CDKN2A Gene Mutations: Implications for Hereditary Cancer Syndromes.

Malignant neoplasms, including pancreatic cancer and melanoma, are major global health challenges. This study investigates melanoma pancreatic syndrome, a rare hereditary tumor syndrome associated with CDKN2A gene mutations. CDKN2A mutations contribute to a lifetime risk of melanoma ranging from 28% to 67%. This study reports the clinical features of six individuals with CDKN2A mutations and identifies recurrent alterations such as c.307_308del, c.159G>C and c.71G>C. It highlights the need for CDKN2A mutation testing in suspected cases of familial atypical multiple mole melanoma. Clinically significant variants show associations with melanoma and pancreatic cancer. The challenges of treating individuals with CDKN2A mutations are discussed, and the lack of specific targeted therapies is highlighted. Preclinical studies suggest a potential benefit of CDK4/6 inhibitors, although clinical trials show mixed results. This study underscores the importance of continued research into improved diagnostic and therapeutic strategies to address the complexities of hereditary cancer syndromes.

The CFTR Gene Germline Heterozygous Pathogenic Variants in Russian Patients with Malignant Neoplasms and Healthy Carriers: 11,800 WGS Results.

More than 275 million people in the world are carriers of a heterozygous mutation of the CFTR gene, associated with cystic fibrosis, the most common autosomal recessive disease among Caucasians. Some recent studies assessed the association between carriers of CFTR variants and some pathologies, including cancer risk. The aim of this study is to analyze the landscape of germline pathogenic heterozygous CFTR variants in patients with diagnosed malignant neoplasms. For the first time in Russia, we evaluated the frequency of CFTR pathogenic variants by whole-genome sequencing in 1800 patients with cancer and compared this with frequencies of CFTR variants in the control group (1825 people) adjusted for age and 10,000 healthy individuals. In the issue, 47 out of 1800 patients (2.6%) were carriers of CFTR pathogenic genetic variants: 0.028 (42/1525) (2.8%) among breast cancer patients, 0.017 (3/181) (1.7%) among colorectal cancer patients and 0.021 (2/94) (2.1%) among ovarian cancer patients. Pathogenic CFTR variants were found in 52/1825 cases (2.85%) in the control group and 221 (2.21%) in 10,000 healthy individuals. Based on the results of the comparison, there was no significant difference in the frequency and distribution of pathogenic variants of the CFTR gene, which is probably due to the study limitations. Obviously, additional studies are needed to assess the clinical significance of the heterozygous carriage of CFTR pathogenic variants in the development of various pathologies in the future, particularly cancer.

Whole genome non-invasive prenatal testing in prenatal screening algorithm: clinical experience from 12,700 pregnancies.

BACKGROUND: A fast adoption of a non-invasive prenatal testing (NIPT) in clinical practice is a global tendency last years. Firstly, in Russia according a new regulation it was possible to perform a widescale testing of pregnant women in chromosomal abnormality risk. The aim of the study-to assess efficiency of using NIPT as a second-line first trimester screening test in Moscow. METHODS: Based on the first trimester combined prenatal screening results 12,700 pregnant women were classified as a high-risk (cut-off ≥ 1:100) and an intermediate-risk (cut-off 1:101 - 1:2500) groups followed by whole genome NIPT. Women from high-risk group and those who had positive NIPT results from intermediate-risk group were considered for invasive prenatal diagnostic. RESULTS: 258 (2.0%) samples with positive NIPT results were detected including 126 cases of trisomy 21 (T21), 40 cases of T18, 12 cases of T13, 41 cases of sex chromosome aneuploidies (SCAs) and 39 cases of rare autosomal aneuploidies (RAAs) and significant copy number variations (CNVs). Statistically significant associations (p < 0.05) were revealed for fetal fraction (FF) and both for some patient's (body mass index and weight) and fetus's (sex and high risk of aneuploidies) characteristics. NIPT showed as a high sensitivity as specificity for common trisomies and SCAs with an overall false positive rate 0.3%. CONCLUSIONS: NIPT demonstrated high sensitivity and specificity. As a second-line screening test it has shown a high efficiency in detecting fetus chromosomal anomalies as well as it could potentially lower the number of invasive procedures in pregnant women.

A Unique Observation of a Patient with Vulto-van Silfhout-de Vries Syndrome.

Introduction: Vulto-van Silfhout-de Vries Syndrome (VSVS; OMIM#615828) is a rare hereditary disease associated with impaired intellectual development and speech, delayed psychomotor development, and behavioral anomalies, including autistic behavioral traits and poor eye contact. To date, 27 patients with VSVS have been reported in the literature. Materials and Methods: We describe a 23-year-old male patient with autism spectrum disorder (ASD) who was admitted to the gastroenterological hospital with signs of pseudomembranous colitis. ASD was first noted in the patient at the age of 2.5 years. Later, he developed epileptic seizures and important growth retardation. Prior to the hospitalization, chromosomal aberrations, Fragile X syndrome, and aminoacidopathies/aminoacidurias associated with ASD were excluded. Whole-genome sequencing (WGS) was prescribed to the patient at 23 years old. Results: The patient had a heterozygous carrier of "de novo" variant c.662C > T (p.S221L) in exon 4 of the DEAF1 gene. c.662C > T had not been previously described in genomic databases. According to the ACMG criteria, this missense variant was considered to be pathogenic. VSVS was diagnosed in the patient. Conclusions: The phenotype of the patient is very similar to the data presented in the world literature. However, growth retardation and cachexia, which have not been described previously in the articles, are of interest.

Application of the Appropriate Use Criteria for Coronary Revascularization in Patients with Acute Coronary Syndrome in the Russian Federation: Data from the Federal Registry.

OBJECTIVE: The aim of the study was to apply the appropriate use criteria (AUC) for coronary revascularization on Russian Acute Coronary Syndrome Registry (RusACSR) data to analyze validity of the decision to perform percutaneous coronary interventions (PCIs) among patients with acute coronary syndrome (ACS). MATERIAL AND METHODS: In Russia, the frequency of performing PCI increased almost 7.5 times, and more than half of all interventions were performed in patients with ACS, in the period from 2006 to 2015. AUC 2012 were used to assess PCI appropriateness. Data were exported from RusACSR from a period of January 1, 2016 to December 31, 2016. We analyzed 33 893 cases, but 13 957 patients were excluded owing to absence of data needed. The study group therefore included 19 936 patients with ACS (mean age, 65.3 ± 11.9 years; 40.3% women), and it was divided into 2 subgroups: 13 757 (67.2%) patients who were treated conservatively and 6179 (32.8%) patients who underwent PCI. According to AUC, physicians' choice of strategy was validated. RESULTS: Patients treated conservatively differed significantly (P < .001) from those who underwent PCI. In this group, non-ST segment elevation ACS was significantly more common than in the group of patients who received PCI (84.4% vs. 43.9%, P < .001). They also had more severe clinical status. According to AUC, among patients with ACS treated with PCI, the decision was warranted in 86.3% (valid decision). In 7.6% of cases, there was no need for PCI. Among patients who underwent conservative treatment, 77.7% of patients needed PCI according to AUC. According to our data, only 3.8% of patients who were treated conservatively did not need PCI. Appropriateness of invasive treatment was uncertain in 18.5% and 6.1% in the PCI and non-PCI groups, respectively. All differences were significant (P < .001). CONCLUSION: AUC implementation showed low availability of PCI for patients with non-ST segment elevation ACS accompanied by complicated clinical status. AUC for coronary revascularization could be applied in Russian clinical practice for unbiased PCI candidate selection and for evaluation of decision validity.