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At least 19 recordsLinked to original sources

PubMed2025

Inherited rare epidermal growth factor receptor mutation and somatic mutations in patients with non-small cell lung cancer: a case report.

BACKGROUND: Recent advances in molecular oncology have increasingly illuminated the role of germline EGFR mutations in non-small cell lung cancer (NSCLC). This case report presents the presence of a unique familial occurrence of EGFR mutations in patients with NSCLC. CASE DESCRIPTION: A mother and son, both never-smokers of Caucasian ethnicity, were diagnosed with advanced metastatic lung adenocarcinoma. In one patient, tumor molecular analysis by next generation sequencing (NGS) identified two EGFR mutations: the activating mutation c.2573T > G; p.Leu858Arg (p.L858R) in exon 21 of the EGFR gene, and the somatic non-pathogenic mutation c.2612 C > A; p.Ala871Glu (p.A871E) in exon 21 of the EGFR gene. The second patient also harbored the same two EGFR mutations. The patient underwent genetic testing which revealed the germline origin of the A871E mutation. Whether the presence of this mutations was associated with increased predisposition to cancer has yet to be determined. Our case report highlights the need for further exploration of the role of germline mutations, including the A871E mutation, in tumorigenesis and its implications for treatment response and inheritance patterns. CONCLUSIONS: The investigation and comprehension of the significance of each individual EGFR mutation hold the promise for potential in cancer prevention or early diagnosis within family cohorts and understanding the mechanisms of tumorigenesis in sporadic cases.

Humans↗

PubMed2026

Caloric restriction modulates genome-wide somatic mutation in mice.

Somatic mutations accumulate throughout life in every cell, and this process constitutes one of the hallmarks of aging-genomic instability. Caloric restriction (CR) has been shown to extend lifespan across diverse species. Using high-fidelity duplex DNA sequencing of bulk liver, bulk kidney, hepatocytes, and cerebellar neurons, we found that CR in mice reduces genome-wide somatic mutation burdens across multiple tissues and cell types. CR reduced both substitution and insertion/deletion burdens, with the magnitude of these effects varying across sample types. CR also decreased the activity of the enigmatic single-base substitution (SBS) mutational process SBS5 that gives rise to most mutations in mammals. Surprisingly, the mutation burden reduction from CR was greatest in transcriptionally inactive regions. This work illuminates links between diet, aging, and genomic integrity and establishes genomic integrity as a modifiable axis of aging.

DNA↗

PubMed1978

Relationship between somatic mutation and neoplastic transformation.

Somatic mutation and neoplastic transformation of diploid Syrian hamster embryo cells were examined concomitantly. Mutations induced by benzo[a]pyrene and N-methyl-N'-nitro-N-nitrosoguanidine were quantitated at the hypoxanthine phosphoribosyltransferase and Na(+)/K(+) ATPase loci and compared to phenotypic transformations measured by changes in cellular morphology and colony formation in agar. Both cellular transformations had characteristics distinct from the somatic mutations observed at the two loci. Morphological transformation was observed after a time comparable to that of somatic mutation but at a frequency that was 25- to 540-fold higher. Transformants capable of colony formation in agar were detected at a frequency of 10(-5)-10(-6), but not until 32-75 population doublings after carcinogen treatment. Although this frequency of transformation is comparable to that of somatic mutation, the detection time required is much longer than the optimal expression time of conventionally studied somatic mutations. Neoplastic transformation of hamster embryo cells has been described as a multistep, progressive process. Various phenotypic transformations of cells after carcinogen treatment may represent different stages in this progressive transformation. The results are discussed in this context and the role of mutagenesis in the transition between various stages is considered. Neoplastic transformation may be initiated by a mutational change, but it cannot be described completely by a single gene mutational event involving a dominant, codominant, or X-linked recessive locus. Neoplastic transformation induced by chemical carcinogens is more complex than a single gene mutational process. Thus, this comparative study does not give experimental support to predictions of the carcinogenic potential of chemicals based on a simple extrapolation of the results obtained from conventional somatic mutation assays.

Adenosine Triphosphatases↗

PubMed2024

ERCC2 mutations alter the genomic distribution pattern of somatic mutations and are independently prognostic in bladder cancer.

Excision repair cross-complementation group 2 (ERCC2) encodes the DNA helicase xeroderma pigmentosum group D, which functions in transcription and nucleotide excision repair. Point mutations in ERCC2 are putative drivers in around 10% of bladder cancers (BLCAs) and a potential positive biomarker for cisplatin therapy response. Nevertheless, the prognostic significance directly attributed to ERCC2 mutations and its pathogenic role in genome instability remain poorly understood. We first demonstrated that mutant ERCC2 is an independent predictor of prognosis in BLCA. We then examined its impact on the somatic mutational landscape using a cohort of ERCC2 wild-type (n = 343) and mutant (n = 39) BLCA whole genomes. The genome-wide distribution of somatic mutations is significantly altered in ERCC2 mutants, including T[C>T]N enrichment, altered replication time correlations, and CTCF-cohesin binding site mutation hotspots. We leverage these alterations to develop a machine learning model for predicting pathogenic ERCC2 mutations, which may be useful to inform treatment of patients with BLCA.

Humans↗

PubMed2026

Somatic mutations: recent advances in brain aging and neurodegeneration.

Somatic mutations are genetic variants that occur after the single-cell phase of development and have been implicated in disease pathogenesis. While most DNA lesions are detected and repaired, examination of healthy tissue has revealed that some lesions escape repair, leading to somatic mutations that accumulate at a consistent rate, including in human brain tissue and postmitotic neurons. Emerging methodological and analytical advances have revealed the presence of persistent mutagenic mechanisms during healthy brain aging as well as mutational pattern shifts in the context of neurodegenerative diseases. Here, we highlight recent methodological advances, summarize our current understanding of somatic mutagenesis in neurotypical brain aging, and examine the role of somatic mutations in neurodegenerative diseases.

Humans↗

PubMed2026

Somatic mutations and genome mosaicism in aging and disease.

Age-related genome mosaicism is an inherent feature of multicellularity and genomic instability. It occurs because of DNA mutations, the accumulation of which leads to diverse genomic landscapes across different tissues. DNA mutations in the genome are consequences of DNA damage, changes in the chemical structure of DNA, such as strand breaks or loss of bases. DNA damage is very frequent and normally repaired quickly. However, errors intrinsic to DNA repair or replication can give rise to permanent changes in genome sequence information. Such DNA mutations are diverse and include single-nucleotide variants, small insertions and deletions, and larger genome structural variants. Since the 1950s, somatic mutations have been proposed to be a major cause of aging. Indeed, somatic mutations are the cause of cancer, the risk of which increases exponentially with age, and possibly other age-related diseases, such as neurodegenerative diseases and cardiomyopathies. Somatic mutations vary from cell to cell owing to the innate stochasticity of their occurrence, from error-prone processing of randomly inflicted DNA damage. With the emergence of single-cell and single-molecule sequencing, it has become possible to quantitatively analyze somatic mutations in human cells and tissues. Here, we discuss a possible causal relationship between mutation-driven mosaicism of the somatic genome and aging-related functional decline and disease by exploring several predictions of the somatic mutation theory of aging.

Humans↗

PubMed2026

Impact of Somatic Mutations on Treatment Response and Resistance in Chronic Myeloid Leukemia.

INTRODUCTION: Tyrosine kinase inhibitors (TKIs) have transformed the treatment of chronic myeloid leukemia (CML); yet, diverse molecular responses and resistance persist. BCR::ABL1 kinase-domain (TKD) mutations constitute just a fraction of this resistance, and the impact of additional somatic mutations on disease progression and early molecular response remains incompletely defined. METHODS: This single-centre cohort study analyzed 109 NGS-tested patients with CML, comprising 44 with TKI-resistant disease and 65 newly diagnosed patients. Targeted next-generation sequencing using a 135-gene myeloid panel was performed on 109 patients. An additional pilot subgroup of 30 TKI-resistant patients underwent BCR::ABL1 kinase-domain analysis by PCR/Sanger sequencing and was analyzed separately. Molecular response was assessed using BCR::ABL1 transcript levels on the International Scale and interpreted according to ELN 2020 recommendations. RESULTS: Somatic mutations were identified in 52.3% of TKI-resistant and 29.2% of newly diagnosed patients. All Cohort 1 blast-crisis patients were mutation-positive, and several concurrent abnormalities were more common in Cohort 1 than in Cohort 2, indicating clonal complexity. In Cohort 2, MMR was achieved in 28/39 (71.8%) mutation-negative and 6/13 (46.2%) mutation-positive patients. Mutation-positivity at baseline was associated with reduced MMR chances but not statistically significant (odds ratio 0.34; 95% confidence interval 0.09-1.23; p = 0.099). ASXL1 emerged as the most common non-ABL1 mutation but was not statistically significant. CONCLUSIONS: In this Indian CML cohort, somatic mutations were prevalent in TKI-resistant disease, linked to advanced phase and clonal complexity, and demonstrated a non-significant trend toward lower early MMR at diagnosis, highlighting the importance of genomic testing in this context.

Humans↗

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↗

PubMed2025

Methylation-based droplet digital polymerase chain reaction shows high concordance with chronic lymphocytic leukemia IGHV somatic mutation status.

OBJECTIVE: Somatic hypermutation at immunoglobulin heavy chain variable (IGHV) genes, an established prognostic and predictive biomarker for chronic lymphocytic leukemia (CLL), is assessed by gene sequencing. We developed a single methylation-specific droplet digital polymerase chain reaction (methyl-ddPCR) to predict IGHV status in patients with CLL. METHODS: The CLL methylation array and IGHV data from the International Cancer Genome Consortium (ICGC) were used for biomarker discovery. Top-ranked candidate regions were manually screened for PCR primer and probe binding sites. A single methyl-ddPCR was evaluated on an internal cohort of CLLs with mutated (M), unmutated (U), and inconclusive IGHV results originally determined by next-generation sequencing (NGS). RESULTS: Analysis of ICGC data identified array probe cg23844018 as a candidate for the PCR. The corresponding CpG site showed high methylation levels in U-CLL and lower levels in M-CLL. On the internal cohort, a single optimal cutoff correctly classified 104 of 115 U- and M-CLLs (90.4%; area under the curve = 0.96). The PCR data correlated with some prognostic fluorescence in situ hybridization and CLL subset groupings. Limited analysis suggests that the PCR may be able to stratify some patients with CLL who have inconclusive results on IGHV NGS testing. CONCLUSIONS: The methyl-ddPCR showed high concordance with CLL IGHV status in an internal cohort.

Humans↗

PubMed2021

Somatic Mutations in UBA1 Define a Distinct Subset of Relapsing Polychondritis Patients With VEXAS.

OBJECTIVE: Somatic mutations in UBA1 cause a newly defined syndrome known as VEXAS (vacuoles, E1 enzyme, X-linked, autoinflammatory, somatic syndrome). More than 50% of patients currently identified as having VEXAS met diagnostic criteria for relapsing polychondritis (RP), but clinical features that characterize VEXAS within a cohort of patients with RP have not been defined. We undertook this study to define the prevalence of somatic mutations in UBA1 in patients with RP and to create an algorithm to identify patients with genetically confirmed VEXAS among those with RP. METHODS: Exome and targeted sequencing of UBA1 was performed in a prospective observational cohort of patients with RP. Clinical and immunologic characteristics of patients with RP were compared based on the presence or absence of UBA1 mutations. The random forest method was used to derive a clinical algorithm to identify patients with UBA1 mutations. RESULTS: Seven of 92 patients with RP (7.6%) had UBA1 mutations (referred to here as VEXAS-RP). Patients with VEXAS-RP were all male, were on average ≥45 years of age at disease onset, and commonly had fever, ear chondritis, skin involvement, deep vein thrombosis, and pulmonary infiltrates. No patient with VEXAS-RP had chondritis of the airways or costochondritis. Mortality was greater in VEXAS-RP than in RP (23% versus 4%; P = 0.029). Elevated acute-phase reactants and hematologic abnormalities (e.g., macrocytic anemia, thrombocytopenia, lymphopenia, multiple myeloma, myelodysplastic syndrome) were prevalent in VEXAS-RP. A decision tree algorithm based on male sex, a mean corpuscular volume >100 fl, and a platelet count <200 ×103 /μl differentiated VEXAS-RP from RP with 100% sensitivity and 96% specificity. CONCLUSION: Mutations in UBA1 were causal for disease in a subset of patients with RP. This subset of patients was defined by disease onset in the fifth decade of life or later, male sex, ear/nose chondritis, and hematologic abnormalities. Early identification is important in VEXAS given the associated high mortality rate.

Aged↗

PubMed2025

A Universal Duplex Sequencing Approach for Accurate Detection of Somatic Mutations.

Ultra-accurate detection of rare somatic mutations is critical for understanding mutational processes in human disease, aging, and environmental exposures, yet current methods are limited by error rates, restricted genome coverage, and high DNA input. We present UDSeq, a duplex sequencing protocol combining random fragmentation, efficient UMI ligation, and quantitative input control to achieve near-complete genome/exome representation from as little as 100 pg DNA. Benchmarking in human sperm estimates a UDSeq error rate of ~2.5×10-9 per base pair. UDSeq captures mutational signatures from heterogeneous populations without clonal expansion, reproduces exposure-specific patterns in cell lines and rodent models, and enables cross-species profiling. Compared with prior duplex methods, UDSeq yields up to fourfold more usable duplex molecules, improves library conversion, and remains cost-effective. We include a step-by-step protocol with quality-control checkpoints for fragment size, ligation yield, library conversion, and duplication rate. UDSeq provides a scalable, low-input platform for accurate profiling of somatic mutagenesis.

Journal Article↗

PubMed2026

Somatic mutations reveal hyperactive Notch signaling in prurigo nodularis.

Prurigo nodularis (PN) is a chronic inflammatory skin disease characterized by pruritic skin nodules of unknown etiology. Little is known about genetic changes in PN pathogenesis, particularly somatic events, which are often implicated in inflammatory conditions. We thus performed whole-exome sequencing on 54 lesional and nonlesional skin biopsies from 17 patients with PN and 10 patients with atopic dermatitis (AD) for comparison. Somatic mutational analysis revealed that PN lesional skin harbors recurrent somatic mutations in fibrotic, neurotropic, and cancer-associated genes that are absent in adjacent PN nonlesional skin. Nonsynonymous mutations were most frequently present in NOTCH1 and the Notch signaling pathway, a key regulator of cellular proliferation and tissue fibrosis. In contrast, NOTCH1 mutations were absent in AD. Somatic copy-number analysis, combined with expression data, identified recurrently deleted and downregulated genes in PN lesional skin, which are associated with axonal guidance and extension. Follow-up immunofluorescence validation demonstrated increased NOTCH1 expression in PN lesional skin fibroblasts and increased Notch signaling in PN lesional dermis. Finally, a multicenter analysis revealed increased risk of NOTCH1-associated diseases in patients with PN. In characterizing the somatic landscape of PN, this study highlights the potential role of Notch pathway dysregulation in PN pathogenesis and fibrosis.

Humans↗

PubMed2025

iSoMAs: Finding isoform expression and somatic mutation associations in human cancers.

Aberrant alternative splicing, prevalent in cancer, impacts various cancer hallmarks involving proliferation, angiogenesis, and invasion. Splicing disruption often results from somatic point mutations rewiring functional pathways to support cancer cell survival. We introduce iSoMAs (iSoform expression and somatic Mutation Association), an efficient computational pipeline leveraging principal component analysis technique, to explore how somatic mutations influence transcriptome-wide gene expression at the isoform level. Applying iSoMAs to 33 cancer types comprising 9,738 tumor samples in The Cancer Genome Atlas, we identified 908 somatically mutated genes significantly associated with altered isoform expression across three or more cancer types. Mutations linked to differential isoform expression occurred through both cis- and trans-acting mechanisms, involving well-known oncogenes/suppressor genes, RNA binding protein and splicing factor genes. With wet-lab experiments, we verified direct association between TP53 mutations and differential isoform expression in cell cycle genes. Additional iSoMAs genes have been validated in the literature with independent cohorts and/or methods. Despite the complexity of cancer, iSoMAs attains computational efficiency via dimension reduction strategy and reveals critical associations between regulatory factors and transcriptional landscapes.

Humans↗

PubMed2025

The DREAM complex links somatic mutation, lifespan, and disease.

The DREAM complex has emerged as a central repressor of DNA repair, raising questions as to whether such repression exerts long-term effects on human health. Here we establish that DREAM activity significantly impacts lifetime somatic mutation burden, and that such effects are linked to altered lifespan and age-related disease pathology. First, joint profiling of DREAM activity and somatic mutations across a single-cell atlas of 21 mouse tissues shows that cellular niches with lower DREAM activity have decreased mutation rates. Second, DREAM activity predicts the varied lifespans observed across 92 mammals, with low activity marking longer-lived species. Third, reduced DREAM activity in Alzheimer's patients predicts late disease onset and decreased risk for severe neuropathology. Finally, we show DREAM knockout protects against mutation accumulation in vivo, reducing single-base substitutions by 4.2% and insertion/deletions by 19.6% in brains of mice. These findings position DREAM as a key regulator of aging.

Journal Article↗

PubMed2025

Somatic Mutations in MCOLN3 Are Associated With Aldosterone-Producing Adenomas.

BACKGROUND: Primary aldosteronism is a common but underdiagnosed cause of endocrine hypertension that contributes to global cardiovascular morbidity and mortality. It is characterized by renin-independent hyperaldosteronism that originates from adrenal lesions-the majority of which are found to harbor aldosterone-driver somatic mutations in genes encoding ion-transporting proteins. These mutations disrupt intracellular calcium homeostasis, facilitating a pathological increase in aldosterone synthase expression and aldosterone production. Elucidating the exact mechanisms causing aldosterone excess in primary aldosteronism would further the development of targeted treatments and alleviate the global hypertension burden. METHODS: Next-generation sequencing analysis of formalin-fixed paraffin-embedded aldosterone-producing adenomas identified novel somatic variants in MCOLN3 (encoding the cation-permeable channel, TRPML3). Electrophysiological, fura-2 calcium measurements, gene expression, and steroid quantification studies were performed in adrenal HAC15 cells to characterize the functional effects of the novel MCOLN3 mutations. RESULTS: Three somatic MCOLN3 variants (p.Y391D, p.F415I, and p.N411_V412delinsI) were identified in aldosterone-producing adenomas from 4 male primary aldosteronism patients. Mutated MCOLN3 expressed in HAC15 cells resulted in a gain-of-function phenotype, which induced cell membrane depolarization and calcium influx and, in turn, triggered a significant increase in aldosterone synthase expression and aldosterone production. CONCLUSIONS: This is the first report of disease-causing MCOLN3 mutations in humans and the first to implicate mutated MCOLN3 as a driver of dysregulated aldosterone production in primary aldosteronism.

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↗

PubMed1979

A kappa-immunoglobulin gene is formed by site-specific recombination without further somatic mutation.

The active gene for a kappa light chain is formed by a somatic recombination event that joins one of several hundred variable region genes to one of a series of recombination sites (J-segments) encoded close to the kappa constant region gene. The nucleotide sequences of cloned germ line and somatically recombined genes define the precise organisation of these genetic segments and the site and nature of the recombination event that joined them. Apart from somatic recombination, no further alteration of ther germ line sequence has occurred. The J-segment is of special interest as it encodes signals for both DNA and RNA splicing and provides a means of generating further immunoglobulin gene diversity.

Animals↗

PubMed2025

Combined somatic mutation and transcriptome analysis reveals region-specific differences in clonal architecture in human cortex.

The human cerebral cortex is specialized into regions, but little is known about how human cellular lineages shape cortical regional variation and neuronal cell-type distribution during development. Here, we map single-cell lineages of human cortical regions and neuronal subtypes using >1,000 somatic single-nucleotide variants (sSNVs) identified from deep bulk whole-genome sequencing and analyzed over 25 regions and >72,000 single cells. In the fronto-parietal cortex, sSNVs are rarely restricted, marking neuron-generating clones that disperse into neighboring regions. In contrast, the primary visual cortex harbors 30%-70% more sSNVs than the neighboring secondary visual cortex. Clones at this border exhibit more restricted dispersion, suggesting late developmental lineage segregation. Single-nucleus sSNV and whole-transcriptome analysis reveal glutamatergic neuron clones with modest regional restrictions that share low-mosaic sSNVs with some GABAergic neurons, suggesting a recent dorsal cortical progenitor. Our analysis reveals human-specific cortical lineage patterns, regional differences in clonal patterns, and late divergence of some glutamatergic/GABAergic lineages.

Humans↗