagnosis and surveillance of cancer.

The characteristics of ecDNA in tumors resemble the function of eccDNA in organisms like baker’s yeast and plants where gene amplifications on eccDNA can drive the evolution of new lineages.

Despite their importance, we still know little about how circular DNAs affect seemingly healthy cells, how they form and how they are maintained in living cells. The high heterogeneity and dynamics of circular DNA, in terms of size, level and compositions (sequence and epigenetic modifications) further challenge the analysis of circular DNA.

To boost the healthy and sustainable development of the eccDNA community, we call for the formation of an international circular DNA research consortium (ICDC). The ICDC will help establish international guidelines for circular DNA investigations and organize biennial conferences for the circular DNA community.

Newsletter editors:
Birgitte Regenberg
Sonia Diaz Houbak