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PubMed2026

Analysis of APC promoter 1B deletions in Russian families with familial adenomatous polyposis.

OBJECTIVE: Familial adenomatous polyposis (FAP) is a severe autosomal dominant hereditary cancer syndrome. Patients develop hundreds of adenomatous polyps throughout the colon with the risk of colorectal cancer, if untreated, approaching 100%. FAP is caused by pathogenic germline variants in the APC gene. Deletions in the APC 1B promoter cause FAP in a small subgroup of patients. Previous studies suggested that the APC promoter deletions in unrelated FAP patients from the US and Italy are identical and may thus have spread from a single founder. The aim of this study was to investigate whether a similar founder effect can be detected in the Russian population. PATIENTS AND METHODS: We performed whole-genome sequencing on five unrelated patients (three males and two females) with extensive (over 100) colon polyps, family history of FAP, and germline APC 1B promoter deletions previously detected by the multiplex ligation-dependent probe amplification (MLPA) and detected precise deletion boundaries. RESULTS: The patients carried deletions in the APC 1B promoter ranging from ~3 to ~122 kbp. We found no association between the deletion size and either the age of the onset or severity of the disease. All deletions were unique and no identical deletion boundaries were observed. However, in four patients, the right deletion breakpoints fell into a 1 kbp region downstream of the 1B promoter. The right breakpoints of several deletions detected in FAP patients from other countries also fell into this narrow region. CONCLUSION: The APC 1B promoter deletions analyzed in this study had arisen independently and there is thus no evidence of a founder effect. Therefore, at least for the cohort of FAP patients with APC 1B promoter deletions studied here, WGS did not provide an added diagnostic benefit to MLPA aside from precisely determining the deletion breakpoints.

APC promoter 1B deletion↗

PubMed2025

A novel insertion/deletion in APC promotor 1B is associated with both gastric and colon polyposis.

Pathogenic variants in the APC gene are classically associated with autosomal dominant familial adenomatous polyposis (FAP), characterized by tens-to-thousands of colonic adenomatous polyps and a high-penetrance predisposition to colorectal cancer. More recently, specific PVs in the YY1 binding motif of APC promoter 1B have been associated with autosomal dominant gastric adenocarcinoma and proximal polyposis of the stomach (GAPPS), characterized by tens-to-thousands of fundic gland polyps and a predisposition to gastric cancer but which are only rarely associated with features consistent with FAP. Although management guidelines currently treat FAP and GAPPS as mutually exclusive conditions, the extent of phenotypic overlap is not well-characterized. Here, we present a multi-clinic and -laboratory collaboration reporting a previously undescribed APC promoter 1B insertion/deletion likely pathogenic variant in a family with mixed GAPPS and FAP phenotype. The family proband is a female of unspecified white ancestry. She was diagnosed with GAPPS at age 30 and, after developing gastric cancer at age 39, underwent curative gastrectomy. She is now 61 with a cumulative history of between 50 and 100 colon adenomas and recently completed subtotal colectomy. Her multi-gene panel testing in 2022 demonstrated a likely pathogenic insertion/deletion (indel) within the APC promoter 1B YY1 binding motif (APC c.-192_-191delATinsTAGCAAGGG). Review of a four-generation pedigree revealed the ages of gastric cancer presentation in the family ranged from 39-60's, with advanced gastric polyposis and prophylactic gastrectomy as early as ages 11 and 13 in the proband's daughter and nephew, respectively. Six of 10 (60%) family members known or presumed to carry the APC likely pathogenic variant underwent colectomy or hemicolectomy due to colon polyposis. The youngest known carrier in the family is a 12-year-old female, and the oldest living carrier is the proband's brother, age 66. A novel APC indel causes concomitant GAPPS and FAP presentations in this previously unreported large kindred. Mixed gastric and colon phenotypes have been rarely described in GAPPS families and the ages of presentation of gastric polyposis are strikingly young in the current family with prophylactic gastrectomies completed as early as age 11 and 13. These ages are significantly younger than the 15 years of age at which national guidelines currently recommend initiation of EGD for screening in GAPPS. Although the mechanism for this combined GAPPS-FAP phenotype is unclear, patients in this family and those with similar APC promoter 1B variants should be offered both gastric and colon cancer risk management.

Adult↗

PubMed2026

Age-stratified mutation patterns in early-onset colorectal cancer reveal distinct molecular features and therapeutic implications.

BACKGROUND: Colorectal cancer (CRC) is increasingly diagnosed in younger adults, with evidence that early-onset cases (age <50 years) differ in the spectrum of prevalent gene mutations compared with older individuals. To evaluate how these age-related differences may inform testing guidelines and therapeutic development, we examined mutation rates of the most prevalent gene mutations across four age-stratified cohorts. PATIENTS AND METHODS: Clinicogenomic data were obtained from Memorial Sloan Kettering Center for Harmonized Onco-genomic Research Dataset and China Pan-Cancer cohorts available in cBioPortal. A total of 6762 samples were analyzed. Mutation frequencies for a comprehensive panel of the 100 most prevalent CRC genes were compared across four age groups: 18-29 (n = 79), 30-39 (n = 402), 40-49 (n = 1064), and ≥50 (n = 5217) using chi-square analysis. False discovery rate (FDR) correction for multiple comparisons was carried out using Benjamini-Hochberg procedure. RESULTS: Statistically significant variation in mutation frequency across age groups was seen in 22 key genes. APC mutations increased with age and were seen in 49.4% of patients in the 18-29 group, 69.7% in 30-39, 73.3% in 40-49, and 75.25% of patients ≥50 (P < 0.001, FDR < 0.001). The oldest cohort was more than three times more likely to have an APC mutation than the youngest [odds ratio (OR) = 3.74, 95% confidence interval (CI) 2.44-5.74, P < 0.001]. In contrast, SMAD4 mutations were twice as common in the youngest age group at 31.6% compared with those over 40, with a prevalence of 17.29% in patients 40-49, and 18.84% in patients over 50 (OR = 2.03, 95% CI 1.26-3.27, P < 0.001, FDR < 0.001). POLE mutations peaked in the 30-39 age group with a prevalence of 10.7% compared with 6.3% in patients aged 18-29, 4.9% in patients aged 40-49, and 5.9% in patients aged ≥50 (P < 0.001, FDR < 0.001). Individuals in the 30-39 group were nearly twice as likely to carry a POLE mutation compared with those over 40 (OR = 1.96, 95% CI 1.41-2.74, P < 0.001). CONCLUSIONS: Differences in mutations of key genes including a lower prevalence of APC mutations and increased SMAD4 mutations in younger individuals provides further supporting evidence that early-onset CRC may represent a distinct biological subtype of CRC. Enrichment of POLE mutations in younger patients highlights the importance of expanded molecular profiling in early-onset CRC, which could help identify patients most likely to benefit from immunotherapy and advance personalized treatment strategies in CRC. Together, these findings reinforce the need to approach early-onset CRC as a distinct biological entity and ensure that appropriate molecular assays are incorporated to guide care.

APC↗

PubMed2026

Heterozygous germline mutations in MSH3, and probably MLH3, act as classical tumour suppressors, leading to excess somatic deletion mutations, signature ID4 and increased colorectal cancer risk.

BACKGROUND: MSH3 and MLH3 are non-canonical DNA mismatch repair genes, involved in repairing insertion-deletion mutations. Colorectal cancer (CRC) and adenomas have been reported in patients with bi-allelic germline MSH3 mutations, and in a very few bi-allelic MLH3 mutation carriers. OBJECTIVES: We hypothesised that germline loss-of-function MSH3 and MLH3 mutations were akin to constitutional mismatch repair deficiency (cMMRd) and Lynch syndrome, such that CRC could result from either bi-allelic germline mutations or heterozygous germline mutations after second hits. DESIGN: About 12 000 CRC and multiple polyp cases and 460 000 controls were studied. 2023 patients underwent cancer genome sequencing. RESULTS: One CRC/multiple polyp case had bi-allelic MSH3 mutations and another, bi-allelic MLH3 mutations. MSH3 and MLH3 germline heterozygotes had an increased risk of CRC (2.2-fold, p=6.6×10-5 and 1.6-fold, p=0.028, respectively), owing to somatic 'second hits' that inactivated the wildtype allele. Single second hits sometimes inactivated both MSH3 and the nearby APC gene. All CRCs with MSH3 or MLH3 deficiency were microsatellite-stable but hypermutant. Deletions of ≥2 bp were particularly increased (~12-fold) and signature ID4 was usually present (p<0.0001). CRCs from heterozygotes without 'second hits' showed no hypermutation. CONCLUSION: The phenotypes of bi-allelic MSH3 and MLH3 mutation carriers resemble some patients with cMMRd. Heterozygous germline MSH3 and MLH3 alleles have incomplete penetrance, but increase CRC risk via hypermutation, phenotypically resembling PMS2-mutant Lynch syndrome. A causal association with specific mutations has not previously been reported for ID4 in human tumours. ID4 probably does not have a single aetiology, but can result from MSH3 or MLH3 deficiency.

COLONIC POLYPS↗

PubMed2026

Risk of desmoid tumor based on APC pathogenic variant location and surgical history in familial adenomatous polyposis: a U.S. community cohort study.

Desmoid tumors (DT) are a leading cause of morbidity and mortality in patients with familial adenomatous polyposis (FAP), yet available data on DT risk remain limited and have been largely derived from large registries or tertiary referral centers. Risk in community-based U.S. populations is poorly defined, which hinders presurgical counseling. We conducted a retrospective cohort study of patients with pathogenic or likely pathogenic variants (PV/LPV) in APC identified through the Kaiser Permanente Northern California Electronic Database, a community-based system serving 4.6 million members. We evaluated the association of APC PV/LPV location and prior abdominal surgery with DT risk using multivariable logistic regression, adjusting for sex, race and ethnicity, and family history. Among 328 patients with FAP, 36 (11.0%) developed DT. DT risk was highest when the APC variant was centrally located (codon 600-1600). Family history was independently associated with increased risk (adjusted odds ratio [aOR] 4.34; 95% confidence interval [CI] 1.12-16.86). All colorectal surgeries were associated with a significantly elevated DT risk: ileostomy (aOR 12.07; 2.10-69.47), subtotal colectomy with ileorectal anastomosis (aOR 9.03; 1.63-49.96), and total proctocolectomy with ileal pouch-anal anastomosis (aOR 10.98; 2.12-56.81). In contrast, non-colorectal surgery was not associated with increased risk (aOR 0.73). In this large community-based U.S. cohort, central APC variant location, family history, and colorectal surgery were associated with increased DT risk. Our findings extend the current literature on DT risk in FAP and help refine presurgical risk-stratification and counseling for these patients.

Humans↗

PubMed2024

Epigenetic footprints: Investigating placental DNA methylation in the context of prenatal exposure to phenols and phthalates.

BACKGROUND: Endocrine disrupting compounds (EDCs) such as phthalates and phenols can affect placental functioning and fetal health, potentially via epigenetic modifications. We investigated the associations between pregnancy exposure to synthetic phenols and phthalates estimated from repeated urine sampling and genome wide placental DNA methylation. METHODS: The study is based on 387 women with placental DNA methylation assessed with Infinium MethylationEPIC arrays and with 7 phenols, 13 phthalates, and two non-phthalate plasticizer metabolites measured in pools of urine samples collected twice during pregnancy. We conducted an exploratory analysis on individual CpGs (EWAS) and differentially methylated regions (DMRs) as well as a candidate analysis focusing on 20 previously identified CpGs. Sex-stratified analyses were also performed. RESULTS: In the exploratory analysis, when both sexes were studied together no association was observed in the EWAS. In the sex-stratified analysis, 114 individual CpGs (68 in males, 46 in females) were differentially methylated, encompassing 74 genes (36 for males and 38 for females). We additionally identified 28 DMRs in the entire cohort, 40 for females and 42 for males. Associations were mostly positive (for DMRs: 93% positive associations in the entire cohort, 60% in the sex-stratified analysis), with the exception of several associations for bisphenols and DINCH metabolites that were negative. Biomarkers associated with most DMRs were parabens, DEHP, and DiNP metabolite concentrations. Some DMRs encompassed imprinted genes including APC (associated with parabens and DiNP metabolites), GNAS (bisphenols), ZIM2;PEG3;MIMT1 (parabens, monoethyl phthalate), and SGCE;PEG10 (parabens, DINCH metabolites). Terms related to adiposity, lipid and glucose metabolism, and cardiovascular function were among the enriched phenotypes associated with differentially methylated CpGs. The candidate analysis identified one CpG mapping to imprinted LGALS8 gene, negatively associated with ethylparaben. CONCLUSIONS: By combining improved exposure assessment and extensive placental epigenome coverage, we identified several novel genes associated with the exposure, possibly in a sex-specific manner.

Humans↗

PubMed2001

Interaction of Galpha 12 and Galpha 13 with the cytoplasmic domain of cadherin provides a mechanism for beta -catenin release.

The G12 subfamily of heterotrimeric G proteins, comprised of the alpha-subunits Galpha12 and Galpha13, has been implicated as a signaling component in cellular processes ranging from cytoskeletal changes to cell growth and oncogenesis. In an attempt to elucidate specific roles of this subfamily in cell regulation, we sought to identify molecular targets of Galpha12. Here we show a specific interaction between the G12 subfamily and the cytoplasmic tails of several members of the cadherin family of cell-surface adhesion proteins. Galpha12 or Galpha13 binding causes dissociation of the transcriptional activator beta-catenin from cadherins. Furthermore, in cells lacking the adenomatous polyposis coli protein required for beta-catenin degradation, expression of mutationally activated Galpha12 or Galpha13 causes an increase in beta-catenin-mediated transcriptional activation. These findings provide a potential molecular mechanism for the previously reported cellular transforming ability of the G12 subfamily and reveal a link between heterotrimeric G proteins and cellular processes controlling growth and differentiation.

Adenocarcinoma↗

PubMed2026

Risk factors for lung metastasis in children and adolescent patients with papillary thyroid cancer: A retrospective cohort study.

BACKGROUND: Pediatric papillary thyroid cancer (pPTC) exhibits a higher incidence of lung metastasis (LM) compared to its adult counterpart. This study supplements the gap in pediatric management guidelines by exploring factors associated with LM in pPTC and characterizing relevant genetic alterations. METHODS: We retrospectively analyzed pPTC patients under 20 years who underwent initial surgery at our center between December 2008 and December 2022. Clinicopathological features, treatment approaches, outcomes, and target-gene sequencing were reviewed to identify risk factors and genetic variations. RESULTS: Among 114 pPTC cases, 17 developed LM. Risk factors associated with LM included younger age, male gender, larger tumor size, multifocality, extrathyroidal extension, lymphatic invasion, and the number of metastatic lymph nodes (NMLNs), with NMLNs > 14 identified as an independent predictor (OR = 18.20, p = 0.037). Treatment responses with radioiodine related to postoperative stimulated thyroglobulin (sTg) levels (p = 0.003). Genomic analysis identified 1007 somatic mutations, including in the BRAF, APC, RET, and ATM genes, with RET-NCOA4 fusions observed in the LM subgroup. CONCLUSION: LM is common in pPTC, and NMLNs > 14 is a critical risk indicator. The genetic profile, particularly RET mutations, highlights potential therapeutic targets. Further large-scale studies are needed to validate these findings.

Humans↗

PubMed2025

The Genetic Basis of Elongated Tails in Birds: Evidence for Sexual Selection as a Driver of Convergent Evolution.

Elongated tails are exaggerated ornaments observed in various bird species, and their functional and evolutionary dynamics have attracted considerable attention. Empirical studies consistently show that sexual selection is a major drive of tail elongation. However, the genetic basis of this trait remains poorly understood. To address this gap, we performed comparative genomic analyses of 23 bird species, including 7 with extremely long tails and 16 with relative short tails. Genes related to feather development exhibited amino acid convergence replacement (e.g., APC) or displayed faster evolutionary rates (e.g., LEF1, WISP3) in the long-tailed species. Importantly, we identified convergence replacements of amino acids and rapid evolution in genes related to reproductive functions (e.g., PAQR7) and immunity (e.g., ADA), suggesting that elongated tails may serve as honest signals of genetic quality. In conclusion, this study provides genomic evidence supporting the role of sexual selection in the evolution of elongated tails, revealing an intricate interplay between sexually selected traits, fitness, and immune competence.

Animals↗

PubMed2022

Insights on the pathogenesis of type 2 diabetes as revealed by signature genomic classifiers in an African American population in the Washington, DC area.

AIMS: African Americans (AA) in the United States have a high risk of type 2 diabetes mellitus (T2DM) and suffer from disparities in the prevalence, mortality, and comorbidities of the disease compared to other Americans. The present study aimed to shed light on the molecular mechanisms of disease pathogenesis of T2DM among AA in the Washington, DC region. METHODS: We performed TaqMan Low Density Arrays (TLDA) on 24 genes of interest that belong to three categories: metabolic disease and disorders, cancer-related genes, and neurobehavioural disorders genes. The 18 genes, viz. ARNT, CYP2D6, IL6, INSR, RRAD, SLC2A2 (metabolic disease and disorders), APC, BCL2, CSNK1D, MYC, SOD2, TP53 (Cancer-related), APBA1, APBB2, APOC1, APOE, GSK3B, and NAE1 (neurobehavioural disorders), were differentially expressed in T2DM participants compared to controls. RESULTS: Our results suggest that factors including gender, smoking habits, and the severity or lack of control of T2DM (as indicated by HbA1c levels) were significantly associated with differential gene expression. APBA1 was significantly (p-value <0.05) downregulated in all diabetes participants. Upregulation of APOE and CYP2D6 genes and downregulation of the INSR gene were observed in the majority of diabetes patients. CONCLUSIONS: Tobacco smoking and gender were significantly associated with case-control differences in expression of the APBA1 and APOE genes (connected with Alzheimer's disease) and the INSR and CYP2D6 (associated with metabolic disorders). The results highlight the need for more effective management of T2DM and for tobacco smoking cessation interventions in this community, and further research on the associations of T2DM with other disease processes, including cancer and neurobehavioral pathways.

Humans↗

PubMed2025

Molecular alterations in TP53, WNT, PI3K, TGF-Beta and RTK/RAS pathways in gastric cancer among ethnically heterogeneous cohorts.

BACKGROUND/OBJECTIVES: Gastric cancer (GC) remains a leading cause of cancer-related mortality worldwide, with significant racial and ethnic disparities in incidence, molecular characteristics, and patient outcomes. However, genomic studies focusing on Hispanic/Latino (H/L) populations remain scarce, limiting our understanding of ethnicity-specific molecular alterations. This study aims to characterize pathway-specific mutations in TP53, WNT, PI3K, TGF-Beta and RTK/RAS signaling pathways in GC and compare mutation frequencies between H/L and Non-Hispanic White (NHW) patients. Additionally, we evaluate the impact of these alterations on overall survival using publicly available datasets. METHODS: We conducted a bioinformatics analysis using publicly available GC datasets to assess mutation frequencies in TP53, WNT, PI3K, TGF-Beta and RTK/RAS pathway genes. A total of 800 patients were included in the analysis, comprising 83 H/L patients and 717 NHW patients. Patients were stratified by ethnicity (H/L vs. NHW) to evaluate differences in mutation prevalence. Chi-squared tests were performed to compare mutation rates between groups, and Kaplan-Meier survival analysis was used to assess overall survival differences based on pathway alterations among both H/L and NHW patients. RESULTS: Significant differences were observed in the TP53 pathway and related genes when comparing GC in H/L patients to NHW patients. TP53 mutations were less prevalent in H/L patients (9.6% vs. 19%, p = 0.03). Borderline significant differences were noted in the WNT pathway when comparing GC in H/L patients to NHW GC patients, with WNT alterations more frequent in H/L GC (8.4% vs. 4%, p = 0.08), and APC mutations significantly higher (3.6% vs. 0.8%, p = 0.05). Although alterations in PI3K, TGF-Beta and RTK/RAS pathways were not statistically significant, borderline significance was observed in genes related to these pathways, including EGFR (p = 0.07), FGFR1 (p = 0.05), FGFR2 (p = 0.05), and PTPN11 (p = 0.05) in the PI3K pathway, and SMAD4 (p = 0.08) in the TGF-Beta pathway. Survival analysis revealed no significant differences among H/L patients. However, NHW patients with TP53 and PI3K pathway alterations exhibited significant differences in overall survival, while those without TGF-Beta pathway alterations also showed a significant survival impact. In contrast, WNT pathway alterations were not associated with significant survival differences. These findings suggest that TP53, PI3K, and TGF-Beta pathway disruptions may have distinct prognostic implications in NHW GC patients. CONCLUSIONS: This study provides one of the first ethnicity-focused analyses of TP53, WNT, PI3K, TGF-Beta and RTK/RAS pathway alterations in GC, revealing significant racial/ethnic differences in pathway dysregulation. The findings suggest that TP53 and WNT alterations may play a critical role in GC among H/L patients, while PI3K and TGF-Beta alterations may have greater prognostic significance in NHW patients. These insights emphasize the need for precision medicine approaches that account for genetic heterogeneity and ethnicity-specific pathway alterations to improve cancer care and outcomes for underrepresented populations.

PI3K pathway↗

PubMed2026

The Landscape of Genomic and Socioeconomic Variables in Patients with Colorectal Cancer Based on Genetic Ancestry.

BACKGROUND: Despite differences in tumor alterations across genetic ancestries, investigations of the colorectal cancer molecular landscape have used self-reported ethnicity instead of genetic ancestry. METHODS: We used tumor and matched normal whole-exome sequencing data from 16,388 patients with stage I to IV colorectal cancer to investigate colorectal cancer's germline and somatic molecular landscape and the potential influence of socioeconomic factors (Distressed Communities Index, DCI) across diverse genetic ancestries. Genetic ancestry determined via supervised local ancestry inference included African (AFR, N = 1,697), Native American (AMR, N = 1,291), East Asian (EAS, N = 2,247), European (EUR, N = 9,726), Levantine Middle Eastern (LME, N = 1,192), and South Asian (SAS, N = 184). RESULTS: Microsatellite instability (MSI) was the most common form of hypermutation (80.8%), higher in the EUR genetic ancestry than in the AFR, AMR, and EAS genetic ancestry. Among germline findings, positive results were most common in high-penetrance genes associated with Lynch syndrome. Enrichment patterns included MLH1 (SAS) and PMS2 (AFR). There were significant differences in the frequency of driver mutations in APC, BRAF, KRAS, TP53, and PIK3CA between the EUR and other ancestry groups in both MSI and microsatellite stable tumors. Mutational signatures suggested enrichment of reactive oxygen species and POLE in AFR, colibactin in EAS, and aflatoxin and NTHL1 in SAS. DCI scores differed by ancestry (higher distress in AFR/AMR than in EUR), but driver mutation frequencies did not vary across DCI quintiles. CONCLUSIONS: Genetic ancestry shapes hereditary risk, tumor biology, and environmental exposures. IMPACT: These findings suggest that incorporating ancestry into screening, trials, and precision oncology may improve equity, though outcome-linked prospective studies and implementation research are warranted.

Aged↗

PubMed2025

Development of a new flippase-dependent mouse model for red fluorescence-based isolation of KRASG12D oncogene-expressing tumor cells.

Proto-oncogene KRAS, GTPase (KRAS) is one of the most intensively studied oncogenes in cancer research. Although several mouse models allow for regulated expression of mutant KRAS, selective isolation and analysis of transforming or tumor cells that produce the KRAS oncogene remains a challenge. In our study, we present a knock-in model of oncogenic variant KRASG12D that enables the "activation" of KRASG12D expression together with production of red fluorescent protein tdTomato. Both proteins are expressed from the endogenous Kras locus after recombination of a transcriptional stop box in the genomic DNA by the enzyme flippase (Flp). We have demonstrated the functionality of the allele termed RedRas (abbreviated KrasRR) under in vitro conditions with mouse embryonic fibroblasts and organoids and in vivo in the lung and colon epithelium. After recombination with adenoviral vectors carrying the Flp gene, the KrasRR allele itself triggers formation of lung adenomas. In the colon epithelium, it causes the progression of adenomas that are triggered by the loss of tumor suppressor adenomatous polyposis coli (APC). Importantly, cells in which recombination has successfully occurred can be visualized and isolated using the fluorescence emitted by tdTomato. Furthermore, we show that KRASG12D production enables intestinal organoid growth independent of epidermal growth factor (EGF) signaling and that the KRASG12D function is effectively suppressed by specific inhibitor MRTX1133.

Animals↗

PubMed2026

Herbicolin A, an antifungal lipopeptide produced by Pantoea agglomerans APC 4211 is a promising biocontrol agent against food spoilage fungi.

Fungal contamination of food with yeast and molds is associated with major economic losses due to spoilage and also poses health risks in the form of mycotoxin production. The strain Pantoea agglomerans APC 4211 isolated from leaves of Ilex aquifolium (holly tree) has broad spectrum antifungal activity against a variety of food spoilage fungi. Genomic analysis of the strain confirmed the presence of biosynthetic gene clusters potentially encoding for the enzymatic machinery required for the production of the antifungal lipopeptide herbicolin A. Matrix-assisted laser desorption ionization-time of flight mass spectrometry (MALDI-TOF MS) analysis of the cell-free supernatant (CFS) confirmed the presence of molecular masses corresponding to herbicolin A (1300.8 Da), and herbicolin B (1138 Da). Purified herbicolin A has desirable properties for biotechnological applications, including potent antifungal activity against a range of spoilage fungi, thermal stability and resistance to proteases. The lipopeptide has low cytotoxicity against epithelial cell lines and has minimum inhibitory concentrations (MICs) lower than those of some commercial antifungal drugs (0.2-2.5 mg/L). In a model dairy system (10% skim milk), herbicolin A demonstrated excellent solubility and stability, effectively eliminating Aspergillus niger and Penicillium notatum at a concentration of 5 mg/L. Overall, the study determines herbicolin's A spectrum against food spoilage organisms and examines potential applications in food. In conclusion, herbicolin A is a potent, naturally occurring antifungal agent with the potential to be applied as a biopreservative in food systems, providing a safe, clean-label, and efficient compound for synthetic preservatives replacement.

Pantoea↗

PubMed2026

Origin and evolution of colorectal mixed neuroendocrine-non-neuroendocrine neoplasms (MiNEN).

Colorectal neuroendocrine carcinoma (NEC) is a rare and aggressive cancer and in a subset of patients associated with an adenocarcinoma (AC) component. When both components exceed 30% of the tumour, it is classified as mixed neuroendocrine-non-neuroendocrine neoplasm (MiNEN), although there is an ongoing debate about whether any presence of two distinct components should be sufficient for a MiNEN diagnosis. This study aimed to investigate the origin and subsequent genetic changes of these two components. Ten colorectal cases suitable for sampling of an AC and a poorly differentiated NEC component were identified from the NORDIC NEC 2 study and sequenced across a 360-cancer gene panel. Mock phylogenetic trees were constructed from the molecular profiles of each sample within a patient. All ten cases revealed a common trunk of shared somatic mutations, including well-known colorectal cancer driver mutations such as BRAF, KRAS, APC, and TP53. In all cases, a single branching point separated the AC and NEC components. Private AC and NEC mutations generally had low variant allele frequencies, indicating that most AC and NEC cells were genetically similar. NEC, when compared with AC samples, demonstrated a higher frequency of private mutations (P = 0.009), indicating a higher mutation rate and greater ploidy (P = 0.012), suggesting an association between genomic duplication and AC-to-NEC transition. Shared mutations indicate a common clonal origin, underscoring the role of established colorectal driver mutations in the early development of these tumours, while the mechanisms underlying NEC differentiation remain poorly understood and may involve non-genetic factors.

Humans↗

PubMed2026

Distinct mutational landscapes for germline and somatic cancer variants in forty tumor suppressor genes.

Germline and somatic cancer variants in tumor suppressor genes (TSGs) share loss-of-function mechanisms, but studies of a few genes (DICER1 and CEBPA) have demonstrated differences in variant consequence and location. To systematically assess whether TSGs display distinct mutational patterns, we leveraged large public genetic databases and compared 32,941 high-quality pathogenic/likely pathogenic (P/LP) germline variants in ClinVar, with 12,907 oncogenic/likely oncogenic (O/LO) somatic tumor variants from cBioPortal across 40 TSGs. Only 3,863 (9.2%) variants were shared. Eighteen TSGs showed significantly different distributions of variant occurrences by molecular consequence, replicated with non-overlapping somatic data from the COSMIC database (chi-squared tests, false discovery rate = 5%). DICER1, TP53, and SMAD4 displayed excess somatic missense events, while nine TSGs (e.g., RB1 and APC) contained excess somatic stop-gain events throughout the coding sequence. Analysis by tumor type revealed excess stop-gain events in tissues exposed to environmental mutagens with corresponding mutation signatures. For several TSGs (WT1), germline variants predispose to tumors (Wilms' tumor) distinct from the majority source of somatic data (myeloid leukemia). Germline and somatic events are also distributed unevenly across cDNA locations, with 103 regions of preferential clustering in 39 TSGs (78 somatic and 25 germline). Twenty somatic clusters contained recurring frameshifts in homopolymer runs, many in tumors with microsatellite instability. Germline clusters contain more germline-exclusive variants, some driving non-cancer phenotypes reflecting genetic pleiotropy. Altogether, germline and somatic variants of TSGs represent unique sets with substantially different patterns shaped by selection pressures from gene-specific and somatic mutational mechanisms. Characterizing these distinctions enables more accurate clinical interpretation of TSG variants.

Humans↗

PubMed1979

Deletion mutants from R plasmids with increased copy number.

Rms 201-12 and Rms 201-46 are R mutants with increased copy number, and are derived from a conjugative plasmid Rms 201 that encodes resistance to five drugs, ampicillin (Apc), tetracycline (Tc), chloramphenicol (Cm), streptomycin (Sm), and sulfonamides (Sa). The mutants expressed increased levels of resistance to Apc, Sm, and Cm, and a decreased level of resistance to Tc than those of the parent Rms 201 plasmid. When the Rms 201-12+ or Rms 201-46+ cells were inoculated onto plates containing a high concentration of Tc, colonies developed on the plate at a frequency of 10-3 to 10-4 after overnight incubation. The cells grown on the Tc plate carried a tet (Tc gene)-deleted R mutant besides tet-possessing Rms 201-12 or Rms 201-46, and we isolated the tet-deleted R mutant by purifying the R+ cells on drug-free plates. On the other hand, various deletion mutants possessing tet were isolated by prolonged culture of the cells. We have presented a circular gene order of Rms 201 by comparing the genetic markers of all deletion mutants derived from Rms 201, Rms 201-46, and Rms 201-12. The gene(s) regulating the copy number was closely linked to the rep gene. The gene(s) specifying entry exclusion was jointly lost with the tra region.

Anti-Bacterial Agents↗

PubMed2003

Characterization and development of T-Cell immune responses in B-cell-deficient (Igh-6(-/-)) mice with Salmonella enterica serovar Typhimurium infection.

Infection of mice with Salmonella enterica serovar Typhimurium induces strong Th1 T-cell responses that are central to the control of the infection. In the present study, we examined the role of B cells in the development of Th1 T-cell responses to Salmonella by using gene-targeted B-cell-deficient mice (Igh-6(-/-) mice). The development of Th1 T-cell responses in Igh-6(-/-) mice was impaired in the early stage of a primary infection. This impairment persisted throughout the course of the disease. The ability of T cells to produce the Th1 cytokine gamma interferon and the frequency at which they did so were lower in Igh-6(-/-) mice than in control mice. We also observed a transient switch toward Th2 cytokine production in Igh-6(-/-) mice. Thus, B cells are important for the induction of protective Th1 T-cell responses in the early phase of a Salmonella infection. Activated B cells express high levels of major histocompatibility complex and costimulatory molecules and are nearly as effective as dendritic cells in their antigen-presenting cell (APC) activity. However, their importance as APCs in infection and their role in initiating and/or maintaining T-cell responses are unknown. Here, we show that B cells upregulate costimulatory molecules upon in vitro stimulation with S. enterica serovar Typhimurium and that they can present Salmonella antigens to Salmonella-specific CD4(+) T cells. Our results show that B cells are important for the development of T-cell responses in the early stage of a Salmonella infection and that this property may be due to their ability to present antigens to T cells.

Animals↗