Mutational spectrum and classification of novel mutations in patients with metastatic gastrointestinal stromal tumours.

In total, ~85% of malignant gastrointestinal stromal tumours (GISTs) harbour activating mutations in one of the genes KIT or PDGFRA, while 10­15% of all GISTs have no detectable KIT or PDGFRA mutations, but could have alterations in genes of the succinate dehydrogenase complex or in BRAF, PIK3CA or rarely RAS family genes. The clinical benefit of tyrosine kinase inhibitors, such as imatinib, depends on the GIST genotype, therefore molecular characterization of GIST has a crucial role in overall management of GIST. The aim of the present study was to molecularly characterize a cohort of 70 patients with metastatic GISTs from the Slovenian Cancer Registry (National Cancer Registry) treated between January 2002 and December 2011. Exons 9, 11, 13 and 17 of the KIT gene and exons 12, 14 and 18 of the PDGFRA gene were analysed by direct Sanger sequencing. All KIT/PDGFRA wild­type GISTs were tested for the presence of mutations in hot spot regions of KRAS, NRAS, BRAF, PIK3CA and AKT1 genes. Novel variants were characterized and classified using Cancer Genome Interpreter and according to The American College of Medical Genetics and Genomics/Association for Molecular Pathology guidelines. In total, 60 (85.7%) patients had mutations in KIT and 2 (2.9%) in PDGFRA. Whereas, 8 (11.4%) patients with GIST had no mutation in either of the analysed genes. The majority of GIST cases (n=52) had a mutation in KIT exon 11, where 40 different mutations were detected. Eight of the variants were novel: c.1652_1672del, c.1653_1660delinsAA, c.1665_1672delinsCC, c.1668_1686del, c.1676_1720del, c.1715_1756dup, c.1721_1765dup, and c.1722_1766dup. Mutation frequencies of KIT and PDGFRA genes observed in Slovenian patients are comparable with those in other European populations. In the present group of patients analysed, the most frequently mutated region was exon 11 in the KIT gene, responsible for coding juxtamembrane domain of KIT protein. In this region, eight novel mutations were identified and classified as likely pathogenic driver variants. In addition, the present study identified 6 patients with secondary KIT mutation and 1 patient with double mutant GIST, who had two different mutations in PDGFRA exon 14.

Prevalence of BRAF, NRAS and c-KIT mutations in Slovenian patients with advanced melanoma.

Background BRAF, NRAS and c-KIT mutations are characteristics of tumour tissues that influence on treatment decisions in metastatic melanoma patients. Mutation frequency and their correlation with histological characteristics in Slovenian population have not been investigated yet. Patients and methods In our retrospective analysis we analysed mutational status of BRAF, NRAS and c-KIT in 230 pathological samples of patients who were intended to be treated with systemic therapy due to metastatic disease at the Institute of Oncology Ljubljana between 2013 and 2016. We collected also histological characteristics of primary tumours and clinical data of patients and correlated them with mutational status of tumour samples. Results The study population consisted of 230 patients with a mean age 59 years (range 25-85). 141 (61.3%) were males and 89 (38.7%) females. BRAF mutations were identified in 129 (56.1%), NRAS in 31 (13.5%) and c-KIT in 3 (1.3%) tissue samples. Among the 129 patients with BRAF mutations, 114 (88.4%) patients had V600E mutation and 15 (11.6%) had V600K mutation. Patients with BRAF mutations tended to be younger at diagnosis (52 vs. 59 years, p < 0.05), patients with NRAS mutations older (61 vs. 55 years, p < 0.05). Number of c-KIT mutations were too low for any statistical correlation, but there was one out of 3 melanoma located in mucus membranes. Conclusions The analysis detected high rate of BRAF mutations, low NRAS mutations and low c-KIT mutations compared to previously published studies in Europe and North America. One of the main reasons for this observation is specific characteristics of study population.

Completed suicide, depression, and RELN polymorphisms.

OBJECTIVE: Suicidal behavior is a complex phenomenon, an outcome of both environmental and genetic factors. In the present study, we looked for a potential association between suicide and the reelin gene as reelin has been associated previously with several psychiatric disorders, including depression. MATERIALS AND METHODS: We analyzed three single nucleotide polymorphisms (SNPs) in the reelin gene, rs2965087, rs7341475, and rs362691, in a population of 483 suicide victims and 332 healthy controls, all Caucasians. An analysis was carried out according to sex and the method of suicide. In a group of 77 suicide victims with psychological autopsy data, suicide threats, suicide in the family, and number of depression symptoms were also considered. RESULTS: Analysis of all three polymorphisms did not confirm an association with suicide in general. However, for subjects included in psychological autopsy study, association with previous announcement of suicide in the group of subjects with TT genotype for polymorphism rs2965087 was determined. Furthermore, the results pointed to an association with reported suicide in the family of suicide victims in case of the TT genotype. In contrast, the number of depressive symptoms, besides suicidal threats, was lower in the group with the TT genotype. LIMITATIONS: Psychological autopsies can be associated with recall bias and the sample was rather small and therefore underpowered. CONCLUSION: The present investigation, performed on a study sample from a population with one of the highest suicide rates in the world, indicated an association between rs2965087 in the reelin gene and the expression of suicidal threats a month before suicide in contrast to other symptoms of depression.