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.

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.

[Hereditary cancer syndromes: a modern paradigm].

About 5-10% of malignant neoplasms (MN) are hereditary. Carriers of mutations associated with hereditary tumor syndromes (HTS) are at high risk of developing tumors in childhood and young age and synchronous and metachronous multiple tumors. At the same time, this group of diseases remains mainly an oncological problem, and clinical decisions are made only when MNs are detected in carriers of pathogenic mutations.Individual recommendations for cancer screening, treatment, and prevention should be developed for carriers of mutations associated with HTS to prevent an adverse outcome of the disease. It is essential to identify patients at risk by doctors of all specialties for further referral to medical and genetic counseling with molecular genetic testing (in case of indications). The problems of standardization of enrollment criteria for genetic tests, further tactics of prevention, screening, and treatment of many hereditary oncological diseases remain unsolved.This review was created to inform doctors of various specialties, including endocrinologists, about the HTS. This allows them to get acquainted with main clinical features of specific syndromes, helps to understand the difference between hereditary and non-hereditary cancer, recognize signs of hereditary cancer, and introduce the indications for genetic examination and genetic counseling of the patient. Also, significant differences between international and domestic recommendations on screening measures, diagnosis, and treatment of HTS underline the need to review the existing and develop new algorithms for medical support of patients with HTS.

Hepatitis B and C viruses and survival from hepatocellular carcinoma in the Arkhangelsk region: a Russian registry-based study.

INTRODUCTION: Hepatocellular carcinoma (HCC) is one of the most common cancers worldwide. The prevalence of hepatitis B (HBV) and C (HCV) in Russia was 7.6 and 5.4 per 100,000, respectively. The aim of this study was to assess the proportion of HCV and HBV infection among HCC patients, to evaluate associations between HCV, HBV and stage of HCC and to compare survival of HCC patients by their HBV/HCV status in the Arkhangelsk region of northwest Russia. MATERIALS AND METHODS: A retrospective cohort study was conducted using data on all histologically confirmed HCC cases. Proportions of infected and non-infected HCC cases were calculated by Wilson's method. The associations between HBV, HCV and severity of HCC were assessed by Pearson's Chi-squared test. Survival data were presented using Kaplan-Meier curves and median survival. Survival time between the groups was compared using log-rank tests. Adjustment for potential confounders (sex, age groups, stage of HCC and cirrhosis stage by Child-Paquet scale) was performed using Cox regression. RESULTS: There were 583 histologically confirmed HCC cases. The viral status was registered in 311 of patients with pre-mortem diagnosis, where 124 or 39.9% (95% confidence interval (CI), 34.4-45.4) had HBV, 54 or 17.4% (95% CI, 13.5-21.9) had HCV and 16 or 5.1% (95% CI, 3.2-8.2) were infected with both HBV and HCV. The median survival rates of patients were 3 months (95% CI, 2.3-3.8), 3 months (95% CI, 2.0-3.9) and 1 month (95% CI, 0.0-0.6) for patients with HBV, HCV and HBV and HCV, respectively. For virus-free patients, it was 5 months (95% CI, 3.5-6.5), log-rank test=10.74, df=3, p=0.013. Crude Cox regression showed increased risk of death for HBV and HBV and HCV groups in comparison with virus-free patients, and not reaching the level of statistical significance for HCV. After adjustment, the hazard ratios (HRs) decreased to non-significant levels or even reversed, with only exception for the group of patients infected with both hepatitis viruses. CONCLUSIONS: We found that more than half of HCC patients were infected with HBV or HCV. The study did not reveal an association between viral status of HCC patients and stage of HCC. The viral hepatitis may have an impact on survival of HCC patients.