(1) Background: Comorbidity between Alcohol Use Disorders (AUD), mood, and anxiety disorders represents a significant health burden, yet its neurobiological underpinnings are elusive. The current paper reviews all genome-wide association studies conducted in the past ten years, sampling patients with AUD and co-occurring mood or anxiety disorder(s). (2) Methods: In keeping with PRISMA guidelines, we searched EMBASE, Medline/PUBMED, and PsycINFO databases (January 2010 to December 2020), including references of enrolled studies. Study selection was based on predefined criteria and data underwent a multistep revision process. (3) Results: 15 studies were included. Some of them explored dual diagnoses phenotypes directly while others employed correlational analysis based on polygenic risk score approach. Their results support the significant overlap of genetic factors involved in AUDs and mood and anxiety disorders. Comorbidity risk seems to be conveyed by genes engaged in neuronal development, connectivity, and signaling although the precise neuronal pathways and mechanisms remain unclear. (4) Conclusion: given that genes associated with complex traits including comorbid clinical presentations are of small effect, and individually responsible for a very low proportion of the total variance, larger samples consisting of multiple refined comorbid combinations and confirmed by re-sequencing approaches will be necessary to disentangle the genetic architecture of dual diagnosis.

Triple‑negative breast cancer (TNBC) is an immunohistochemical tumor type characterized by the absence of estrogen, progesterone and human epidermal growth factor receptors. Its complexity renders it difficult to select an effective therapy. TNBC accounts for ~15% of all breast cancer cases in the Caucasian population and 35% among African American women; it is most common in women <40 years of age. The present study examined the spectrum and frequency of germline mutations in genes with a high and moderate penetrance in a cohort of women with TNBC. Molecular analysis was performed with a multigene panel of 94 genes for cancer predisposition using next‑generation sequencing. The mean age of the TNBC cohort at the time of diagnosis was 44 years, 14 years younger than the mean age of the non‑TNBC cohort (58 years). The results revealed a high frequency (41.2%) of pathogenic/likely pathogenic variants in susceptible genes in women with TNBC. Pathogenic germline variants in BRCA1/2 were found in 32% of the women (70% of pathogenic variants detected), and alterations in other predisposing genes (FANCM, CDKN2A and BLM) were found in 9% of the women. The data of all the patients with TNBC studied revealed a family history of cancer in 30% of the cases; most frequently, this involved relatives with breast cancer (11.8%). In the present study, the most frequent variant detected (in 11.8% of patients with TNBC) was a pathogenic variant in the BRCA1 gene (c.5266dup). The recommendations of genetic counselors for patients with a pathogenic BRCA1/2 germline variant followed accepted prevention and risk reduction guidelines. By contrast, in the case of a detected pathogenic germline variant in genes with a moderate or low penetrance, the recommendations depended on the assessment of genetic counselors based on age at diagnosis, family history, the gene affected and the pathogenic variant.

Lynch syndrome (LS) is an autosomal dominant cancer syndrome. It can be caused by mutations of several genes, including MLH1, MSH2, MSH6, PMS2, MLH3 and MSH3, which are responsible for DNA mismatch repair, and LS affects 3‑5% of patients with colorectal cancer (CRC). LS is associated with a high risk of cancer in several different locations, although the most commonly affected regions are the colon (20‑70% risk), endometrium (15‑70% risk), stomach (6‑13% risk) and ovaries (4‑12% risk). In the present report, the familial case of LS with a detected pathogenic variant in the MSH2 gene is described. The proband was a male who was diagnosed with CRC at the age of 25 years. Genealogy analysis revealed a total of seven affected relatives (including the proband), one of whom (I degree relative, mother) had synchronous cancers (endometrial and ovarian) and five others (of II and III degree relation) had ovarian cancer. Genetic analysis using next generation sequencing detected a heterozygous germline mutation in the MSH2 gene (c.1386 + 1G >A) in the proband and his mother, confirming the diagnosis of LS. The results of the recommended genetic test in an asymptomatic relative of the proband (II degree relative, uncle), found the same familial mutation. Subsequent prophylactic colonoscopy of this relative revealed early stage CRC. The presented case confirms the need for specific genetic analysis, alongside genetic counseling, in hereditary cancer syndromes. Active genetic prophylaxis in patients with LS allows early detection of primary cancers in other locations, and pre‑symptomatic genetic analysis of relatives is an option for early diagnosis.

Background: Synchronous endometrial and ovarian cancer (SEOC) accounts for 50–70% of all synchronous gynecology cancers in women. Approximately 14% of SEOC cases are caused by Lynch syndrome (LS). The widespread introduction of “universal screening” at LS (all cases with CRC and all EC cases diagnosed before age 60 should be tested for MMR deficiency) has led to an increasing number of suspected LS cases- MMR-deficient tumors without germline mutation in the MMR genes. These cases are attributed to the so-called Lynch-like syndrome (LLS). Case presentation: We present a case of LLS with a detected germline, likely pathogenic variant in the WRN gene. The proband was a woman diagnosed with SEOC at the age of 51 years. Histology of both tumors (endometrium and ovary) was endometroid and showed loss of MLH1 and PMS protein expression. Genetic testing by next generation sequencing (NGS) detected a germline mutation (in the heterozygous state) in the WRN gene - c.4109del, p.(Asn1370ThrfsTer23) in the proband. Conclusions: The presented case contributes to the etiology of LLS and confirms the need for specific genetic testing, together with genetic counseling, in hereditary cancer syndromes. The use of combined information from clinicians, pathologists, genetic counselors, and data from NGS testing for cancer predisposition, clinical surveillance, and follow-up management in women with gynecology cancers, especially SEOC, could be improved.

Summary: Detection of mutations in breast cancer 1 (BRCA1) and breast cancer 2 (BRCA2) gene is an effective method of early diagnosis and prevention of breast cancer (BC). The mutational spectrum of both genes in Bulgarian population has not been studied in depth. The aim of this study was to investigate the prevalence of five deleterious BRCA1/2 point mutations in high-risk BC women, selected according to the National Comprehensive Cancer Network (NCCN) Guidelines including early age of onset, triple-negative BC and family history of breast or ovarian cancer. The prevalence of two BRCA1 mutations (C61G and 5382insC) and three BRCA2 mutations (6079del4, 9326insA and 9908delA) was evaluated in 80 females with BC, obtained from the Cancer Registry of University Hospital - Pleven. Genetic testing was performed by direct DNA sequencing. One deleterious mutation (5382insC in exon20 in BRCA1) was been found in two patients (2.5%). Both women were diagnosed with BC before age 45. The prevalence of BRCA mutations established in our study was lower than the one found in another preliminary study on Bulgarian population. We concluded that this discrepancy was due to the genetic heterogeneity of the population and the specific mutational spectrum of the BC patients from the Pleven region.

Giant congenital melanocytic nevi (GCMN) are rare pigmented skin lesions present at birth that carry an increased risk of malignant melanoma and neurocutaneous melanosis. Early diagnosis and long‑term follow‑up care are essential for high‑risk patients. The combination of modern imaging techniques with genetic testing can enable a more comprehensive risk assessment. The present case describes a 55‑year‑old woman with a bathing‑trunk‑type GCMN and >30 additional nevi. The patient was monitored using total body mapping combined with artificial intelligence (AI)‑assisted dermoscopy (MoleAnalyzer Pro; FotoFinder Systems GmbH). Due to suspicious features, several lesions were surgically excised. Histopathology revealed a rare plexiform melanocytic schwannoma with low proliferative activity, showing immunopositivity for S100 protein and SOX10, with focal expression of Melan‑A (MART‑1). Germline testing by next‑generation sequencing identified two high‑risk melanocortin 1 receptor (MC1R) variants, p.Arg151Cys and p.Arg160Trp, in compound heterozygous state, both associated with melanoma susceptibility. No pathogenic variants were detected in NRAS or BRAF. The present case highlighted the integrative value of AI‑assisted dermoscopy, histopathology, and genetic profiling in the surveillance of patients with GCMN. Compound heterozygosity for MC1R high‑risk alleles may explain the extensive nevus burden and support intensified surveillance. Personalized follow‑up strategies guided by advanced imaging and genomics can improve early detection and prevention of melanoma.