Hakan Gurkan

Background: Germline pathogenic variants in BRCA1 and BRCA2 are established contributors to hereditary breast cancer, yet their separate prognostic effects in non-metastatic disease remain uncertain because they are frequently analyzed as a single group. Methods: We retrospectively evaluated 360 patients with stage I–III invasive breast cancer who underwent germline genetic testing. Patients were categorized as BRCA-negative (n = 281), BRCA1-positive (n = 43), or BRCA2-positive (n = 36). Disease-free survival (DFS) and overall survival (OS) were analyzed using Kaplan–Meier methods and Cox proportional hazards models with adjustment for molecular subtype and clinicopathological variables. Results: During follow-up, 76 DFS events and 27 deaths were observed. BRCA2 positivity was independently associated with worse DFS (hazard ratio [HR] 2.13, 95% confidence interval [CI] 1.14–3.98; p = 0.017), whereas BRCA1 positivity showed an association with improved OS (HR 0.08, 95% CI 0.01–0.51; p = 0.007). The OS finding should be interpreted cautiously because of the limited number of death events and the risk of model instability. Conclusions: Germline BRCA1 and BRCA2 variants may have divergent prognostic implications in non-metastatic breast cancer and should not be treated as a single homogeneous prognostic entity. Separate evaluation of these variants may improve risk stratification and support more individualized patient management, although validation in larger cohorts is warranted.

Triple-negative breast cancer (TNBC/18–21%) lacks targeted treatment options due to the lack of ER/PR and HER2 expression. The transport of lncRNAs via exosomes plays a role in tumor progression and metastasis and reshapes tumor-associated signaling pathways. This study aimed to compare the expression of exosomal HOTAIR, NEAT1, MALAT1, AFAP1-AS1, ANRIL, and HULC lncRNAs in primary tumor tissue and blood of patients with sporadic TNBC to evaluate their potential as biomarkers. The patients diagnosed with TNBC between the years 2021 and 2025, 21 of 62 (33.87%) with sporadic breast cancer and thirty healthy controls were included in the study. Primary tumor tissue and peripheral venous blood samples were collected from 21 patients who did not receive neoadjuvant chemotherapy. Expression levels of exosomal lncRNAs (HOTAIR, NEAT1, MALAT1, AFAP1-AS1, ANRIL, and HULC) were determined in both tissues and blood samples from the patient and control groups using Real-Time PCR method. In the patient group, HOTAIR, HULC, ANRIL, and AFAP1_AS1 gene expression was lower (downregulated) in tissue and serum compared to the control group, whereas NEAT1 and MALAT1 were higher (upregulated). Tissue and serum samples taken from the patient group were found to have statistically consistent expression levels of HOTAIR, HULC, and ANRIL genes. Furthermore, HOTAIR, HULC, and ANRIL serve as biomarkers and can be studied using exosomal RNA samples obtained from patient serum without invasive procedures. Our current study, which has different lncRNA expression profiles, reflects the biological heterogeneity of TNBC and contributes to a better understanding of its subtypes at the molecular level.

Introduction: Myocardial infarction with nonobstructive coronary artery disease (MINOCA) poses a challenge for diagnosis and treatment because of its heterogeneous etiology. The mechanisms underlying MINOCA are diverse and include plaque disruption, coronary spasm, microvascular dysfunction, and thromboembolism. However, the specific molecular pathways involved are not fully understood. MicroRNAs (miRNAs) are known as potential biomarkers and regulators of various cardiovascular diseases. In our study, we aimed to investigate the relationship between MINOCA and exosomal miRNA expression and to determine the potential of these exosomal miRNAs as biomarkers for prognosis, diagnosis, and treatment. Methods: Three groups were included in the study: (1) the MINOCA group, (2) the myocardial infarction with obstructive coronary artery disease group, and (3) the healthy control group. Exosomal miRNA isolation was performed from all participants, and the expression levels of hsa-miR-16-5p, hsa-miR-92a-3p, hsa-miR-487a-5p, and hsa-miR-490-3p were analyzed by quantitative real-time PCR (polymerase chain reaction). ΔΔCt values were determined, and statistical analyses were performed after these values were obtained. Results: Statistical analysis of hsa-miR-16-5p, hsa-miR-92a-3p, hsa-miR-487a-5p, and hsa-miR-490-3p revealed that the expression levels of hsa-miR-490-3p were significantly different between the groups in the MINOCA group (p = 0.022). hsa-miR-16-5p was found to be closely related to the statistical significance level (p = 0.078). hsa-miR-92a-3p and hsa-miR-487a-5p were not significantly different between the groups. Conclusion: Our study revealed that miR-490-3p, which was detected at a statistically significant level in the MINOCA group, is an effective biomarker in MINOCA patients. This miRNA has been reported in only a few studies on myocardial infarction, and our study is the first to report it in relation to MINOCA. The fact that hsa-miR-16-5p is close to statistical significance, whereas statistical significance was not detected for hsa-miR-92a-3p and hsa-miR-487a-5p, indicates that studies with a larger number of individuals are needed.

Background: Autism spectrum disorder (ASD) has a strong genetic basis, yet specific etiological factors remain unidentified in the majority of cases. Mitochondrial DNA (mtDNA) variations have been hypothesized as potential contributors to ASD development. However, the precise role of mtDNA remains unclear due to inconsistent findings across studies, which often suffer from methodological limitations. Aims: This study aimed to comprehensively investigate the association between mtDNA variants, gene‐level variant burden and haplogroup distributions in a Turkish paediatric ASD cohort. Study Design: Case control study. Methods: Whole mtDNA analysis of peripheral blood samples from 95 children with ASD and 95 healthy controls was performed using next‐generation sequencing. Identified variations were evaluated for pathogenicity via genomic databases and in silico analyses. Potentially pathogenic variations underwent segregation analysis. Additionally, mtDNA haplogroup distributions were compared between the groups. Results: The overall frequency of mtDNA variants was significantly higher in the ASD group than in the control group ( p = 0.033). The ASD cohort harboured 23 distinct variants (initially classified as three pathogenic/likely pathogenic (P/LP) and 20 variants of uncertain significance [VUS]); while the control group had 13 VUS and no P/LP variants. Gene‐based burden analysis identified a significantly higher variant load in the MT‐CYB gene within the ASD cohort (FDR = 0.048). However, segregation analysis of the P/LP variants (including m.827A > C, m.9804G > A and a novel MT‐CYB variant) revealed maternal inheritance from asymptomatic mothers. Consequently, all P/LP variants were reclassified as VUS. No significant difference was found in mtDNA haplogroup distribution between groups. Conclusion: Through comprehensive mtDNA scanning and rigorous pathogenicity assessment, our findings suggest that mtDNA variations are not implicated in the pathogenesis of ASD. However, given the complex nature of ASD, future research is needed with larger sample sizes, standardized pathogenicity assessment criteria and detailed phenotypic analyses to further elucidate the relationship between mtDNA variants and ASD.

In our study, we aimed to investigate the relationship between miRNA-21, miRNA-155, miRNA-34a, IL-6, TGF-β, and TNF-α expression levels and serum trace element levels in the development and progression of bladder cancer. RT-PCR was used to establish miRNA-21, miRNA-155, and miRNA-34a expression levels while serum IL-6, TGF-β, and TNF-α levels were determined using the ELISA and measured with an atomic absorption spectrophotometer. In the patient group, miRNA-21 and miRNA-155 expression levels were significantly higher compared with the healthy control group (p < 0.001). Furthermore, in the patient group, miRNA-34a expression was significantly lower compared with the control group (p < 0.001). IL-6, TNF-α, TGF-β, copper levels, and the copper to zinc ratio were significantly higher in the patient group (p < 0.001). Serum iron and zinc levels in the patient group were significantly lower compared with the control group (p < 0.001). There was a significant positive correlation between miRNA-155 and IL-6 and TNF-α (r = 0.279, p = 0.015*; r = 0.325**, p = 0.004). A significant positive correlation was detected between miRNA-34a and IL-6 and TGF-β (r = 0.294*, p = 0.010; r = 0.447**, p < 0.001). By evaluating these important biomarkers together, it might be possible to implement clinical applications for bladder cancer treatment and develop individual therapeutic strategies.

Purpose: The aim of the study is to examine the expression levels of the GATA6 and TBX3 genes in hernia sacs from patients with indirect inguinal hernia (IIH) in the Trakya region, Türkiye and shed light on the etiology of this common surgical disease in childhood. Materials and methods: In this cross-sectional study, GATA6 and TBX3 gene expression and single nucleotide polymorphism analyses were conducted on tissue samples obtained from 20 boys with IIH (study group) and 20 circumcised children (control group) who were operated in Trakya University Hospital, Pediatric Surgery Clinic. The tissue samples were collected from IIH sacs and prepuces. RNA isolation from tissue and complementary DNA (cDNA) synthesis were performed in accordance with the protocols of the kits used. In the DNA sequence variants (DSVs) study, DNA isolation was performed in accordance with the protocol of the kit used Allelic discrimination was also performed for the GATA6 rs1416421760 and rs1040912117 and TBX3 rs968910973 DVSs. Mann–Whitney U test was used to statistically compare the outcomes. Results: The expression of GATA6 demonstrated a significant increase ( p < 0.001), while TBX3 expression exhibited a significant decrease ( p < 0.001) in the study group. In terms of genotype and allele frequencies of GATA6 rs1416421760, rs1040912117, and TBX3 rs968910973 DSVs, no statistically significant difference was found between the study and control groups. Conclusion: According to the results of the study, it can be asserted that dysfunctions in the GATA6 and TBX3-mediated stages of the apoptotic pathway may contribute to the development of IIH.

Introduction: Verheij syndrome is associated with a deletion on chromosome 8q24.3 region or PUF60 gene mutations. A variety of symptoms including feeding problems, microcephaly, joint laxity, intellectual disability, cardiac defects, and renal abnormalities are the characteristic features of the syndrome. Case Presentation: In the current report, 2 cases are presented with Verheij syndrome in different ages. With this study, we aimed to present the clinical findings of a likely pathogenic novel variant in the first case NM_078480.3(PUF60):c.297+1G>C, and in the second case a likely pathogenic heterozygous missense variant NM_078480.3(PUF60):c.47G>T p.(G16V). Conclusion: A very rare syndrome – Verheij syndrome – is reported in 2 cases with genotype phenotype correlation in this report.

Spastic paraplegia type 4 is a common type of autosomal-dominant pure hereditary spastic paraplegia that is brought on by variations in the SPAST gene. In this investigation, the SPAST genotype and clinical phenotype of a Turkish SPG4 patient were analyzed in an effort to provide additional genetic evidence for the pathophysiology of HSP. The clinical data of the proband and his family members were collected. After complete genomic DNA was isolated from peripheral blood, whole-exome sequencing technology was used to identify genes and analyze the pathogenicity of variants. Variants suspected of being pathogenic were found. Within this family, Sanger sequencing was used for verification. The sequencing of SPAST revealed a de novo missense c.1496G > A (p.Arg499His) and missense MEFV c.2177T>C (p.Val726Ala) variants. The parents and paternal relatives did not have the SPAST mutation. De novo variants of the c.1496G > A mutation in SPAST can arise at notably high frequencies. We discussed the case of a Turkish patient and examined the clinical characteristics of patients with the p.Arg499His variation in SPAST that have been documented in the literature. There is growing evidence that the p.Arg499His missense mutation in SPAST may be linked to early-onset HSP. The majority of pathogenic mutations were found in the protein's AAA domain, according to analysis of SPAST sequences; this may be closely related to the pathophysiology of SPG4. The results of this investigation may broaden the range of therapeutic applications for the p.Arg499His mutation in SPAST and offer a chance to investigate the genotype-phenotype relationship of SPG4 in more detail.

Background: Primary heart muscle diseases called cardiomyopathy (CMP) constitute an important group of subsequent heart disorders. CMPs are basically divided into four subgroups associated with the heart muscle but clinically distinguishable: hypertrophic CMP (HCM), dilated CMP (DCM), restrictive CMP (RCM), and left ventricular non-compaction CMP. Material and Methods: The results of the patients who applied to the Genetic Diseases Evaluation Center with the preliminary diagnosis of clinical CMP were evaluated retrospectively in the current study. In the current study, 103 cases were included and evaluated for phenotype-genotype association with the CMP next-generation sequencing (NGS) panel. Results: Fifty-eight different variants were identified in 45 patients. Sixteen out of those 58 variants were novel. Of these variants, 19 (32.75%) were likely pathogenic (LP)/pathogenic (P), and 35 (60.34%) were variants of uncertain significance. Conclusion: The prevalence of pathogenic variants in target genes associated with CMP is important for our current country's population, and multiple gene groups associated with CMP can be screened through NGS. The contribution rate to the clinical diagnosis was 18.44% in terms of the individual population who applied to our medical genetics center and were compatible with the CMP indication.