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The study focuses on the VRAC channel and its significant roles in cancer development. It addresses a research gap by conducting a pan-cancer analysis with multi-omics bioinformatics tools, integrating data from the Human Protein Atlas (HPA) and Genotype-Tissue Expression (GTEx) datasets to examine mRNA expression patterns of its Leucine Rich Repeat Containing 8 (LRRC8) subunits in various tissues and cancers. The study links variations in LRRC8s expression with patient outcomes and includes analyses of DNA and RNA methylation. The study reveals significant correlations between LRRC8s expression and immune cell infiltration, as well as a positive association with cancer-associated fibroblasts and key immune regulators such as major histocompatibility complex (MHCs) and chemokines. Furthermore, the research suggests that LRRC8s are involved in cancer-signalling pathways, which may offer new therapeutic targets. Additionally, a drug sensitivity analysis shows that LRRC8 subunits affect drug responses differently, supporting the use of personalized therapeutic strategies. In conclusion, the study emphasizes the significance of VRAC subunits in cancer biology and suggests their potential as biomarkers and targets in cancer immunotherapy and personalized medicine.

Ion channels are critical in enabling ion movement into and within cells and are important targets for pharmacological interventions in different human diseases. In addition to their ion transport abilities, ion channels interact with signalling and scaffolding proteins, which affects their function, cellular positioning, and links to intracellular signalling pathways. The study of “channelosomes” within cells has the potential to uncover their involvement in human diseases, although this field of research is still emerging. LRRC8A is the gene that encodes a crucial protein involved in the formation of volume-regulated anion channels (VRACs). Some studies suggest that LRRC8A could be a valuable prognostic tool in different types of cancer, serving as a biomarker for predicting patients’ outcomes. LRRC8A expression levels might be linked to tumour progression, metastasis, and treatment response, although its implications in different cancer types can be varied. Here, publicly accessible databases of cancer patients were systematically analysed to determine if a correlation between VRAC channel expression and survival rate exists across distinct cancer types. Moreover, we re-evaluated the impact of LRRC8A on cellular proliferation and migration in colon cancer via HCT116 LRRC8A-KO cells, which is a current topic of debate in the literature. In addition, to investigate the role of LRRC8A in cellular signalling, we conducted biotin proximity-dependent identification (BioID) analysis, revealing a correlation between VRAC channels and cell-cell junctions, mechanisms that govern cellular calcium homeostasis, kinases, and GTPase signalling. Overall, this dataset improves our understanding of LRRC8A/VRAC and explores new research avenues while identifying promising therapeutic targets and promoting inventive methods for disease treatment.

Germline pathogenic variants (PVs) in the Ataxia Telangiectasia mutated (ATM) gene (MIM* 607585) increase the risk for breast, pancreatic, gastric, and prostatic cancer and, to a reduced extent, ovarian and colon cancer and melanoma, with moderate penetrance and variable expressivity. We describe a family presenting early-onset gastric cancer and harboring a heterozygous pathogenic ATM variant. The proband had gastric cancer (age 45) and reported a sister deceased due to diffuse gastric cancer (age 30) and another sister who developed diffuse gastric cancer (age 52) and ovarian serous cancer. Next generation sequencing for cancer susceptibility genes (APC, ATM, BRD1, BRIP1, CDH1, CDK4, CDKN2A, CHEK2, EPCAM, MLH1, MRE11, MSH2, MSH6, MUTYH, NBN, PALB2, PMS2, PTEN, RAD50, RAD51C, RAD51D, RECQL1, SMAD4, STK11, and TP53) was performed. Molecular analysis identified the truncating c.5944C>T, p.(Gln1982*) variant in the ATM (NM_000051.3; NP_000042.3) in the proband. The variant had segregated in the living affected sister and in the unaffected daughter of the deceased affected sister. Familial early-onset gastric cancer is an unusual presentation for ATM-related malignancies. Individual variants may result in different specific risks. Genotype–phenotype correlations are challenging given the low penetrance and variable expressivity. Careful family history assessments are pivotal for prevention planning and are strengthened by the availability of molecular diagnoses.

This study was carried out to evaluate the relationship between mtDNA D-loop variations and the pathogenesis of a brain tumor. In this experimental study, 25 specimens of brain tumor tissue with their adjacent tissues from patients and 454 blood samples from different ethnic groups of the Iranian population, as the control group, were analysed by the polymerase chain reaction (PCR)-sequencing method. Thirty-six variations of the D-loop area were observed in brain tumor tissues as well as the adjacent normal tissues. A significant difference of A750G (P=0.046), T15936C (P=0.013), C15884G (P=0.013), C16069T (P=0.049), T16126C (P=0.006), C16186T (P=0.022), T16189C (P=0.041), C16193T (P=0.045), C16223T (P=0.001), T16224C (P=0.013), C16234T (P=0.013), G16274A (P=0.009), T16311C (P=0.038), C16327T (P=0.045), C16355T (P=0.003), T16362C (P=0.006), G16384A (P=0.042), G16392A (P=0.013), G16394A (P=0.013), and G16477A (P=0.013) variants was found between the patients and the controls. The results indicated individuals with C16069T [odds ratio (OR): 2.048], T16126C (OR: 2.226), C16186T (OR: 3.586), G16274A (OR: 4.831), C16355T (OR: 7.322), and T16362C (OR: 6.682) variants with an OR more than one are probably associated with a brain tumor. However, given the multifactorial nature of cancer, more investigation needs to be done to confirm this association.

Juvenile polyposis syndrome (JPS) is an autosomal dominant disorder characterized by hyperplastic polyps in the upper and lower gastrointestinal (GI) tract with a high risk of developing GI cancers. We have described a three-generation Italian family with all the spectrum of SMAD4 phenotype. A multigene panel test was performed on the genomic DNA of the proband by next-generation sequencing, including genes related to hereditary GI tumor syndromes. Molecular analysis revealed the presence of the c.1140-2A>G substitution in the SMAD4 gene, a novel splice variant that has never been described before. Our family is remarkable in that it illustrates the variable expressivity of the SMAD4 phenotype within the same family. The possibility of phenotype variability should also be considered within family members carrying the same mutation. In JPS, a timely genetic diagnosis allows clinicians to better manage patients and to provide early surveillance and intervention for their asymptomatic mutated relatives in the early decades of life.

CHEK2 (checkpoint kinase 2; MIM# 604373) is a tumor suppressor gene that encodes a serine threonine kinase involved in pathways such as DNA repair, cell cycle arrest, mitosis, and apoptosis. Pathogenic variants in CHEK2 contribute to a moderately increased risk of breast and other cancers. Several variant classes have been reported, either point mutations or large intragenic rearrangements. However, a significant portion of reported variants has an uncertain clinical significance. We report an intragenic CHEK2 duplication, ranging from intron 5 to intron 13, identified in an Italian family with hereditary breast cancer. Using long range PCR, with duplication-specific primers, we were able to ascertain the genomic breakpoint. We also performed a real-time PCR to assess a possible loss-of-function effect. The genomic characterization of large intragenic rearrangements in cancer susceptibility genes is important for the clinical management of the carriers and for a better classification of rare variants. The molecular definition of breakpoints allows for the prediction of the impact of the variant on transcripts and proteins, aiding in its characterization and clinical classification.

Potassium (K+) channels have been frequently linked to cancer progression; however, their contribution varies across tumour types and experimental models. This heterogeneity indicates that gene-level characteristics such as expression, co-expression, or mutational status are inadequate for explaining channel involvement in oncogenic signalling. Here, we performed a cross-study comparison of experimentally validated K+ channel interactomes, we show that K+ channel regulation is highly context-dependent and does not exhibit conserved pan-cancer signatures. By directly comparing proximity-labeling and affinity-purification datasets across different K+ channel families, we identify a limited number of recurrent organizational architectures rather than universal signalling modules. KCa3.1 (encoded by KCNN4), Kir2.1 (KCNJ2), and TASK-1 (KCNK3) assemble signalling-permissive interactomes integrating adhesion complexes, junctional scaffolds, vesicular trafficking pathways, and receptor-associated signalling nodes. In contrast, Kv11.1 (encoded by KCNH2) displays an interactome predominantly enriched for proteostasis and endoplasmic reticulum–associated components, indicating a proteostasis-centered organizational profile with comparatively limited signalling integration. Kv1.3 (encoded by KCNA3), instead, consistently associates with mitochondrial and metabolism-linked proteins and functionally connects metabolic state to downstream transcriptional regulators, rather than regulating its own transcription. Higher-order intersection and pathway-specific analyses indicate that functional convergence across the above channels emerges from shared architectural principles rather than extensive molecular overlap. In conclusion, this study identifies interactome architecture as a central organizational level for understanding K+ channel function in cancer. The integration of pan-cancer gene-level analyses with systematic comparison of interaction architectures offers a coherent framework for interpreting the functional heterogeneity observed across channels, families, and tumor contexts. This perspective suggests that therapeutic strategies may benefit from targeting channel-centered network architectures rather than isolated channels alone, highlighting ion channels as structural components of broader signalling systems rather than solely bioelectrical regulators.