In the paper published in Nature Communications Polish and American team of researchers  presented a simple diagnostic test to assess the risk of breast and ovarian cancer. The authors suggested that the simple test should allow to assess the risk of breast od ovarian cancer without the need of genetic testing. The researchers from Dana-Farber Cancer Institute (DFCI) and The Medical University of Lodz (MUL) demonstrated that a specific combination of serum microRNA indicates an increased risk of cancer development in the future.

The researchers from Dana-Farber Cancer Institute and the Medical University of Lodz designed a method for detection of BRCA1 and BRCA2 mutations without DNA sequencing. The test is not based on direct identification of the gene mutation but on the detection of its consequences: disturbed cellular processes related to these proteins.  Prof. Chowdhury (the main author of the project): ‘ It is for the first time that a simple test was sufficient to identify the blood signal which suggests the changes leading to cancer development”. The new method may provide the grounds for widely available, cheaper and simpler tests to identify the risk of hereditary cancers.

BRCA1 i BRCA2 genes belong to the DNA repair-regulating pathway. Some BRCA1 i BRCA2 mutations cause disturbance to the gene repair, which leads to further genome damage and, consequently, to breast, ovarian, prostate or pancreatic cancers. In Poland, as in most developed countries,  genetic testing is available to patients with a known familial history of the cancers in question. The risk-reducing surgical interventions, salpingo-oophorectomy or mastectomy, are the opportunities available to BRCA1/2 mutation carriers.  Alas, only ~10% of them are aware that they are BRCA1/2 mutation carriers.

Prof. Fendler (the paper corresponding author): ‘The aim of the project was to find a solution which could enable a population-scale identification of cancer risk without prohibitively costly methods. The microRNA discussed in the paper by Elias and Smyczyńska  demonstartes that such a tool is feasible”.

MicroRNA are small, single-stranded, RNA molecules of a specific structure. Their biological function includes protein synthesis regulation, but this study focused on another aspect: pathological changes in the number of copies of specific serum microRNAs. A specified serum microRNA profile therefore indicates some specific diseases. 653 samples were collected by 6 research teams from the USA, India and Poland and microRNAs were counted in each sample by RNA-sequencing. Next, the team Prof. Fendler’s team used bioinformatic and biostatic techniques, including machine learning, identified 19 miRNAs significantly associated with BRCA mutations.

U. Smyczyńska MD PhD (the first author): ‘The primary challenge in the project was to find the processing method for a large body of data of varied technical quality and clinical characteristics. The elimination of non-biological sources of variation allowed us to define which microRNAs are associated with impaired DNA repair and can be used as a diagnostic test.

The designed model can correctly identify patients with germline BRCA1/2 mutations with 94% sensitivity. As the presented models rely on micro-RNA sequencing, they cannot yet be used in screening tests, but  they provide the background for the tool calibration by means of, e.g. qPCR technique, the very same one that is applied in COVID-19 testing.

The teams led by Prof. Chowdhury and Prof. Fendler demonstrated that the identified microRNA profile provides more information than BRCA1/2 sequencing alone or other DNA repair-related genes. The obtained outcomes show the functional effect of genetic variations regardless of which gene is affected by mutation. Prof. Chowdhury: ‘New genes and variants that interfere with DNA repair are constantly being discovered, which means that results that are considered negative may need to be re-evaluated. Having a test that does not require a reference database of genes and their pathogenic variants could much better identify people requiring more thorough oncological supervision.

Further research conducted by both teams will focus on calibration of the test for practical use and testing its effectiveness in population screening.

Congratulations!

 

The research funded by:

Dana-Farber / Harvard Cancer Center Ovarian Cancer SPORE, the National Institutes of Health, the National Cancer Institute, the Massachusetts Life Sciences Center Bits to Bytes Program, the Deborah and Robert First Family Fund, the Honorable Tina Broman Foundation, the V Foundation, the Mighty Moose Foundation, and the DST-UKERI (the Government of India Department of Science and Technology and the UK-India Education and Research Initiative).