Medical Genetics Center

Precision cancer medicine aims to improve patient outcomes by providing individually tailored recommendations for clinical management based on the evaluation of biological disease profiles in multidisciplinary molecular tumor boards (MTBs). The quality of MTB decisions depends on the comprehensive, reliable, and reproducible interpretation of increasingly complex molecular data. We developed and implemented, as part of a multicenter precision oncology program, the Knowledge Connector (KC), a decision support system that integrates individual patients' molecular and clinical data with world knowledge to generate and document MTB recommendations. The KC supports data curation, database integration, and discussion based on multiomics data and provides an interface for creating a cross-institutional knowledge base. Furthermore, it extracts relevant biomarker-drug associations and increases the efficacy of data interpretation in a clinically relevant manner by reducing reliance on external sources and optimizing inter-curator concordance. Our results demonstrate that the KC is a versatile tool that supports medical decision-making in MTBs, thus enabling the scalability of precision cancer medicine.

Genetic tumor risk syndromes (genturis) contribute substantially to the overall cancer burden and provide opportunities for early detection, prevention, and individualized treatment. Yet, many affected individuals remain undiagnosed due to restrictive testing criteria and challenges in variant interpretation. This review summarizes recent advances in the diagnostic evaluation of genturis. We trace the evolution from single-gene testing to multigene panel testing, highlighting gains in diagnostic yield alongside the growing prevalence of uncertain and incidental findings. We then describe emerging functional approaches such as RNA sequencing and proteomics that generate molecular evidence to refine variant classification. Next, we outline how long-read sequencing overcomes technical limitations in complex genomic regions. Finally, we discuss practical aspects of clinical implementation, including reporting practices, workflow integration, and professional education, and propose strategies to improve diagnostic accuracy, efficiency, and equitable access to testing.

Background: Vitamin D deficiency is a global health concern affecting all age groups, despite the implementation of supplementation strategies. This study aimed to investigate the roles of genetic polymorphisms, epigenetic mechanisms, and microbiota interactions in vitamin D metabolism, as well as their potential contributions to allergies, autoimmune thyroiditis, and autism spectrum disorder.Methods: This retrospective, descriptive study analyzed data from 60 individuals (16 males and 44 females) who underwent nutrigenetic testing between 2022 and 2024 at Epigenetic Coaching, Istanbul, Turkey. Genetic analyses focused on the cytochrome P450 family 2 subfamily R member 1 (CYP2R1) gene, group-specific component (GC) gene, and vitamin D receptor (VDR) polymorphisms. Inclusion criteria included the presence of allergic symptoms, a diagnosis of autism spectrum disorder, or a diagnosis of Hashimoto’s thyroiditis, along with prior genetic testing for the selected variants. Individuals with any known genetic disorder other than the studied variants were excluded.Results: CYP2R1, GC, and VDR polymorphisms associated with vitamin D insufficiency were found at higher frequencies in patients with autism, Hashimoto’s thyroiditis, and allergic conditions. When examining the associations between genetic variants and diseases, VDR FokI, VDR ApaI, and VDR BsmI variants were more frequently observed in patients with Hashimoto’s thyroiditis, while the VDR TaqI variant was more common in individuals with autism. In the allergy group, BsmI, FokI, ApaI, and TaqI variants were identified at higher frequencies.Conclusion: Genetic variants and epigenetic modifications may disrupt vitamin D metabolism and alter gut microbiota diversity, contributing to the development of various diseases. Evaluating vitamin D deficiency together with its genetic, epigenetic, and microbiota determinants is essential for developing effective prevention and treatment strategies. These findings emphasize the necessity of personalized, nutrigenetic-based approaches to optimize vitamin D function and support overall health.

Abstract Purpose To evaluate safety and immunogenicity of intramuscularly delivered personalized neoantigen synthetic long peptide (SLP) vaccines in patients with advanced solid tumors. Patients and Methods In this Phase I trial, 12 patients with advanced melanoma (n=9) or renal cell carcinoma (n=3) who could no longer access further standard treatments received intramuscular neoantigen SLP vaccines with poly-ICLC. Each vaccine contained ∼20 predicted neoantigen peptides. Adverse events were monitored throughout vaccination and follow-up. Immune profiling was performed at baseline and predefined post-vaccination time points. Results Intramuscular neoantigen vaccination was well tolerated, with only grade 1–2 local pain or fever and no immune-mediated toxicities. All participants developed de novo T-cell responses, detectable within one week. On average, 46% of peptides per patient were immunogenic, inducing both CD8⁺ and CD4⁺ neoantigen-specific responses. Patients previously treated with immune checkpoint inhibitors (ICIs) had higher baseline immunity but achieved comparable post-vaccination responses to ICI-naïve patients. IFN-γ–dominant CD8⁺ and TNF-α–dominant CD4⁺ responses were observed, along with increased effector memory differentiation. Two patients with higher CD8⁺ TEMRA proportions were the longest survivors. Tumor biopsies revealed enhanced CD8⁺ infiltration, and epitope spreading occurred in one of two evaluable cases. Analysis of 239 peptides showed greater immunogenicity for dual MHC I/II–binding, cysteine-containing, and in-frame indel- or low-VAF–derived mutations, while proline substitutions reduced responses. Conclusions Intramuscular neoantigen SLP vaccination with poly-ICLC is safe and induces rapid, mutation-specific T-cell immunity with robust CD8⁺ effector responses. These findings support intramuscular administration as a promising strategy for peptide-based cancer vaccines. Translational relevance Personalized neoantigen vaccines offer a promising strategy to enhance tumor-specific immunity, but most prior studies using intradermal or subcutaneous delivery have shown limited induction of cytotoxic CD8⁺ T cells. This study demonstrates that intramuscular administration of personalized neoantigen synthetic long peptide vaccines with poly-ICLC is safe, feasible, and capable of eliciting rapid, mutation-specific CD4⁺ and CD8⁺ T-cell responses in patients with advanced melanoma and renal cell carcinoma. Vaccine-induced immunity was dominated by IFN-γ–producing cells and accompanied by a shift toward effector memory phenotypes. In selected cases, post-treatment tumor biopsies revealed increased CD8⁺ infiltration. These findings support intramuscular delivery as a practical and effective platform for neoantigen-based cancer vaccine.

Proximal 11p duplication is often derived from a balanced translocation in a parent or inherited from a carrier (father or mother) with normal phenotype, and part of this duplication is a de-novo mutation. The main clinical manifestations in carriers are: mental retardation, eye abnormalities such as abnormal optic nerve morphology, strabismus, hyperopia, nystagmus, and facial abnormalities such as wide nose bridge and tapered fingers. A woman underwent amniocentesis at 18 weeks of gestation because the additional report of noninvasive prenatal testing plus (NIPT-Plus) revealed 13-Mb duplication from 11p13 to 11p11.2. Chromosomal microarray analysis (CMA) on the uncultured amniocytes revealed a 12.57 Mb chromosomal duplication in the region of 11p13p11.2, ultrasound examination showed no dysmorphisms or intrauterine growth restriction in the fetus. At 40 weeks of gestation, the expectant mother gave birth vaginally to a male baby. The baby's growth parameters at birth were in the normal ranges. The baby received a complete physical examination, and the results were normal. Combination of NIPT, prenatal ultrasound, karyotype analysis, CMA, and genetic counselling is helpful for the prenatal diagnosis of copy number variations.