Valentina Karadzic

Lynch syndrome (LS) is the most common hereditary colorectal cancer (CRC) syndrome, caused by germline pathogenic or likely pathogenic variants (PV/LPV) in mismatch repair (MMR) genes. Data on the spectrum of LS-associated variants in Slavic populations, including Serbia, remain limited. Given the high burden of CRC and endometrial cancer and the limited implementation of hereditary CRC screening, characterizing the spectrum of germline variants in clinically selected high-risk individuals is important for improving genetic testing strategies, risk assessment, and clinical management. Between 2018 and 2025, 176 individuals underwent germline testing for hereditary CRC syndrome based on the Amsterdam/Bethesda criteria, validated LS risk prediction models, and/or family history (FH). Next-generation sequencing (NGS) was performed using the Illumina TruSight Hereditary Cancer Panel, and variants were classified according to American College of Medical Genetics and Genomics and Association for Molecular Pathology (ACMG/AMP) guidelines. PV/LPVs in MMR genes were identified in 27/176 (15.3%) and were associated with positive FH of LS-related tumors (p = 0.0001). Most PV/LPVs were identified in MLH1 (10.2%), followed by MSH2 (4.0%) and MSH6 (1.1%), with no PV/LPVs identified in PMS2. Additionally, no pathogenic sequence-level EPCAM variants detectable by the applied panel-based NGS approach were identified. Recurrent MLH1 variants were observed in multiple families, and two previously unreported MLH1 variants were identified. This first systematic analysis of a clinically selected high-risk Serbian cohort provides novel data on the spectrum of LS-associated variants in this referral population, demonstrates the predominance of MLH1 variants, and supports broader implementation of genetic testing, tumor screening, and genetic counseling.

Background: It is projected that, by 2040, the number of new cases of colorectal cancer (CRC) will increase to 3.2 million, and the number of deaths to 1.6 million, highlighting the need for prevention strategies, early detection and adequate follow-up. In this study, we aimed to provide an overview of the progress in personalized medicine of CRC in Serbia, with results and insights from the Institute for Oncology and Radiology of Serbia (IORS), and to propose guidance for tackling observed challenges in the future. Methods: Epidemiological data were derived from official global and national cancer registries and IORS electronic medical records. Germline genetic testing for Lynch syndrome was performed by Next Generation Sequencing. RAS and BRAF mutation analyses were performed using qPCR diagnostic kits. Results: Epidemiology and risk factors, prevention and early detection programs, as well as treatment options and scientific advances have been described in detail. Out of 103 patients who underwent germline testing for Lynch syndrome, 19 (18.4%) showed a mutation in MMR genes with pathogenic or likely pathogenic significance and 8 (7.8%) in other CRC-associated genes (APC, CHEK2, MUTYH). Of 6369 tested patients, 50.43% had a mutation in KRAS or NRAS genes, while 9.54% had the V600 mutation in the BRAF gene. Conclusions: Although significant improvements in CRC management have occurred globally in recent years, a strategic approach leading to population-based systemic solutions is required. The high incidence of young-onset CRC and the growing elderly population due to a rise in life expectancy will be especially important factors for countries with limited healthcare resources like Serbia.

Background/Objectives: The global burden of colorectal cancer (CRC) is projected to increase by 2040, highlighting the need for prevention strategies, early detection and adequate follow. The aim of this study was to provide an overview of the progress in personalized medicine of CRC in Serbia, with results and insights from the Institute for Oncology and Radiology of Serbia (IORS), and to propose guidance for tackling observed challenges in the future. Methods: Epidemiological data was derived from official global and national cancer registries and IORS electronic medical records. Germline genetic testing for Lynch syndrome was performed by Next Generation Sequencing. RAS and BRAF mutation analyses were performed using qPCR diagnostic kits. Results: Epidemiology and risk factors, prevention and early detection programs, as well as treatment options and scientific advances have been described in detail. Out of 103 patients who underwent germline testing for Lynch syndrome, 19 (18.4%) had a pathogenic or likely pathogenic mutation in one of the MMR genes, and 8 (7.8%) in other CRC-associated genes (APC, CHEK2, MUTYH). Of 6369 tested patients, 50.43% had a mutation in KRAS or NRAS genes, while 9.54% had the V600 mutation in the BRAF gene. Conclusions: Although significant improvements in CRC management have occurred globally in recent years, the high incidence of young-onset CRC and the growing elderly population due to a rise in life expectancy require a strategic approach leading to population-based systemic solutions, especially important for countries with limited health care resources as Serbia.

The T790M mutation in the EGFR gene is a critical biomarker of resistance in patients undergoing EGFR tyrosine kinase inhibitor (TKI) therapy. Accurate and efficient detection of this mutation is essential for guiding treatment decisions in non-small cell lung cancer (NSCLC) patients. This study, conducted over two years at the Institute for Oncology and Radiology of Serbia, compared the effectiveness of digital PCR (dPCR) and quantitative PCR (qPCR) in detecting the EGFR T790M mutation in liquid biopsies of patients with disease progression on EGFR TKIs. Our findings reveal higher detection rate using dPCR (30.48%) compared to qPCR (19.44%). The improved sensitivity of dPCR supports its implementation as a preferred technique for EGFR T790M mutation detection, enhancing clinical decision-making and personalized treatment options for patients with NSCLC.