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PubMed2026

Detection of a Rare Intra-ALK Inversion and ALK Rearrangement in a Lung Adenocarcinoma Patient by FoundationOne Liquid CDx and Successful Treatment with Alectinib: Case Report.

A 50-year-old woman with stage IVB lung adenocarcinoma tested negative for driver mutations using the Oncomine Dx Target Test Multi-CDx system (Thermo Fisher Scientific, Waltham, MA). After undergoing chemotherapy and immunotherapy, FoundationOne Liquid CDx (Foundation Medicine, Inc., Cambridge, MA) identified a rare EML4-ALK gene rearrangement. Treatment with alectinib led to rapid clinical improvement and sustained disease control for more than 7 months. This case highlights the value of next-generation sequencing-based profiling in detecting rare actionable alterations missed by standard tests. We also include a discussion on why the EML4-AKL fusion was not detected in the usual test.

ALK-EML4 rearrangement↗

PubMed2026

Gastrointestinal involvement in Ehlers-Danlos syndrome classical-like type 2 associated with a novel AEBP1 splice-site variant.

Ehlers-Danlos syndrome classical-like type 2 (clEDS2) is a rare autosomal recessive connective tissue disorder caused by biallelic loss-of-function variants in the gene encoding adipocyte enhancer-binding protein 1 (AEBP1). While cutaneous and skeletal manifestations are commonly observed, gastrointestinal complications, including bowel rupture, have been reported only rarely, and their histopathological basis remains poorly characterized. Here, we report findings of molecular investigations, gastrointestinal histopathological evaluation, and long-term clinical follow-up in the 16th reported patient with AEBP1-related clEDS2, complicated by spontaneous bowel perforation. A homozygous AEBP1 splice-site variant (NM_001129.5:c.1401-2 A > G) was identified by a custom next-generation sequencing-based panel analysis for hereditary connective tissue disorders. Transcript-level analysis by reverse transcription-polymerase chain reaction and Sanger sequencing demonstrated complete skipping of exon 12, resulting in a frameshift and predicted loss of function. Clinically, the patient experienced postoperative perforation in the sigmoid colon shortly after rectal cancer surgery, followed nearly 20 years later by spontaneous small intestinal perforation. Histopathological examination of the affected colonic tissue demonstrated mildly widened intermuscular spaces without other overt structural abnormalities. Notably, repeated upper and lower gastrointestinal endoscopic procedures were performed during long-term oncological surveillance without procedure-related bowel perforation. This observation could offer an opportunity to learn about gastrointestinal involvement in AEBP1-related clEDS2 and suggests that its gastrointestinal manifestations may differ in clinical context from those typically associated with vascular Ehlers-Danlos syndrome, warranting further investigation as additional cases are accumulated.

Humans↗

PubMed2026

Genomic profiling as an option for ovarian cancer diagnostics.

INTRODUCTION: Ovarian cancer (OC) is a highly heterogeneous and lethal gynecological malignancy. Precision oncology has shifted the management paradigm to comprehensive molecular profiling. Genomic-based diagnostics are now a clinical necessity for accurate prognostic stratification and the rational selection of targeted therapeutics, such as PARP and immune checkpoint inhibitors. AREAS COVERED: This review evaluates current literature regarding the distinct genomic landscapes defining OC histotypes to underlined the role of molecular profiling in the diagnostic field of OC. We discuss the practical implementation, technical aspect, and clinical validity of the main molecular diagnostic platforms, focusing on tissue-based Comprehensive Genomic Profiling (CGP) and Homologous Recombination Deficiency (HRD). Furthermore, we explore emerging translational data on liquid biopsy (LBx) applications. EXPERT OPINION: While current tissue-based methodologies provide critical baseline data, the OC diagnostic paradigm must pivot from static testing to proactive and longitudinal tracking. Integrating advanced LBx approaches enables a real-time monitoring of dynamic parameters as minimal residual disease (MRD) and acquired resistance. Integrating these dynamic blood-based assays with multi-omic profiling and artificial intelligence (AI)-driven tools allows a full understanding of the complex tumor behavior.

Humans↗

PubMed2025

MRDagent: iterative and adaptive parameter optimization for stable ctDNA-based MRD detection in heterogeneous samples.

MOTIVATION: Minimal residual disease (MRD) as critical biomarker for cancer prognosis and management plays a crucial role in improving patient outcomes. However, detecting MRD via next-generation sequencing-based circulating tumor DNA variant calling remains unstable due to the extremely low variant allele frequency and significant inter- and intra-sample heterogeneity. Although parameter optimization can theoretically enhance the detection performance of variants, achieving stable MRD detection remains challenging due to three key factors: (i) the necessity for individualized parameter tuning across numerous heterogeneous genomic intervals within each sample, (ii) the tightly interdependent parameter requirements across different stages of variant detection workflows, and (iii) the limitations of current automated parameter optimization methods. RESULTS: In this study, we propose MRDagent, a novel variant detection tool designed specifically for MRD detection. MRDagent incorporates an iterative and self-adaptive optimization framework capable of handling unknown objectives, varying constraints, and highly coupled parameters across stages. A key innovation of MRDagent is the integration of a convolutional neural network-based meta-model, trained on historical data to enable rapid parameter prediction. This significantly enhances computational efficiency and generalization performance. Extensive evaluations on simulated and real-world datasets demonstrate MRDagent's superior and stable performance, providing an efficient, reliable solution for MRD detection in clinical and high-throughput research applications. AVAILABILITY AND IMPLEMENTATION: MRDagent is freely available at https://github.com/aAT0047/MRDagent.git. The corresponding dataset and software archive are available at Zenodo: https://doi.org/10.5281/zenodo.15458496.

Circulating Tumor DNA↗

PubMed2025

BISON: bi-clustering of spatial omics data with feature selection.

MOTIVATION: The advent of next-generation sequencing-based spatially resolved transcriptomics (SRT) techniques has reshaped genomic studies by enabling high-throughput gene expression profiling while preserving spatial and morphological context. Understanding gene functions and interactions in different spatial domains is crucial, as it can enhance our comprehension of biological mechanisms, such as cancer-immune interactions and cell differentiation in various regions. It is necessary to cluster tissue regions into distinct spatial domains and identify discriminating genes (DGs) that elucidate the clustering result, referred to as spatial domain-specific DGs. Existing methods for identifying these genes typically rely on a two-stage approach, which can lead to the phenomenon known as double-dipping. RESULTS: To address the challenge, we propose a unified Bayesian latent block model that simultaneously detects a list of DGs contributing to spatial domain identification while clustering these DGs and spatial locations. The efficacy of our proposed method is validated through a series of simulation experiments, and its capability to identify DGs is demonstrated through applications to benchmark SRT datasets. AVAILABILITY AND IMPLEMENTATION: The R/C++ implementation of BISON is available at https://github.com/new-zbc/BISON.

Software↗

PubMed2024

Mutant KRAS in Circulating Tumor DNA as a Biomarker in Localized Pancreatic Cancer Patients Treated With Neoadjuvant Chemotherapy.

OBJECTIVE: The primary objective was to determine the prognostic significance of circulating tumor DNA (ctDNA) in patients receiving neoadjuvant chemotherapy (NAC) for localized pancreatic ductal adenocarcinoma (PDAC) using digital droplet polymerase chain reaction (ddPCR). BACKGROUND: Increasingly, ctDNA is being used for clinical decision-making in a variety of solid malignancies. However, the detection and prognostic value of KRAS ctDNA as assessed by ddPCR during NAC for PDAC has yet to be characterized. METHODS: Patients with localized PDAC eligible to receive NAC were prospectively enrolled. Peripheral blood samples were obtained at diagnosis, after NAC, and after resection and analyzed for ctDNA using ddPCR. Log-rank tests and Cox proportional hazards model were used to assess for associations with OS. RESULTS: Eighty-four patients were included in the analysis. Mutant KRAS ctDNA was detected in 49.3% of patients at diagnosis, 69.6% of patients after NAC, and 69.7% of patients after resection, respectively. There were 15 (17.9%) patients who cleared mutational ctDNA over the course of treatment. Clearance of ctDNA during NAC was associated with improved overall survival (OS) (18.4 mo. vs NR, P <0.05). Detection of mutant KRAS G12V after NAC and resection was associated with shorter OS (18.0 mo vs NR, P <0.031). Detection of the KRAS G12V mutation after resection was associated with reduced OS (aHR 36.75, 95% CI: 2.93-461.38). CONCLUSIONS: Throughout treatment, KRAS ctDNA is detectable by ddPCR in patients with localized PDAC treated with NAC. Detection of mutant KRAS G12V after resection was associated with reduced OS.

Humans↗

PubMed2026

Prenatal Alcohol Exposure Produces Selective Changes in Neuroimmune Gene Expression Across Brain Regions of Adult Mice.

BACKGROUND: An overwhelming body of evidence suggests neuroimmune dysfunction as a key underlying mechanism of fetal alcohol spectrum disorder (FASD)-associated adverse central nervous system (CNS) outcomes. While few studies have highlighted the lingering effects of prenatal alcohol exposure (PAE) on producing specific immune factors, others suggest a primed neuroimmune state in adulthood, in which a proinflammatory bias is unmasked following subsequent immune activation in later life. However, the PAE-induced neuroimmune landscape in adulthood remains poorly defined. We hypothesized that PAE induces long-term changes in gene expression linked to neuroimmune function that may be brain region-specific. METHODS: Using long-read next-generation RNA sequencing of brain tissues from a previously established model of a moderate PAE in mice, we compared across six regions: medial prefrontal cortex (mPFC), anterior cingulate cortex (ACC), hypothalamus, hippocampus, midbrain, and medulla. A comprehensive bioinformatics analysis investigated PAE-induced changes, dysregulated gene pathways, and transcriptional regulators with a focus on neuroimmune function. RESULTS: Our data identified at least 60 differentially expressed genes per brain region, many of which were associated with neuroimmune function. Upregulation of multiple pro-inflammatory factors and pathways was observed, suggesting ongoing baseline neuroimmune activation, potentially involving PXR, TNF, TLR4, the complement pathway, and various cytokine and chemokine signaling. A comparative analysis identified multiple upstream transcriptional regulators across multiple brain regions, including MECP2, TCF7L2, and IL-4. Importantly, this unbiased analysis revealed heterogeneity across brain regions in the activation of canonical immune pathways and highlighted previously unprecedented roles of pathways such as PXR, matrix metalloproteases, and cytokine signaling (e.g., IL-15, IL-27, IL-17) in PAE. CONCLUSIONS: PAE creates a unique inflammatory signature in the adult brain, even in the absence of secondary injury, with novel patterns of region-specific changes in genes implicated in glial-immune function. These data identify potential immune targets to elucidate the mechanisms underlying behavioral dysfunction and provide a framework for future therapeutic interventions.

Animals↗

PubMed2025

Deletion of the HLA-B Gene in One of the Inherited Haplotypes in a Northern European Family.

Targeted next generation sequencing-based HLA typing of a 17-year-old female transplant patient showed homozygosity for the HLA-B allele. The segregation analysis of HLA haplotypes of family members only allowed the conclusion that the B-allele was deleted in the haplotype inherited from the father and accordingly paternal grandfather, resulting in false homozygous genotyping. The subsequent whole-genome sequencing of the patient and her father confirmed an approximately 85 kb deletion at 6p21.33 from the 5' end of the HLA-B to the 3' end of the HLA-C gene extending telomeric to HLA-C.

Adolescent↗

PubMed2024

Clinicogenomic predictors of survival and intracranial progression after stereotactic radiosurgery for colorectal cancer brain metastases.

OBJECTIVE: Brain metastases (BM) from colorectal cancer (CRC) are associated with dismal prognosis. When BM-directed therapy is considered, better methods are needed to identify patients at risk of poor oncological outcomes in order to optimize patient selection for closer surveillance or escalated therapy. The authors sought to identify clinicogenomic predictors of survival and intracranial disease progression after CRC BM have been treated with stereotactic radiosurgery (SRS). METHODS: Patients with newly diagnosed CRC BM treated with SRS between 2009 and 2022 who had next-generation genomic sequencing data available were included. Frameless SRS was delivered in 1-5 fractions, alone or after neurosurgical resection. Outcomes included overall survival (OS) and intracranial progression (IP), evaluated per patient treated with SRS, and local progression (LP), evaluated per BM. Associations between baseline clinicogenomic features and outcomes were evaluated with Cox regression and competing risk regression, with death as a competing risk. RESULTS: This analysis included 123 patients with 299 BM. At BM diagnosis, 111 patients (90%) had progressive extracranial disease, and 79 patients (64%) had ≥ 3 sites of extracranial metastasis. The median (IQR) number of BM was 2 (1-3) per patient. The median (IQR) biologically effective dose (BED) was 51.3 (51.3-65.1) Gy, corresponding to a prescription of 27 Gy in 3 fractions. OS, IP, and LP estimates at 1 year after SRS were 36%, 55%, and 12%, respectively. OS was independently associated with progressive extracranial disease (HR 4.26, 95% CI 1.63-11.2, p = 0.003) and ≥ 3 extracranial metastatic sites (HR 1.84, 95% CI 1.12-3.01, p = 0.02). LP was less likely when BM received BED ≥ 51.3 Gy (HR 0.24, 95% CI 0.07-0.78, p = 0.02), independent of BM diameter (HR 1.21/cm, 95% CI 0.8-1.84, p = 0.4). IP was independently associated with genomic alterations; TP53 driver alterations were associated with higher risk of IP (HR 2.71, 95% CI 1.26-5.79, p = 0.01), whereas MYC pathway alterations were associated with lower risk (HR 0.15, 95% CI 0.03-0.68, p = 0.01). CONCLUSIONS: The authors identified clinicogenomic features associated with adverse outcomes after SRS for CRC BM. Progressive and extensive extracranial metastases predicted worse OS. Insufficient SRS doses predicted greater risk of LP. Wild-type TP53 and alterations in the MYC pathway were independently associated with lower risk of IP. Patients at high risk of IP may be considered for closer surveillance or escalated therapy.

Humans↗

PubMed2026

HLA-DRB1*14 is associated with lower odds of symptomatic SARS-CoV-2 infection in Mexican individuals.

Mexico has been one of the countries most affected by the COVID-19 pandemic. Several factors can influence the susceptibility to SARS-CoV-2 infection, particularly highly polymorphic genes in the HLA system. Therefore, this pilot study analyzed the association between HLA-DRB1 genetic polymorphisms and the susceptibility and/or resistance to symptomatic SARS-CoV-2 infection in a population from the Metropolitan Area of the Valley of Mexico. Individuals with a confirmed SARS-CoV-2 infection were recruited (n = 90), as well as a seronegative control group without reported symptomatic infection (n = 60). The HLA-DRB1 locus was typed using NGS. We found a significant increase in the frequency of the HLA-DRB1*14 allele in the control group (OR = 0.37; 95% CI: 0.18-0.72; p = 0.003; pc = 0.03). These data suggest that HLA-DRB1*14, a prevalent allele in the Mexican population, is associated with a reduced risk of symptomatic SARS-CoV-2 infection in this cohort.

Humans↗

PubMed2026

Comprehensive Genomic Profiling Reveals the Mutational Spectrum and Clinical Significance of BRCA1/2 and Other Cancer-Susceptibility Genes in Breast Cancer Patients from Southern Tunisia.

BACKGROUND/OBJECTIVES: This study aims to investigate the mutational spectrum of BRCA1 and BRCA2 genes in a cohort of breast cancer (BC) patients from southern Tunisia, and to evaluate their clinical and prognostic significance. Additionally, this study explores the contribution of other cancer predisposition genes and the prevalence of variants of uncertain significance (VUS). RESULTS: Among the 165 patients included, pathogenic or likely pathogenic variants (P/LPVs) in BRCA1/BRCA2 were identified in 19 cases (11.51%), including 8 in BRCA1 and 11 in BRCA2. The presence of BRCA P/LPVs associated with young patients (p = 0.006) and those with TNBC (p = 0.036). Beyond BRCA1/2, PV/LPVs were detected in other cancer-related genes, including TP53 (n = 3), CHEK2, RAD50 (n = 2 cases each), and MUTYH, BARD1, and BRIP1 (one case each). Furthermore, 56 VUS were identified; among them, 7 were prioritized based on in silico predictive analyses, suggesting a potential deleterious effect. However, these VUS should not be used for clinical decision-making without additional evidence from functional and familial segregation studies. CONCLUSIONS: Our findings provide novel insights into the genetic landscape of breast cancer in southern Tunisia, highlighting the clinical relevance of BRCA1/2 mutations and the contribution of other susceptibility genes. These results support the personalized management of breast cancer patients and the implementation of expanded multigene panel testing in routine clinical practice to improve genetic counseling.

BRCA1↗

PubMed2025

Analysis of genomic traits of oral and laryngeal cancer: A comparative study.

Oral and laryngeal cancers exhibit overlapping clinical features but distinct genomic profiles. In a study of 60 Head and neck squamous cell carcinomas(HNSCC) cases (30 OSCC, 30 LSCC), NGS revealed TP53 mutations in 70% of oral squamous cell carcinoma (OSCC) and 83% of laryngeal squamous cell carcinoma (LSCC). CDKN2A alterations were more common in OSCC (40%) than LSCC (20%), while PIK3CA mutations were higher in LSCC (30%). NOTCH1 mutations were more frequent in OSCC (27%) than LSCC (10%). Pathway analysis showed disruptions in p53 and PI3K-Akt, with stronger enrichment in LSCC (ES: 3.42). The results suggest site-specific tumor biology influencing therapeutic targets. Molecular profiling is crucial for precision treatment in head and neck cancers.

Oral cancer↗

PubMed2001

Database verification studies of SWISS-PROT and GenBank.

PROBLEM STATEMENT: We have studied the relationships among SWISS-PROT, TrEMBL, and GenBank with two goals. First is to determine whether users can reliably identify those proteins in SWISS-PROT whose functions were determined experimentally, as opposed to proteins whose functions were predicted computationally. If this information was present in reasonable quantities, it would allow researchers to decrease the propagation of incorrect function predictions during sequence annotation, and to assemble training sets for developing the next generation of sequence-analysis algorithms. Second is to assess the consistency between translated GenBank sequences and sequences in SWISS-PROT and TrEMBL. RESULTS: (1) Contrary to claims by the SWISS-PROT authors, we conclude that SWISS-PROT does not identify a significant number of experimentally characterized proteins. (2) SWISS-PROT is more incomplete than we expected in that version 38.0 from July 1999 lacks many proteins from the full genomes of important organisms that were sequenced years earlier. (3) Even if we combine SWISS-PROT and TrEMBL, some sequences from the full genomes are missing from the combined dataset. (4) In many cases, translated GenBank genes do not exactly match the corresponding SWISS-PROT sequences, for reasons that include missing or removed methionines, differing translation start positions, individual amino-acid differences, and inclusion of sequence data from multiple sequencing projects. For example, results show that for Escherichia coli, 80.6% of the proteins in the GenBank entry for the complete genome have identical sequence matches with SWISS-PROT/TrEMBL sequences, 13.4% have exact substring matches, and matches for 4.1% can be found using BLAST search; the remaining 2.0% of E.coli protein sequences (most of which are ORFs) have no clear matches to SWISS-PROT/TrEMBL. Although many of these differences can be explained by the complexity of the DB, and by the curation processes used to create it, the scale of the differences is notable.

Algorithms↗

PubMed2001

New DNA sequencing methods.

The Human Genome Project and other major genomic sequencing projects have pushed the development of sequencing technology. In the past six years alone, instrument throughput has increased 15-fold. New technologies are now on the horizon that could yield massive increases in our capacity for de novo DNA sequencing. This review presents a summary of state-of-the-art technologies for genomic sequencing and describes technologies that may be candidates for the next generation of DNA sequencing instruments.

Biomedical Engineering↗

PubMed2003

Novel strategy for DNA aptamers inhibiting enzymatic activity using algorithm mimicking evolution.

We screened the DNA aptamer inhibiting thrombin with novel method using algorithm mimicking evolution. For screening, we first randomly designed and synthesized ten 15-mer oligonucleotides supposed to form G-quartet structure and then measured the inhibitory activity for thrombin. The aptamers showing the high activities were selected and we shuffled and mutated those sequences in silico to generate 10 new sequences of aptamers for next generation. After repeating 5 cycles, we successfully obtained the same aptamers reported previously showing high inhibitory activity. In addition, we added 8-mer oligonucleotides to the both 5' and 3' ends of the selected 15-mer aptamer and then repeated evolution in silico. After 2 cycles, we were able to obtain the aptamer showing better inhibitory activity than the 15-mer aptamer.

Algorithms↗

PubMed2004

Development and application of a real-time quantitative PCR assay for determining CYP1A transcripts in three genera of salmonids.

The expression of CYP1A (cytochrome P4501A) can be induced by a large array of aromatic and organic compounds in teleost fishes. We developed a real-time quantitative PCR assay useful for measuring beta-naphthoflavone (BNF) induction of liver CYP1A mRNA in four salmonid species. First, to obtain necessary information for the design of a cRNA standard, full-length CYP1A cDNA sequences were determined for two Salvelinus species, lake trout (S. namaycush) and brook trout (S. fontinalis). Each cDNA was found to share the same characteristics with known CYP1A sequences of Atlantic salmon (Salmo salar) and rainbow trout (Oncorhynchus mykiss): a start codon, conserved heme-binding region, putative poly-adenylation signal, stop codon, relatively long 3'-untranslated region (UTR; >1 kb), and a protein length of 523 amino acid residues. The brook trout and lake trout CYP1A cDNA's were 2636 and 2672 base pairs (bp) in length and shared greater than 97% coding region sequence identity with Atlantic salmon and rainbow trout CYP1A's. Next, using the generated sequence information, we developed a CYP1A-specific real-time quantitative PCR assay. Primers and a fluorescent-labeled probe were designed from a 68 bp region that was found to be conserved among salmonid CYP1A genes. The assay was designed to allow for simultaneous comparison of CYP1A expression among each experimental group. Finally, groups (n = 4-8) of hatchery-raised Atlantic salmon, brook trout, lake trout, and rainbow trout were given an intraperitoneal injection of a corn oil control, 25 mg kg(-1) BNF, or 50 mg kg(-1) BNF and sacrificed after 48 h. Liver tissue was collected and CYP1A mRNA levels were estimated. In all species, BNF treated fish showed 1.8-3.0 orders of magnitude higher CYP1A than control fish. The CYP1A induction levels were not different in fish treated with both dosages. Mean base levels of CYP1A expression ranged from 7.24 x 10(6) (rainbow trout) to 1.05 x 10(7) (brook trout) transcripts microg(-1) total RNA. Mean induced levels of CYP1A expression ranged from 1.07 x 10(8) (lake trout) to 1.05 x 10(9) (brook trout) trancripts microg(-1) total RNA.

Amino Acid Sequence↗

PubMed2000

Saturated BLAST: an automated multiple intermediate sequence search used to detect distant homology.

MOTIVATION: Two proteins can have a similar 3-dimensional structure and biological function, but have sequences sufficiently different that traditional protein sequence comparison algorithms do not identify their relationship. The desire to identify such relations has led to the development of more sensitive sequence alignment strategies. One such strategy is the Intermediate Sequence Search (ISS), which connects two proteins through one or more intermediate sequences. In its brute-force implementation, ISS is a strategy that repetitively uses the results of the previous query as new search seeds, making it time-consuming and difficult to analyze. RESULTS: Saturated BLAST is a package that performs ISS in an efficient and automated manner. It was developed using Perl and Perl/Tk and implemented on the LINUX operating system. Starting with a protein sequence, Saturated BLAST runs a BLAST search and identifies representative sequences for the next generation of searches. The procedure is run until convergence or until some predefined criteria are met. Saturated BLAST has a friendly graphic user interface, a built-in BLAST result parser, several multiple alignment tools, clustering algorithms and various filters for the elimination of false positives, thereby providing an easy way to edit, visualize, analyze, monitor and control the search. Besides detecting remote homologies, Saturated BLAST can be used to maintain protein family databases and to search for new genes in genomic databases.

Algorithms↗

PubMed1997

Evolution of the folding ability of proteins through functional selection.

An evolutionary process is simulated with a simple spin-glass-like model of proteins to examine the origin of folding ability. At each generation, sequences are randomly mutated and subjected to a simulation of the folding process based on the model. According to the frequency of local configurations at the active sites, sequences are selected and passed to the next generation. After a few hundred generations, a sequence capable of folding globally into a native conformation emerges. Moreover, the selected sequence has a distinct energy minimum and an anisotropic funnel on the energy surface, which are the imperative features for fast folding of proteins. The proposed model reveals that the functional selection on the local configurations leads a sequence to fold globally into a conformation at a faster rate.

Evolution, Molecular↗