Tampere University Hospital

A new study revealed how aberrant epigenetic regulation contributes to the development of atypical teratoid/rhabdoid (AT/RT) tumors, which are aggressive brain tumors that mainly affect young children. There is an urgent need for more research in this area as current treatment options are ineffective against these highly malignant tumors. A new study conducted by researchers at Tampere University and Tampere University Hospital revealed how aberrant epigenetic regulation contributes to the development of atypical teratoid/rhabdoid (AT/RT) tumours, which are aggressive brain tumours that mainly affect young children. There is an urgent need for more research in this area as current treatment options are ineffective against these highly malignant tumours. Most tumours take a long time to develop as harmful mutations gradually accumulate in cells' DNA over time. AT/RT tumours are a rare exception, because the inactivation of one gene gives rise to this highly aggressive form of brain cancer. AT/RT tumours are rare central nervous system embryonic tumours that predominantly affect infants and young children. On average, 73 people are diagnosed with AT/RT in the USA each year. However, AT/RT is the most common central nervous system tumour in children under one years old and accounts for 40-50% of diagnoses in this age group. The prognosis for AT/RT patients is grim, with a postoperative median survival of only 11-24 months. The collaborative study conducted by Tampere University and Tampere University Hospital examined how aberrant DNA methylation distorts cellular developmental trajectories and thereby contributes to the formation of AT/RT. DNA methylation is a process whereby methyl groups are added to the DNA strand. DNA methylation is one of the mechanisms that cells use to control gene expression, and methylation patterns change during normal brain development. The new study showed that DNA methylation interferes with the activity of multiple regulators, which under normal circumstances regulate the differentiation and maturation of central nervous system cells during brain development. Disrupted cell differentiation promotes the abnormal, uncontrolled proliferation of cells that eventually form a tumour. The study also found several genes that regulate cell differentiation or inhibit tumour development and are silenced in AT/RT together with increased DNA methylation. The findings will pave the way for a more detailed understanding of the epigenetic dysregulation mechanisms in AT/RT pathogenesis and enable researchers to identify which genes contribute to the malignant progression of the tumour. "These results will provide deeper insights into the development of AT/RTs and their malignancy. In the future, the results will help to accelerate the discovery of new treatments for this aggressive brain tumour," says Docent Kirsi Rautajoki from Tampere University. At Tampere University, the research was mainly carried out by the research groups led by Kirsi Rautajoki and Professor Matti Nykter. The key partners from Tampere University Hospital included paediatrician, LM Kristiina Nordfors, neurosurgeon and Docent Joonas Haapasalo and neuropathologist and Docent Hannu Haapasalo.

A large randomized trial shows that a new three-step prostate cancer screening method can find a considerable number of aggressive cancers. Population-level screening programs have not been launched in most countries. A large randomized trial conducted at Tampere University and the University of Helsinki shows that a new three-step prostate cancer screening method can find a considerable number of aggressive cancers. Population-level screening programmes have not been launched in most countries including Finland. The ProScreen trial coordinated by Tampere University and the University of Helsinki investigated the performance of a three-step prostate cancer screening method. The aim was to analyse whether the new method would efficiently reduce mortality while decreasing the major adverse effect of previous screening methods: the overdiagnosing of insignificant prostate cancers. Some prostate cancers are clinically insignificant because they do not become symptomatic even when left untreated. Such cancers are frequently detected at autopsy. Thus, treating cancer with a good prognosis does not bring benefits, but the treatment itself can still harm the patients' quality of life. The screening method used in the ProScreen study includes two blood tests and, if necessary, magnetic resonance imaging (MRI) of the prostate. The previously studied screening method has only been based on one blood test, the prostate-specific antigen test (PSA). In the ProScreen study, both blood tests were positive in 7% of the participants and they were invited to an MRI of the prostate. In about half of these men, a suspicious area was detected by MRI and a prostate biopsy was taken. Cancer was eventually found in about 2% of the participants. Clinically insignificant cancers were diagnosed in four in a thousand men. "We have previously demonstrated that PSA screening can decrease prostate cancer mortality to some extent. However, PSA screening produces so many unnecessary cancer diagnoses that the harms outweigh the benefits. The new results show that the three-step method now used produces fewer insignificant cancer diagnoses than PSA screening," says Professor of Epidemiology Anssi Auvinen from Tampere University. Diagnosing cancer with a good prognosis is not beneficial Some prostate cancers are clinically insignificant, i.e. they will not progress to the symptomatic stage or cause any harm. The co-lead investigator of the project, Professor of Urology Antti Rannikko from the University of Helsinki, points out that the detection of such latent cancers does not bring any benefits and that they should not even be diagnosed. "The vast majority of tumours found with the previous PSA screenings are low-risk cases that are likely to represent overdiagnosis. Most of them do not progress to the symptomatic stage even when left untreated. If a prostate cancer with a good prognosis is diagnosed, the primary treatment is always active surveillance," Rannikko says. Local prostate cancer is usually treated surgically or with radiation therapy. The common side effects of treatment include erectile dysfunction, urinary incontinence, and bowel symptoms. The main goal of screening is to reduce cancer mortality The study included more than 60,000 men aged 50 -- 63 years who were randomly allocated for either the three-step screening or a control group without intervention. The study continues and the study population will expand to also include the neighbouring municipalities of Tampere and Helsinki. Men who have already participated will be invited to a new screening after 2 -- 6 years based on the outcomes of their first screening. No population-level screening programme has been launched in Finland or in most other European countries but there is a health policy debate on the topic. According to the researchers, only preliminary evidence of the benefits of the new screening model is available so far. However, the results seem to indicate that major benefits could potentially be achieved in the future. The benefits can only be estimated after a 10-year follow up when the effects on prostate cancer mortality have been analysed. "The aim of cancer screening is always to reduce mortality. The main criterion for decisions on cancer screening should always be the reduction of mortality to be gained," Auvinen says. "The ProScreen study, due to its large size and randomised design, can produce the research evidence needed to justify screening decisions," he adds. There is currently no reliable research data on the benefits and harms of MRI screening. The study was carried out by a large team of researchers, including radiologists, pathologists, urologists, and experts from other fields at Tampere University and Tampere University Hospital (TAYS), as well as the University of Helsinki and Helsinki University Hospital (HUS). The cooperation partners included the local laboratory networks and Lund University. The study was supported by Cancer Foundation Finland, Research Council of Finland, Jane and Aatos Erkko Foundation, Päivikki and Sakari Sohlberg Foundation and state research funding administered by the Pirkanmaa wellbeing county. The research article was published in the JAMA -- Journal of the American Medical Association. Prostate cancer is the most common cancer in men.