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Results for “Somatic Amplification”

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PubMed2025

In Vivo CRISPR Activation Screening Reveals Chromosome 1q Genes VPS72, GBA1, and MRPL9 Drive Hepatocellular Carcinoma.

BACKGROUND & AIMS: Hepatocellular carcinoma (HCC) frequently undergoes regional chromosomal amplification, resulting in elevated gene expression levels. We aimed to elucidate the role of these poorly understood genetic changes by using CRISPR activation (CRISPRa) screening in mouse livers to identify which genes within these amplified loci are cancer driver genes. METHODS: We used data from The Cancer Genome Atlas to identify that frequently copy number-amplified and up-regulated genes all reside on human chromosomes 1q and 8q. We generated CRISPRa screening transposons that contain oncogenic Myc to drive tumor formation. We conducted CRISPRa screens in vivo in the liver to identify tumor driver genes. We extensively validated the findings in separate mice and performed RNA sequencing analysis to explore mechanisms driving tumorigenesis. RESULTS: We targeted genes that frequently undergo amplification in human HCC using an in vivo CRISPRa screening system in mice, which induced extensive liver tumorigenesis. Human chromosome 1q genes Zbtb7b, Vps72, Gba1, and Mrpl9 emerged as drivers of liver tumorigenesis. In human HCC there is a trend in correlation between levels of MRPL9, VPS72, or GBA1 and poor survival. In validation assays, activation of Vps72, Gba1, or Mrpl9 resulted in extensive liver tumorigenesis and decreased survival in mice. RNA sequencing revealed different mechanisms driving HCC, with Mrpl9 activation altering genes functionally related to mitochondrial function, Vps72 levels altering phospholipid metabolism, and Gba1 activation enhancing endosomal-lysosomal activity, all leading to promotion of cellular proliferation. Analysis of human tumor tissues with high levels of MRPL9, VPS72, or GBA1 revealed congruent results, indicating conserved mechanisms driving HCC. CONCLUSIONS: This study reveals chromosome 1q genes Vps72, Gba1, and Mrpl9 as drivers of HCC. Future efforts to prevent or treat HCC can focus on these new driver genes.

Animals↗

PubMed2026

Genome-wide etiology analysis of autoimmune hypothyroidism supports somatic mutations of at-risk DNA as the underlying cause.

Autoimmune hypothyroidism (AIHT) is the most common autoimmune disease. Through an unidentified mechanism, the immune system attacks the thyroid gland, destroys thyroid follicular cells, and causes hypothyroidism. A new theory poses that all DNA is continuously damaged and, as a result, is exposed to somatic mutations at a constant rate. Based on this theory, several assumptions related to epidemiology and DNA sequence can be made. These have been summarized as a method called genome-wide etiology analysis (GWEA) to facilitate the interpretation of GWAS results of autoimmune diseases. Here, GWEA is applied to AIHT. The results show that existing epidemiological and genomic data of AIHT adhere to the principles of GWEA. Therefore, AIHT appears to be the result of somatic mutations in people at risk for the disease. AIHT develops once sufficient mutations create a new "autoimmune pathway" driven by non-self-signal and supported by neopeptide formation and signal amplification. Given the random nature of somatic mutations throughout life, the new theory explains why some people with AIHT develop additional autoimmune diseases, why family members may develop a range of non-AIHT autoimmune diseases, why the age of onset cannot be predicted, and why AIHT is transferred to the following generations through dominant inheritance with delayed, incomplete penetrance.

Humans↗

PubMed2026

A comprehensive survey of genetic variants in neuroblastoma.

BACKGROUND: Neuroblastoma (NB) is the most common extracranial solid tumor in children and is characterized by marked clinical and molecular heterogeneity. Genomic alterations play a critical role in NB pathogenesis; however, population-specific mutational features remain insufficiently characterized, particularly among Chinese patients. METHODS: Whole-exome sequencing (WES) was performed on tumor, para-tumor, and matched peripheral blood samples from nine pathologically confirmed Chinese patients with NB. Somatic variant profiles were compared with four publicly available NB datasets from cBioPortal, published in 2012, 2013, 2015, and 2023. Mutational patterns, recurrently altered genes, and Gene Ontology (GO) enrichment were analyzed using R version 4.3.2 and clusterProfiler version 4.10.0. RESULTS: A total of 77 missense variants were identified in our cohort. Single-nucleotide polymorphisms (SNPs) represented the predominant variant type, and C > T substitutions were the most frequent nucleotide change. MAP1A variants, comprising two missense variants in one patient, and RBM33 variants, comprising two distinct variants in two patients, were detected in our cohort and, to the best of our knowledge, have not been previously reported in NB, although their frequencies were low. No MYCN amplification or variants in ALK, ATRX, or DAXX were detected. Comparative analysis with the cBioPortal datasets revealed no somatic variants universally shared across all cohorts. In addition, high-risk patients exhibited distinct mutational patterns, with enrichment of the Gene Ontology term "collagen-containing extracellular matrix." CONCLUSIONS: These findings highlight the molecular diversity of NB and suggest the presence of potential population-specific genetic features in Chinese patients. The low-frequency MAP1A and RBM33 variants identified in this cohort warrant further validation in larger, independent cohorts. Moreover, the enrichment of extracellular matrix-related pathways in high-risk NB supports further investigation of tumor-microenvironment interactions as potential therapeutic targets.

Extracellular matrix↗

PubMed2025

Backtracking Cell Phylogenies in the Human Brain with Somatic Mosaic Variants.

Somatic mosaic variants, and especially somatic single nucleotide variants (sSNVs), occur in progenitor cells in the developing human brain frequently enough to provide permanent, unique, and cumulative markers of cell divisions and clones. Here, we describe an experimental workflow to perform lineage studies in the human brain using somatic variants. The workflow consists in two major steps: (1) sSNV calling through whole-genome sequencing (WGS) of bulk (non-single-cell) DNA extracted from human fresh-frozen tissue biopsies, and (2) sSNV validation and cell phylogeny deciphering through single nuclei whole-genome amplification (WGA) followed by targeted sequencing of sSNV loci.

Humans↗

PubMed2026

Immune pathway activation in gastric cancers with LINE-1 retrotransposon overexpression and homologous recombination deficiency.

There are only a few whole genome sequencing studies of human gastric cancer (GC) conducted so far. We performed comprehensive whole genome, bulk RNA, and methylation sequencing analyses of 100 samples of GC and adjacent normal tissue. In a smaller non-EBV/non-MSI subset (n = 23), we also performed proteomic profiling by mass spectrometry. We validated the proteomic findings in an independent dataset. Using this unprecedented dataset of human GC samples, we examined the extent of chromothripsis, homologous recombination deficiency, and retrotransposition, and correlated these events with patient outcomes. We found that chromothripsis occurred in 22% of GCs and correlated with poor prognosis. Multichromosomal chromothripsis was associated with a particularly high risk of death. Based on copy number (CN) signature analysis, we identified a distinct non-CN9 subgroup with significantly worse outcomes. Homologous recombination deficiency was present in 4% of GCs and was associated with overexpression of immune signaling pathways. Somatic retrotransposition events were most strongly associated with global hypomethylation. We also identified BYSL as a putative oncogenic driver within the 6p21 locus whose amplification is associated with poor prognosis. Collectively, our findings provide novel insights into the dysregulation of DNA stability and repair and their clinical relevance in human GCs.

Journal Article↗

PubMed2025

A personalized multi-platform assessment of somatic mosaicism in the human frontal cortex.

Somatic mutations in individual cells create genomic mosaicism, influencing genetic disorders and cancers. While clonal mutations in cancers are well-studied, rarer somatic variants in normal tissues remain poorly characterized. This study systematically evaluates detection methods using a personalized donor-specific assembly (DSA) from a neurotypical individual's dorsolateral prefrontal cortex assessed with Oxford Nanopore, NovaSeq, linked-read sequencing, Cas9-targeted long-read sequencing (TEnCATS), and single-neuron MALBAC amplification. The haplotype-resolved DSA improved cross-platform analysis, dramatically increasing phasing rates. Germline SNVs, structural variations (SVs), and transposable elements (TEs) were recalled with 99.4%-99.7% accuracy in bulk tissue, and phased haplotype analysis reduced false positives by 15.4%-75.1% for putative somatic candidates. Long-read single-neuron sequencing detected nine somatic SV candidates, demonstrating enhanced sensitivity for rare variants, while TEnCATS identified eight low-frequency somatic TE candidates. These findings highlight advanced methodologies for precise somatic variant detection, critical for understanding mosaicism's role in health and disease.

Multi-platform Sequencing↗

PubMed2026

Amplification-Driven S100A11 Overexpression in Hepatocellular Carcinoma Is Associated with Metabolic Reprogramming, ECM Remodelling, and Immune Evasion: A Pan-Cancer Genomic Study.

BACKGROUND: S100A11, a calcium-binding S100 family protein, is increasingly implicated in carcinogenesis, yet its molecular regulation and clinical relevance across cancers remain unclear. Hepatocellular carcinoma (HCC) carries a dismal prognosis, in part due to a lack of reliable biomarkers for risk stratification of established disease. METHODS: We conducted a pan-cancer analysis of S100A11 genomic alterations across 31 studies (10,767 samples) obtained from TCGA, encompassing copy number alterations, somatic mutations, and DNA methylation. HCC-specific analyses evaluated S100A11 expression, its potential as a diagnostic/prognostic marker, co-expression networks, and pathway enrichment using TCGA-LIHC data, with univariate and multivariate Cox regression to assess survival associations. RESULTS: S100A11 alterations were predominantly driven by copy number amplification, with the highest frequencies in hepatobiliary cancers, lung and breast cancers. Copy number amplification showed a consistent inverse relationship with promoter methylation, indicating amplification-driven transcriptional activation. In HCC, S100A11 was markedly overexpressed compared with normal liver tissue, with strong diagnostic discriminatory capacity. High S100A11 expression was significantly associated with inferior overall survival (log-rank p = 0.032; HR = 1.46, 95% CI 1.03-2.06) and remained an independent predictor of overall survival after adjustment for age, sex, and AJCC pathologic stage (HR = 1.27, 95% CI 1.01-1.60, p = 0.038). Co-expression and pathway analyses demonstrated an association between S100A11 and metabolic reprogramming, extracellular matrix remodelling, and immune dysregulation. CONCLUSIONS: These findings identify S100A11 as a candidate diagnostic and prognostic biomarker in HCC whose overexpression is associated with metabolic reprogramming, ECM remodelling, and immune dysregulation, warranting experimental validation of a mechanistic role.

ECM↗

PubMed2022

The evolutionary dynamics of extrachromosomal DNA in human cancers.

Oncogene amplification on extrachromosomal DNA (ecDNA) is a common event, driving aggressive tumor growth, drug resistance and shorter survival. Currently, the impact of nonchromosomal oncogene inheritance-random identity by descent-is poorly understood. Also unclear is the impact of ecDNA on somatic variation and selection. Here integrating theoretical models of random segregation, unbiased image analysis, CRISPR-based ecDNA tagging with live-cell imaging and CRISPR-C, we demonstrate that random ecDNA inheritance results in extensive intratumoral ecDNA copy number heterogeneity and rapid adaptation to metabolic stress and targeted treatment. Observed ecDNAs benefit host cell survival or growth and can change within a single cell cycle. ecDNA inheritance can predict, a priori, some of the aggressive features of ecDNA-containing cancers. These properties are facilitated by the ability of ecDNA to rapidly adapt genomes in a way that is not possible through chromosomal oncogene amplification. These results show how the nonchromosomal random inheritance pattern of ecDNA contributes to poor outcomes for patients with cancer.

Biological Evolution↗

PubMed2026

Paired genomic profiling of primary tumor and lymph-node metastases identifies candidate prognostic features in penile squamous cell carcinoma.

BACKGROUND: Penile squamous cell carcinoma (PSCC) is a rare malignancy with limited genomic data in Asian populations. Lymph node metastasis heavily dictates prognosis, yet molecular determinants of progression remain poorly understood. We aimed to characterize the genomic landscape and explore candidate prognostic genomic features using paired primary and metastatic PSCC tumors. PATIENTS AND METHODS: Targeted next-generation sequencing (437 cancer-related genes) was performed on primary tumors and matched lymph node metastases from 20 Chinese patients. Somatic alterations, intralesional heterogeneity, and tumor mutation burden (TMB) were analyzed and correlated with disease-free survival (DFS) and overall survival (OS). RESULTS: The most frequent primary tumor mutations included TP53 (45%) and TERT (40%). Notably, CCND1/FGF19 co-amplification (20% of cases) was associated with inferior DFS (P = .027) and showed a trend toward shorter OS (P = .050). Conversely, T-cell receptor (TCR) pathway alterations correlated with markedly improved survival. Comparing paired lesions revealed 59.8% shared alterations. Elevated TMB in metastases relative to matched primary tumors was significantly associated with poorer DFS (P = .008), while higher intralesional heterogeneity showed a trend toward worse OS. CONCLUSION: Paired profiling revealed broadly conserved genomic features together with lesion-specific divergence in PSCC. Recurrent CCND1/FGF19-containing 11q13 amplification, TCR pathway alterations, and elevated metastatic TMB warrant evaluation as potential prognostic features in larger, independently validated cohorts with integrated HPV and immune profiling.

Humans↗

PubMed2026

Intraductal Papillary Squamous Neoplasm (IPSN) of the Pancreas: Histological and Molecular Characterization of a Novel and Distinct Intraductal Cancer Precursor.

We report 6 intraductal papillary squamous neoplasms (IPSNs) of the pancreas, a rare but distinctive tumor whose biological features remain largely unknown. Five cases were investigated using an integrated approach combining histomorphological evaluation, immunohistochemistry, and multiregional molecular profiling through whole-exome DNA sequencing and whole-transcriptome RNA sequencing. Only targeted DNA sequencing was available on a sixth recently diagnosed case. Histologically, the intraductal lesions were characterized by large, confluent papillae with fibrovascular cores lined by multilayered epithelial cells with diffuse squamous differentiation. All cases harbored a concomitant invasive carcinoma. The associated invasive carcinomas consistently included a pancreatic tubular/ductal adenocarcinoma; in 5 cases, a poorly differentiated squamous cell carcinoma was also present, the proportion/features of which met the diagnostic criteria of adenosquamous carcinoma in 2 of them. Genomic analyses revealed that IPSNs and their matched invasive carcinomas shared the majority of somatic alterations, supporting a shared clonal origin for the 2 components. Activating KRAS mutations and biallelic inactivation of CDKN2A were detected in all cases. Recurrent mutations involved members of the SWI/SNF chromatin-remodeling complex and KMT2D. Additionally, FGFR1 and MYC amplifications were identified in 2 distinct cases (1 case each). Molecular alterations restricted to the invasive component involved mediators of the transforming growth factor-β signaling pathway. Transcriptomic profiling demonstrated a basal-like expression pattern in all IPSNs and squamous cell carcinomas, although in 2 cases, the matched pancreatic tubular/ductal adenocarcinoma shifted toward a classical transcriptomic subtype. In conclusion, through integrated histological assessment and multiregional molecular sequencing, we demonstrate that IPSN represents a bona fide precursor of invasive pancreatic cancer, a new addition to the intraductal neoplasms category. This study challenges the current paradigm that pancreatic squamous epithelium plays no role in the initiation of pancreatic carcinogenesis, providing the first evidence of its involvement in early tumorigenic processes and yielding immediate implications for pancreatic tumor classification and biological understanding.

Humans↗

PubMed2026

Novel Co-Occurrence of Germline EGFR p.V843I and Somatic EGFR Exon 19 Deletion in NSCLC: Insights into Reduced Sensitivity to EGFR-TKIs.

Germline EGFR pathogenic variants (PVs) are rare and define a distinct hereditary subset of NSCLC with unique clinical characteristics. Germline EGFR p.T790M is the most frequent and best characterized, with reported sensitivity to first- and second-generation EGFR-TKIs. Yet, the response of germline EGFR variants, especially the rarer ones such as p.V843I, to osimertinib remains poorly characterized. Given the very low frequency of germline non-p.T790M variants, their clinical relevance can only be investigated via case reports. Herein, we report what is, to the best of our knowledge, the first case of advanced lung adenocarcinoma harboring a germline EGFR p.V843I variant coexisting in cis with the unusual somatic EGFR exon 19 C-helix deletion, p.S752_I759del. Additionally, a somatic TP53 variant was detected. Treatment with afatinib induced a partial response lasting only six months, as rapid disease progression occurred without identifiable acquired resistance mechanisms. Subsequently, no objective response to osimertinib or afatinib rechallenge was observed. Acquired EGFR and MET amplification were detected in corresponding rebiopsies. Overall survival was 29 months. Our findings suggest that, despite the presence of the previously reported EGFR-TKI-sensitive, EGFR p.S752_I759del, the co-occurrence of germline p.V843I may have contributed to reduced sensitivity to afatinib and osimertinib. This case expands the molecular spectrum of hereditary EGFR-mutated NSCLC and, together with our narrative review of the literature, supports an emerging model in which germline EGFR PVs may act both as tumor-predisposing events and as potential mechanisms of early resistance to EGFR-TKIs.

Humans↗

PubMed2025

Tracking Somatic Mutations for Lineage Reconstruction.

The human genome is composed of distinct genomic regions that are susceptible to various types of somatic mutations. Among these, Short Tandem Repeats (STRs) stand out as the most mutable genetic elements. STRs are short repetitive polymorphic sequences, predominantly situated within noncoding sectors of the genome. The intrinsic repetition characterizing these sequences makes them highly mutable in vivo. Consequently, this characteristic provides the chance to unravel the natural developmental history of human viable cells retrospectively. However, STRs also introduce stutter noise in vitro amplification, which makes their analysis challenging. Here we describe our integrated biochemical-computational platform for single-cell lineage analysis. It consists of a pipeline whose inputs are single cells and whose output is a lineage tree of input cells.

Humans↗

PubMed2025

AmpSeqR: an R package for amplicon deep sequencing data analysis.

Amplicon sequencing (AmpSeq) is a methodology that targets specific genomic regions of interest for polymerase chain reaction (PCR) amplification so that they can be sequenced to a high depth of coverage. Amplicons are typically chosen to be highly polymorphic, usually with several highly informative, high frequency single nucleotide polymorphisms (SNPs) segregating in an amplicon of 100-200 base pair (bp). This allows high sensitivity detection and quantification of the frequency of each sequence within each sample making it suitable for applications such as low frequency somatic mosaicism detection or minor clone detection in mixed samples. AmpSeq is being increasingly applied to both biological and medical studies, in applications such as cancer, infectious diseases and brain mosaicism studies. Current bioinformatics pipelines for AmpSeq data processing lack downstream analysis, have difficulty distinguishing between true sequences and PCR sequencing errors and artifacts, and often require bioinformatic expertise. We present a new R package: AmpSeqR, designed for the processing of deep short-read amplicon sequencing data, with a focus on infectious diseases. The pipeline integrates several existing R packages combining them with newly developed functions to perform optimal filtering of reads to remove noise and improve the accuracy of the detected sequences data, permitting detection of very low frequency clones in mixed samples. The package provides useful functions including data pre-processing, amplicon sequence variants (ASVs) estimation, data post-processing, data visualization, and automatically generates a comprehensive Rmarkdown report that contains all essential results facilitating easy inclusion into reports and publications. AmpSeqR is publicly available at https://github.com/bahlolab/AmpSeqR.

High-Throughput Nucleotide Sequencing↗

PubMed2026

URMD-Seq: A high-throughput method for scalable detection of ultra-rare mutations in the human mitochondrial genome.

The study of mitochondrial genetics has long been limited to polymorphisms and high frequency mutations owing in part to technical and technological limitations in reliably detecting and quantifying rare somatic mutations. Over the past decade or so, the study of rare somatic mitochondrial DNA (mtDNA) variants has expanded and continues to garner increasing interest in a wide range of research fields. Here, we describe Ultra-Rare Mutation Detection-Sequencing (URMD-Seq), a high-throughput method that combines unique molecular identifier (UMI)-based library preparation and Next Generation Sequencing (NGS) for the accurate and scalable detection of ultra-rare mutations in the mtDNA control region. Our method exploits degenerate primers to label individual mtDNA molecules. This is followed by several purification, quantification and amplification steps, to obtain high quality amplicons for sequencing on the Illumina MiSeq platform. Our approach enables the use of total genomic DNA extract as starting point for the assay, overcoming the need for organelle isolation and/or mtDNA enrichment, hence broadening the type of specimen that can be studied, while offering cost and time benefits. The assay described herein has been demonstrated to reliably measure variants present at on average 0.09%, but as low as 0.03%, variant allele frequency in a variety of tissues, including fresh and frozen biobanked specimens. Using this protocol, library preparation of 300 specimens can be completed by a single individual with general nucleic acid handling experience in approximately 20 days. Given its flexibility and scalability, URMD-Seq is particularly well suited for epidemiological studies using a large number of specimens.

Humans↗

PubMed2026

Prevalence of BRCA1/2 variants in an Ovarian Cancer Cohort: outcomes from a Nationwide Testing Program.

Poly(ADP-ribose) polymerase inhibitors (PARPi) have revolutionized the management of BRCA1- and BRCA2-associated ovarian cancer (OC). In 2020, Ireland implemented a nationwide, oncology-led pathway for mainstreamed BRCA1/2 testing in patients with OC. This study evaluated the pathway and characterised the BRCA1/2 landscape in an Irish cohort of patients with OC. Samples collected between January 2020 and December 2023 were tested in two national molecular diagnostic laboratories. Single-molecule molecular inversion probe sequencing was used to detect single nucleotide variants, while multiplex ligation-dependent probe amplification assessed large genomic rearrangements. Variants were classified according to the American College of Medical Genetics and Genomics and Association for Clinical Genomic Science 2020 guidelines and CanVIG-UK specifications. In total, 535 patients were included, with a median age of 65.5 years (range, 27-89 years). Of these, 455/535 (85.0%) underwent germline BRCA1/2 (gBRCA) testing using peripheral blood, and 360/535 (67.2%) underwent tumour BRCA1/2 (tBRCA) testing, resulting in 292/535 (54.6%) patients having paired testing. Among gBRCA-tested patients, 10.3% (47/455) had a clinically actionable variant (CAV), while 2.1% (10/455) had a variant of uncertain significance. Of the 262 patients who underwent paired testing and had negative gBRCA results, 9.5% (25/262) had a somatic BRCA CAV. Recurrent germline BRCA CAVs were identified in regional clusters, including BRCA1 c.5266dup, BRCA1 c.1175_1214del, and BRCA2 c.4398_4402del. This nationwide real-world study demonstrates that mainstreamed germline and somatic BRCA1/2 testing is feasible in Ireland and reports the prevalence of BRCA CAVs in a cohort of patients with OC. Although the observed prevalence of germline BRCA CAVs was lower than anticipated, it is consistent with UK real-world data. The identification of recurrent, regionally clustered germline variants further enhances the characterisation of the Irish genomic landscape.

Journal Article↗

PubMed2026

Bilateral Conversion Risk in Unilateral Retinoblastoma Using Age and Genetic Testing.

IMPORTANCE: Metachronous bilateral conversion in initially unilateral retinoblastoma is uncommon but clinically consequential, potentially requiring intensified treatment and carrying worse prognosis. Clarifying how age at diagnosis refines genetic-risk stratification could enable safer, more efficient surveillance protocols. OBJECTIVE: To estimate the incidence and timing of metachronous bilateral conversion in unilateral retinoblastoma and assess whether age at diagnosis and RB1 testing are associated with bilateral conversion risk. DESIGN, SETTING AND PARTICIPANTS: This was a retrospective cohort study at a tertiary center in Shanghai, China, including 1108 consecutive children with initially unilateral retinoblastoma diagnosed from July 2010 to October 2024 (after exclusions for short follow-up [n = 139], missing data [n = 53], or synchronous bilateral disease [n = 10]). The median (IQR) follow-up was 43.4 (24.2-67.6) months. EXPOSURES: Age at diagnosis and RB1 genetic status/subtypes assessed by next-generation sequencing and multiplex ligation-dependent probe amplification, including penetrance class (high vs low) and mosaic vs germline categorization. MAIN OUTCOMES AND MEASURES: Time to metachronous bilateral conversion; cumulative incidence functions with death as a competing risk; spatial distribution of fellow-eye tumors. RESULTS: Among 1108 patients (median [IQR] age at diagnosis, 22.2 [12.0-31.4] months; 591 [53.3%] male), 24 (2.2%) developed metachronous bilateral disease. At 24 months, cumulative incidence was 2.2% (95% CI, 1.3-3.1) overall. By genetic status, the 24-month cumulative incidence was 24.8% (95% CI, 13.8-35.9) in RB1 variant-positive vs 1.6% (95% CI, 0.0-3.1) in RB1 variant-negative patients. Among RB1 variant-positive patients, risk clustered among those diagnosed before 9 months, whereas no conversions were observed among those diagnosed at older than 9 months. Four RB1 variant-negative patients who were initially diagnosed at notably late ages (20.9, 42.7, 79.6, and 118 months) subsequently converted; these cases likely represent undetected low-level mosaicism, somatic variants below detection thresholds, or rare genomic events not captured by standard sequencing panels. Fellow-eye tumors did not involve macula and showed a nasal-predominant distribution. CONCLUSIONS AND RELEVANCE: The findings in this study suggest that age at diagnosis may refine genetic risk stratification for metachronous bilateral conversion. RB1 variant-positive patients diagnosed at 9 months or later represent a very low-risk subgroup that may warrant surveillance deescalation, while rare late conversions in RB1 variant-negative patients necessitate continued long-term monitoring.

Humans↗