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PubMed2025

Clinicopathologic and Genomic Characterization of SMARCA4-Deficient Carcinoma of the Gallbladder.

As a key subunit of the SWItch/sucrose nonfermentable chromatin-remodeling complex, SMARCA4 plays a critical role as a tumor suppressor in various tumors. However, the clinicopathological and molecular features of SMARCA4-deficient carcinoma of the gallbladder (SMARCA4-dGBC) have not been well explored. In this study, a retrospective cohort of 926 nonsquamous cell gallbladder carcinomas (GBCs) was analyzed on tissue microarrays using immunohistochemistry for SMARCA4, comprising 813 adenocarcinomas, 53 adenosquamous carcinomas, 43 undifferentiated carcinomas, 7 sarcomatoid carcinomas, 6 small cell neuroendocrine carcinomas, and 4 large cell neuroendocrine carcinomas. Twenty-six (2.8%) SMARCA4-dGBCs were identified and further analyzed using immunohistochemistry, whole-exome sequencing, and clinicopathological data. SMARCA4-dGBCs are frequently identified in advanced stages and exhibit diverse patterns of differentiation. The majority were identified as monotonous diffuse sheets, nests, and cords, whereas a subset exhibited gland-forming and rhabdoid morphologies (11.5%). Tumors retained mismatch repair proficiency (100%) but showed variable HER2 expression (11.5% scored as 2+/3+) and limited PD-L1 positivity. Genomic profiling revealed SMARCA4 alterations in 88.5% (23/26) of patients, predominantly deletions (91.3%) and truncating mutations-p.K892∗ and p.R979∗-that disrupt the critical ATPase/helicase domains. Co-occurring TP53 mutations (56.5%) highlighted the presence of synergistic chromatin-remodeling defects. Enrichment of oncogenic signaling pathways, including the RTK-RAS (78.3%), TP53 (60.9%), NOTCH (47.8%), and HIPPO (39.1%) pathways, was observed. Patients with SMARCA4-dGBC exhibited significantly shorter progression-free survival (median, 6 vs 14 months) and overall survival (median, 11 vs 16 months) than those with SMARCA4-retained tumors. Overall, these findings revealed that SMARCA4-dGBC is a rare, distinct entity characterized by the destabilization of the SWItch/sucrose nonfermentable complex, genomic instability, and resistance to conventional therapies. The prevalence of targetable pathways, such as RTK-RAS and cell cycle dysregulation, highlights opportunities for precise therapeutic strategies involving EZH2, CDK4/6, or ATR inhibitors. SMARCA4 immunohistochemistry and molecular profiling are essential for accurate diagnosis, prognostic stratification, and therapeutic innovation of this GBC subtype.

Humans↗
PubMed2026

Challenges of genomic testing for patients and clinicians in Latin America: Foundations of a qualitative multi-country study.

Genomic medicine is expanding across Latin America (LATAM), yet access to essential ancillary services such as genetic counselling remains limited. 'Latin-SEQ' is a study that provides whole exome sequencing (WES) for neuromuscular diseases across 18 countries, aiming to improve diagnostic rates and generate region-specific genetic insights. However, funding constraints exclude genetic counselling and cascade testing, raising concerns about equitable and harm-free care. This paper reports early findings from 'Latin-SEQ Plus,' a mixed-methods study exploring patient and healthcare practitioner (HCP) perspectives on WES and genetic counselling. Data were generated via surveys with patients and HCPs, and participatory workshops with HCPs across six countries. We found that patients strongly valued genetic testing for diagnostic clarity, improved care, and family planning. HCPs acknowledged the diagnostic benefits of WES but highlighted absence of local genetic counselling services, inconsistent pre and post-test practices, and uncertainty in managing incidental findings and variants of uncertain significance (VUS). Psychological impacts related to WES results are not always addressed, underscoring risks of psychological and emotional harm for patients. Access to WES and genetic counselling is limited in LATAM due to financial hardship and the absence of a clear genetic counselling infrastructure. Our findings also reveal a mismatch between patient expectations and HCPs' capacity to deliver comprehensive genomic care. We argue for urgent investment in genetic counselling infrastructure, HCP training, culturally tailored resources, and policy frameworks to support equitable implementation of genomic medicine in LATAM.

Humans↗
PubMed2025

Detection of heterogeneous resistance mechanisms to tyrosine kinase inhibitors from cell-free DNA.

Though there has been substantial progress in the development of anti-human epidermal growth factor receptor 2 (HER2) therapies to treat HER2-positive metastatic breast cancer (MBC) within the past two decades, most patients still experience disease progression and cancer-related death. HER2-directed tyrosine kinase inhibitors can be highly effective therapies for patients with HER2-positive MBC; however, an understanding of resistance mechanisms is needed to better inform treatment approaches. We performed whole-exome sequencing on 111 patients with 73 tumor biopsies and 120 cell-free DNA samples to assess mechanisms of resistance. In 11 of 26 patients with acquired resistance, we identified alterations in previously characterized genes, such as PIK3CA and ERBB2, that could explain treatment resistance. Mutations in growing subclones identified potential mechanisms of resistance in 5 of 26 patients and included alterations in ESR1, FGFR2, and FGFR4. Additional studies are needed to assess the functional role and clinical utility of these alterations in driving resistance.

Humans↗
PubMed2026

Mass Spectrometry-Based Profiling of Personalized Immunopeptidomes in Thai Renal Cell Carcinoma.

This study profiles the personalized immunopeptidomes of 13 Thai patients with renal cell carcinoma (RCC), addressing a critical knowledge gap in Southeast Asian populations characterized by distinct HLA allele distributions. We combined whole-exome sequencing (WES)-based personalized proteome construction with liquid chromatography-tandem mass spectrometry (LC-MS/MS), using both database-driven searches and de novo peptide sequencing. HLA typing identified several class I allotypes that are underrepresented in publicly available immunopeptidome resources, including seven alleles not previously represented in the databases examined; HLA-A*11:01 was the most frequent allele in this cohort. Database-based analysis identified a single tumor-specific neoantigen derived from a mutant JADE2 peptide in the patient with the highest tumor mutational burden, which was validated by a mutant-specific ELISPOT response. In contrast, de novo sequencing revealed numerous noncanonical peptides, a subset of which were supported by proteogenomic validation using PepQuery and detected exclusively in cancer proteomes but not in normal tissue data sets, indicating their potential as tumor-associated antigen candidates. Together, these results establish an integrated and scalable framework for identifying HLA-presented tumor-derived peptides and provide a foundational immunopeptidome resource to support personalized cancer immunotherapy development in Southeast Asia.

Humans↗
PubMed2026

The importance of integrating genetic testing into reproductive medicine: a retrospective observational study investigating the monogenic causes of human infertility in couples considering ICSI.

The genetic landscape of human infertility is complex with diverse etiologies. Identifying the underlying etiology is crucial for guiding reproductive decisions and improving management for infertile couples. Here, we aim to report on the molecular spectrum of monogenic genetic causes of reproductive failure. Over a 3-year period, we recruited all infertile couples considering assisted reproductive technologies (ART) for whom the underlying genetic cause had been identified, in either partner, using exome sequencing (ES). Clinical data of all participants along with their hormonal profiles, sonographic findings and spermograms were recorded. The study included 50 couples with primary infertility. Clinically, male factor infertility was documented in 26 patients, female factor infertility in 10, while reproductive failure was unexplained in the remaining 14 couples. All participating couples had potentially disease-causing variants in infertility genes. ES identified variants related to male infertility in 26 men, while variants in female infertility-related genes were detected in the remaining couples (n = 24). According to ACMG classification criteria, 78% (39/50) of couples harbored pathogenic/likely pathogenic (P/LP) variants, whereas 22% (11/50) carried variants of uncertain significance (VUS). In view of the identified genetic etiologies, the cohort was stratified into two groups based on the predicted reproductive outcome: (1) couples with significantly impaired reproductive potential, and (2) couples who can have biological children using appropriate medical interventions. However, classifications involving VUS were interpreted cautiously and considered exploratory. This study provides further evidence for the molecular heterogeneity of human infertility and highlights the usefulness of genetic testing for infertile couples pursuing ARTs.

Humans↗
PubMed2026

Integration of multi-omics data uncovers novel germline susceptibility candidates in early-onset colorectal cancer.

Colorectal cancer (CRC) is increasingly diagnosed in individuals under 50 years of age, yet the underlying genetic predisposition remains largely unexplained, particularly in mismatch repair (MMR)-proficient cases. This study aimed to identify novel hereditary CRC susceptibility genes by integrating germline and tumour whole-exome sequencing (WES) with transcriptomic profiling across a cohort of early-onset CRC (EOCRC) patients. Tumours were categorised using Consensus Molecular Subtypes (CMS) classification and analysed for mutational signature and burden. We used a novel 'All vs One' multi-omic integration approach to identify loss-of-function rare germline variants with concordant gene expression alterations in tumour tissue. Five candidate genes (ADCY4, NOXO1, CDHR2, ARHGAP10, EEF2K) were prioritised based on this approach and potential biological relevance in CRC. These findings highlight the molecular heterogeneity of EOCRC and demonstrate the utility of multi-omic approaches in refining germline variant interpretation. Integrating tumour transcriptomics enhances gene discovery efforts and supports a more comprehensive understanding of CRC heritability in younger individuals.

Humans↗
PubMed2026

Sequencing approaches in hereditary cancer testing: strengths, limitations and future directions.

Over the past three decades, Hereditary Cancer Testing (HCT) has evolved from single gene assays into multigene panel testing (MGPT), which allows for the screening of all known hereditary cancer genes in a single assay. MGPT is currently the standard approach for clinical HCT. However, with decreasing sequencing costs and increased instrument throughput, the scalability of exome sequencing (ES) and genome sequencing (GS) for HCT indications is becoming more viable. These methods provide broader insights into the coding exons and/or the entire genome, respectively. ES/GS data can also be reanalyzed to identify variants in novel genes that were not characterized at the time of initial testing, or to support research efforts aimed at uncovering additional associations between germline variants and cancer predisposition. Additionally, the emerging use of long-read sequencing (LRS) is noteworthy, enabling improved variant detection compared to short-read sequencing, especially for complex/structural variants and variation in difficult-to-sequence or paralogous regions in genes such as PMS2. This has the potential to increase the accuracy of HCT, reduce the turnaround time, find previously unidentifiable cancer risk variants, and ultimately increase the diagnostic yield. This article provides a comprehensive summary of the sequencing approaches used in HCT, discussing their strengths and limitations. We also highlight the added value of complementing DNA-only testing with RNA and tumor sequencing. Furthermore, we explore LRS-based approaches and discuss opportunities for their implementation in routine genetic testing for hereditary cancer.

Humans↗
PubMed2025

Complex de novo structural variants are an underestimated cause of rare disorders.

Complex de novo structural variants (dnSVs) are crucial genetic factors in rare disorders, yet their prevalence and characteristics in rare disorders remain poorly understood. Here, we conduct a comprehensive analysis of whole-genome sequencing data of 12,568 families, including 13,698 offspring with rare diseases, obtained as part of the UK 100,000 Genomes Project. We identify 1,870 dnSVs, constituting the largest dnSV dataset reported to date. Complex dnSVs (n = 158; 8.4%) emerge as the third most common type of SV, following simple deletions and duplications. We classify 65% of these complex dnSVs into 11 subtypes. Among probands with dnSVs (n = 1,696), 9% exhibit exon-disrupting pathogenic dnSVs associated with the probands' phenotype. Notably, 12% of exon-disrupting pathogenic dnSVs and 22% of de novo deletions or duplications previously identified by array-based or whole-exome sequencing methods are found to be complex dnSVs. We also find distinct genomic properties of de novo deletions depending on the parent of origin. This study highlights the importance of complex dnSVs in the cause of rare disorders and demonstrates the necessity of specific genomic analysis to avoid overlooking these variants.

Humans↗
PubMed2026

Amiloride mitigates respiratory distress caused by WFDC2 deficiency via inhibiting the epithelial sodium channel.

Chronic airway diseases such as cystic fibrosis (CF) and primary ciliary dyskinesia (PCD) pose substantial clinical challenges. Here, we explore the p.C97W variant in WAP four-disulfide core domain protein 2 (WFDC2), proposed as a new genetic origin of respiratory distress, especially among Koreans. Whole-exome and whole-genome sequencing (WES/WGS) are performed on 64 patients from 62 families presenting with severe bronchiectasis and chronic rhinosinusitis. Pathogenic variants are found in 19.4% of families, including a novel homozygous WFDC2 missense variant (c.291 C > G, p.Cys97Trp) in five unrelated families. WFDC2 is expressed in lung epithelial cells, and the p.C97W variant impairs WFDC2 protein folding, secretion, and function. Wfdc2 p.C147W knock-in mice exhibit respiratory failure due to the hyperactive epithelial sodium channel (ENaC) linked to increased PRSS8 activity and recapitulate human disease. Treatment with amiloride, an ENaC inhibitor, improves survival and respiratory function in these mice. In conclusion, the p.C97W variant in WFDC2 is a critical genetic factor in severe chronic airway disease that shares clinical features with CF and PCD. Given its implications for diagnosis and treatment, genetic testing for WFDC2 mutations in individuals with CF- or PCD-like symptoms is recommended.

Humans↗
PubMed2025

Accurate somatic small variant discovery for multiple sequencing technologies with DeepSomatic.

Somatic variant detection is an integral part of cancer genomics analysis. While most methods have focused on short-read sequencing, long-read technologies offer potential advantages in repeat mapping and variant phasing. We present DeepSomatic, a deep-learning method for detecting somatic small nucleotide variations and insertions and deletions from both short-read and long-read data. The method has modes for whole-genome and whole-exome sequencing and can run on tumor-normal, tumor-only and formalin-fixed paraffin-embedded samples. To train DeepSomatic and help address the dearth of publicly available training and benchmarking data for somatic variant detection, we generated and make openly available the Cancer Standards Long-read Evaluation (CASTLE) dataset of six matched tumor-normal cell line pairs whole-genome sequenced with Illumina, PacBio HiFi and Oxford Nanopore Technologies, along with benchmark variant sets. Across samples, both cell line and patient-derived, and across short-read and long-read sequencing technologies, DeepSomatic consistently outperforms existing callers.

Humans↗
PubMed2024

Comprehensive molecular profiling of multiple myeloma identifies refined copy number and expression subtypes.

Multiple myeloma is a treatable, but currently incurable, hematological malignancy of plasma cells characterized by diverse and complex tumor genetics for which precision medicine approaches to treatment are lacking. The Multiple Myeloma Research Foundation's Relating Clinical Outcomes in Multiple Myeloma to Personal Assessment of Genetic Profile study ( NCT01454297 ) is a longitudinal, observational clinical study of newly diagnosed patients with multiple myeloma (n = 1,143) where tumor samples are characterized using whole-genome sequencing, whole-exome sequencing and RNA sequencing at diagnosis and progression, and clinical data are collected every 3 months. Analyses of the baseline cohort identified genes that are the target of recurrent gain-of-function and loss-of-function events. Consensus clustering identified 8 and 12 unique copy number and expression subtypes of myeloma, respectively, identifying high-risk genetic subtypes and elucidating many of the molecular underpinnings of these unique biological groups. Analysis of serial samples showed that 25.5% of patients transition to a high-risk expression subtype at progression. We observed robust expression of immunotherapy targets in this subtype, suggesting a potential therapeutic option.

Humans↗
PubMed2026

Rare variant effect estimation and polygenic risk prediction.

Due to their low frequency, estimating the effects of rare variants is challenging. Here we propose RareEffect, a method that first estimates gene-based or region-based heritability and then each variant effect size using an empirical Bayes approach. Our method uses a variance component model, which is popular in rare variant tests, and is designed to provide two levels of effect sizes-gene/region level and variant level-that can provide better interpretation. To adjust for the case-control imbalance in phenotypes, our approach uses a fast implementation of the Firth bias correction. We demonstrate the accuracy and computational efficiency of our method through extensive simulations and analysis of UK Biobank whole-exome sequencing data for 100 traits. Additionally, we show that the effect sizes obtained from our model can be leveraged to improve polygenic score performance, thereby outperforming recently developed methods for rare variant polygenic scoring.

Humans↗
PubMed2025

Integrated genomic analysis of NF1-associated peripheral nerve sheath tumors: an updated biorepository dataset.

Neurofibromatosis type 1 (NF1) is an inherited neurocutaneous condition that predisposes to the development of peripheral nerve sheath tumors (PNST) including cutaneous neurofibromas (CNF), plexiform neurofibromas (PNF), atypical neurofibromatous neoplasms of uncertain biologic potential (ANNUBP), and malignant peripheral nerve sheath tumors (MPNST). The Johns Hopkins NF1 biospecimen repository promotes the successful advancement of therapeutic developments for NF1-associated PNST through acquisition and genomic analysis of human tumor specimens. RNA sequencing (RNAseq) and whole exome sequencing (WES) data were generated from 73 and 114 primary human tumor samples, respectively. These pre-processed data, standardized for immediate computational analysis, are accessible through the NF Data Portal, allowing immediate interrogation. This dataset combines new and previously released samples, offering a comprehensive view of the entire cohort sequenced. As a dedicated effort to systematically bank tumor samples from people with NF1, in collaboration with molecular geneticists and computational biologists, the Johns Hopkins NF1 biospecimen repository offers access to tissue samples and genomic data to promote the advancement of NF1-related tumor biologic insights and therapies.

Humans↗
PubMed2025

AncestryGeni: a novel genetic ancestry classification pipeline for small and noisy sequence data.

MOTIVATION: Efforts to address health disparities are often limited by the lack of robust computational tools for inferring genetic ancestry by calculating an individual's genetic similarity to continental groups. We have already shown that a preferred alternative to self-described race is using ancestry-informative markers (AIMs) that can be classified into ancestral components and used to estimate their similarity to those of known populations to identify continental groups. However, real-world genomic data can present challenges, including limited availability of germline DNA, a small number of AIMs for each sample, and the use of different variant calling software, limiting the application of existing solutions. RESULTS: Here, we describe a novel supervised machine-learning tool AncestryGeni, which infers genetic ancestry for samples with even a hundred markers and is applicable to any genomic data, including whole exome sequencing (WES) and RNA sequencing (RNA-Seq) data. Applying AncestryGeni to a real-world genomic dataset obtained from the Multiple Myeloma Research Foundation (MMRF) CoMMpass study, we show that it is more accurate than the commonly used FastNGSadmix when using nonstandard genomic material. We also demonstrate that when using AncestryGeni, the tumor-derived sequence obtained from WES and RNA-Seq can be a robust data source to accurately estimate an individual's genetic similarity to a continental group. AVAILABILITY AND IMPLEMENTATION: AncestryGeni pipeline is available at https://github.com/eelhaik/AncestryGeni/tree/main.

Humans↗
PubMed2025

Pharmacogenomic Assessment of Genes Implicated in Thiopurine Metabolism and Toxicity in a UK Cohort of Pediatric Patients With Inflammatory Bowel Disease.

BACKGROUND: Thiopurine drugs are effective treatment options in inflammatory bowel disease and other conditions but discontinued in some patients due to toxicity. METHODS: We investigated thiopurine-induced toxicity in a pediatric inflammatory bowel disease cohort by utilizing exome sequencing data across a panel of 46 genes, including TPMT and NUDT15. RESULTS: The cohort included 487 patients with a median age of 13.1 years. Of the 396 patients exposed to thiopurines, myelosuppression was observed in 11%, gastroenterological intolerance in 11%, hepatotoxicity in 4.5%, pancreatitis in 1.8%, and "other" adverse effects in 2.8%. TPMT (thiopurine S-methyltransferase) enzyme activity was normal in 87.4%, intermediate 12.3%, and deficient in 0.2%; 26% of patients with intermediate activity developed toxicity to thiopurines. Routinely genotyped TPMT alleles associated with defective enzyme activity were identified in 28 (7%) patients: TPMT*3A in 4.5%, *3B in 1%, and *3C in 1.5%. Of these, only 6 (21%) patients developed toxic responses. Three rare TPMT alleles (*3D, *39, and *40) not assessed on routine genotyping were identified in 3 patients, who all developed toxic responses. The missense variant p.R139C (NUDT15*3 allele) was identified in 4 patients (azathioprine 1.6 mg/kg/d), but only 1 developed toxicity. One patient with an in-frame deletion variant p.G13del in NUDT15 developed myelosuppression at low doses. Per-gene deleteriousness score GenePy identified a significant association for toxicity in the AOX1 and DHFR genes. CONCLUSIONS: A significant association for toxicity was observed in the AOX1 and DHFR genes in individuals negative for the TPMT and NUDT15 variants. Patients harboring the NUDT15*3 allele, which is associated with myelosuppression, did not show an increased risk of toxicity.

Humans↗
PubMed2025

RELA Haploinsufficiency Manifesting as an Atypical Phenotype of Crohn's Disease.

BACKGROUND: Mutations in RELA, a key component of NF-κB signaling, are associated with dysregulated immune responses and inflammatory disorders. While immunodeficiency phenotypes associated with RELA haploinsufficiency have been reported, gastrointestinal manifestations remain poorly described. This study aimed to characterize the clinical, genomic, and immunological features of a patient presenting with an atypical Crohn's-like phenotype driven by RELA haploinsufficiency. METHODS: Whole-exome sequencing was performed, and results were confirmed by Sanger sequencing. Protein modeling, Western blotting, immunofluorescence, and nuclear extract-based NF-κB activation assays were conducted to assess the functional impact of the identified variant. Immune profiling was performed using mass cytometry time of flight (CyTOF) and single-cell RNA sequencing (scRNA-seq) and compared to controls. RESULTS: We studied a 17-year-old male diagnosed with pan-enteric Crohn's disease (CD), perianal fistulas, chronic mucocutaneous candidiasis, and chronic lymphopenia. Sequencing identified a heterozygous missense variant in RELA (c.587T>C, p.V196A) that potentially impairs RelA (p65) protein stability, confirmed by reduced activity and diminished protein expression. CyTOF analysis revealed decreased circulating T regulatory cells (Tregs), absence of mucosal Tregs, high apoptotic rates, and elevated IFN-γ induced levels, while scRNA-seq demonstrated a robust type I/II interferon signature in multiple immune subsets. Dysregulated mucosal-associated invariant T (MAIT) and cytotoxic CD4+ T cells exhibited upregulation of IL23R and ADAM12, further linking RELA dysfunction to enhanced pro-inflammatory T cell response and tissue inflammation. CONCLUSION: This study links RELA haploinsufficiency with CD-like features, Th1/Th17 polarization, and interferon-driven inflammation, emphasizing the importance of genetic evaluation in patients with atypical or refractory IBD.

Humans↗
PubMed2026

Motif-centered analyses reveal universal and tissue-specific mutagenic mechanisms operating in the human body.

Somatic mutations are inevitable in human genomes and can lead to cancer initiation and tumor progression. Although many mutagenic processes have been linked to cancer, their activities in normal tissues before malignant transformation remain poorly characterized. Here, we analyzed the mutation profiles of 10,625 normal samples across 25 tissues obtained from whole-genome and whole-exome sequencing datasets. We applied stringent statistical hypothesis for detecting enrichment and enrichment-adjusted Minimal Estimate of Mutation Load in trinucleotide motifs preferred by known mutagenic processes. We found several cancer-associated mutational motifs in cancer-free tissues. Samples enriched with C→T mutations in nCg motif associated with clock-like spontaneous meCpG deamination were detected across all tissues. We also identified a second clock-like motif, T→C substitutions in aTn motif associated with exposure to small epoxides and other SN2 electrophiles, in several tissues. Motifs associated with other environmental and chemical mutagens showed sporadic and tissue-specific mutagenesis. APOBEC-induced C→T and C→G mutations in tCw motif were enriched in bladder, lung, small intestine, liver, and breast with preference for APOBEC3A-like mutagenesis in most tissues. Together, our analyses elucidated several cancer-associated mutagenic processes in normal tissues and provided a robust analytical framework for quantifying mutagenic activities from somatic mutation catalogs.

Humans↗
PubMed2024

LRP4 mutations promote tumor progression and resistance to anti-PD-1 therapy in recurrent hepatocellular carcinoma.

BACKGROUND AND AIMS: HCC recurrence is a major factor limiting long-term survival and the cause of most deaths in patients with HCC. However, molecular characterization and potential therapeutic targets of recurrent HCC remain mostly unknown. APPROACH AND RESULTS: We performed whole-exome sequencing in 63 matched primary and recurrent HCC tumors and combined the data with whole-genome sequencing results in 43 paired samples from our previous study. Sanger sequencing was used to identify all low-density lipoprotein receptor-related protein 4 ( LRP4 ) coding exons in 203 additional patients with recurrent HCC. We identified LRP4 somatic mutations in 7.8% (24/309) of recurrent tumors and only 0.97% (3/309) of primary tumors ( p <0.001). Prognosis after the second liver resection was poorer in patients with an LRP4 mutation. Biofunctional investigations demonstrated that inactivating LRP4 mutations promoted tumor progression and immunosuppression. Mechanistically, mutated LRP4 reduced intratumoral conventional type 1 dendritic cell and CD8 + T cell infiltration by repressing C-C motif chemokine ligand 4 expression and secretion through activation of &#x3b2;-catenin signaling, resulting in resistance to anti-programmed cell death protein-1 therapy. Patients with recurrent HCC carrying an LRP4 mutation did not benefit from anti-programmed cell death protein-1 treatment after their second resection surgery. A &#x3b2;-catenin inhibitor-reversed LRP4-induced resistance to anti-programmed cell death protein-1 therapy in humanized tumor-bearing mice. CONCLUSIONS: Our results identified novel LRP4 mutations important in recurrent HCC. Inactivating LRP4 mutations were associated with resistance to anti-programmed cell death protein-1 therapy and could be useful biomarkers for precision therapy in patients with recurrent HCC.

Humans↗