The role of the serine/glycine metabolic pathway (SGP) has recently been demonstrated in tumors; however, the pathological relevance of the SGP in thyroid cancer remains unexplored. Here, we perform ...metabolomic profiling of 17 tumor-normal pairs; bulk transcriptomics of 263 normal thyroid, 348 papillary, and 21 undifferentiated thyroid cancer samples; and single-cell transcriptomes from 15 cases, showing the impact of mitochondrial one-carbon metabolism in thyroid tumors. High expression of serine hydroxymethyltransferase-2 (SHMT2) and methylenetetrahydrofolate dehydrogenase 2 (MTHFD2) is associated with low thyroid differentiation scores and poor clinical features. A subpopulation of tumor cells with high mitochondrial one-carbon pathway activity is observed in the single-cell dataset. SHMT2 inhibition significantly compromises mitochondrial respiration and decreases cell proliferation and tumor size in vitro and in vivo. Collectively, our results highlight the importance of the mitochondrial one-carbon pathway in undifferentiated thyroid cancer and suggest that SHMT2 is a potent therapeutic target.
Mobocertinib, an EGFR exon 20 insertion (Ex20ins)–specific tyrosine kinase inhibitor has been used for treatment of advanced/metastatic EGFR Ex20ins-mutant non-small cell lung cancer (NSCLC). ...However, resistance mechanisms to EGFR Ex20ins-specific inhibitors and the efficacy of subsequent amivantamab treatment is unknown.
To investigate resistance mechanisms, tissue and cfDNA samples were collected before treatment initiation and upon development of resistance from NSCLC patients with EGFR Ex20ins mutations received mobocertinib, poziotinib, and amivantamab treatments. Genetic alterations were analyzed using whole-genome and targeted sequencing, and in vitro resistant cell lines were generated for validation.
EGFR amplification (n = 6, including 2 broad copy number gain) and EGFR secondary mutation (n = 3) were observed at the resistance of mobocertinib. One patient had both EGFR secondary mutation and high EGFR focal amplification. In vitro models harboring EGFR alterations were constructed to validate resistance mechanisms and identify overcoming strategies to resistance. Acquired EGFR-dependent alterations were found to mediate resistance to mobocertinib in patients and in vitro models. Furthermore, two of six patients who received sequential amivantamab followed by an EGFR tyrosine kinase inhibitor had MET amplification and showed partial response.
Our study revealed EGFR-dependent and -independent mechanisms of mobocertinib resistance in patients with advanced EGFR Ex20ins-mutant NSCLC.
Throughout an individual's lifetime, genomic alterations accumulate in somatic cells
. However, the mutational landscape induced by retrotransposition of long interspersed nuclear element-1 (L1), a ...widespread mobile element in the human genome
, is poorly understood in normal cells. Here we explored the whole-genome sequences of 899 single-cell clones established from three different cell types collected from 28 individuals. We identified 1,708 somatic L1 retrotransposition events that were enriched in colorectal epithelium and showed a positive relationship with age. Fingerprinting of source elements showed 34 retrotransposition-competent L1s. Multidimensional analysis demonstrated that (1) somatic L1 retrotranspositions occur from early embryogenesis at a substantial rate, (2) epigenetic on/off of a source element is preferentially determined in the early organogenesis stage, (3) retrotransposition-competent L1s with a lower population allele frequency have higher retrotransposition activity and (4) only a small fraction of L1 transcripts in the cytoplasm are finally retrotransposed in somatic cells. Analysis of matched cancers further suggested that somatic L1 retrotransposition rate is substantially increased during colorectal tumourigenesis. In summary, this study illustrates L1 retrotransposition-induced somatic mosaicism in normal cells and provides insights into the genomic and epigenomic regulation of transposable elements over the human lifetime.
Abstract Genomic alterations in tumors play a pivotal role in determining their clinical trajectory and responsiveness to treatment. Targeted panel sequencing (TPS) has served as a key clinical tool ...over the past decade, but advancements in sequencing costs and bioinformatics have now made whole-genome sequencing (WGS) a feasible single-assay approach for almost all cancer genomes in clinical settings. This paper reports on the findings of a prospective, single-center study exploring the real-world clinical utility of WGS (tumor and matched normal tissues) and has two primary objectives: (1) assessing actionability for therapeutic options and (2) providing clarity for clinical questions. Of the 120 patients with various solid cancers who were enrolled, 95 (79%) successfully received genomic reports within a median of 11 working days from sampling to reporting. Analysis of these 95 WGS reports revealed that 72% (68/95) yielded clinically relevant insights, with 69% (55/79) pertaining to therapeutic actionability and 81% (13/16) pertaining to clinical clarity. These benefits include the selection of informed therapeutics and/or active clinical trials based on the identification of driver mutations, tumor mutational burden (TMB) and mutational signatures, pathogenic germline variants that warrant genetic counseling, and information helpful for inferring cancer origin. Our findings highlight the potential of WGS as a comprehensive tool in precision oncology and suggests that it should be integrated into routine clinical practice to provide a complete image of the genomic landscape to enable tailored cancer management.
The primary role of a red blood cell (RBC) is delivering oxygen throughout our body. Abnormalities of this basic function lead to anemia and are caused by numerous diseases such as malaria and sickle ...cell anemia. As prompt and inexpensive tests for blood screening are in demand, we have developed a faster and reliable way to measure morphological parameters associated with the structure of red blood cells and the size distribution of the cells in a whole blood smear. Modeling the RBC shape under Born approximation, we are able to determine parameters of clinical relevance, such as the diameter, thickness and dimple size. From a measured quantitative phase image of a blood smear, we can determine the average and standard deviation of the red blood cell volume simultaneously, i.e., without analyzing each cell individually. This approach may open the door for a new generation of label-free, high-throughput blood testing.
The comprehensive genomic impact of ionizing radiation (IR), a carcinogen, on healthy somatic cells remains unclear. Using large-scale whole-genome sequencing (WGS) of clones expanded from irradiated ...murine and human single cells, we revealed that IR induces a characteristic spectrum of short insertions or deletions (indels) and structural variations (SVs), including balanced inversions, translocations, composite SVs (deletion-insertion, deletion-inversion, and deletion-translocation composites), and complex genomic rearrangements (CGRs), including chromoplexy, chromothripsis, and SV by breakage-fusion-bridge cycles. Our findings suggest that 1 Gy IR exposure causes an average of 2.33 mutational events per Gb genome, comprising 2.15 indels, 0.17 SVs, and 0.01 CGRs, despite a high level of inter-cellular stochasticity. The mutational burden was dependent on total irradiation dose, regardless of dose rate or cell type. The findings were further validated in IR-induced secondary cancers and single cells without clonalization. Overall, our study highlights a comprehensive and clear picture of IR effects on normal mammalian genomes.
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•Single-cell-resolution DNA sequencing reveals IR-associated mutational signatures•IR-associated mutations include short deletions and simple and complex rearrangements•Simultaneous multiple DSBs cause chromothripsis, chromoplexy, and SVs by BFB cycles•1 Gy IR exposure generates ∼2.33 mutations per Gb in mammalian cells
Youk, Kwon, Lim, Kim, Kim et al. used single-cell-resolution DNA sequencing to investigate the quantitative and qualitative impact of ionizing radiation (IR) on the mammalian genome. They found characteristic mutational signatures, comprised of specific short deletions and simple and complex structural variations. Complex genomic rearrangements, prevalent in cancer, were induced in post-irradiated cells, suggesting their role in tumor development. The study reveals mutational rates proportional to IR dose and consistent across cell types, underscoring IR’s universal mutagenic impact on mammalian cells.
Background
Reduction in skin elasticity due to aging causes skin sagging and wrinkles. Although there are various objective and reliable techniques for measuring skin elasticity, it is difficult to ...obtain a visual representation of skin elasticity with them. Therefore, we developed a novel device, the Swing anglemeter, and analyzed its effectiveness for measuring skin elasticity of the cheek.
Materials and Methods
Forty‐five healthy Korean women (age, 23‐60 years) participated. The Swing anglemeter works by dropping a rubber ball on a subject's cheek, which draws a curve as it collides with the cheek. After recording the movement of the ball using the slow‐motion function on a mobile phone, we defined the maximum angle at which the ball bounces off the skin as the elastic angle, using frame‐by‐frame video analysis. Changes in the elastic angle were assessed according to age, and correlation with the Ballistometer® results (Dia‐stron Ltd., Andover, UK) was analyzed for validation.
Results
Elastic angles differed significantly (P < .001) according to age. A negative correlation was found between the elastic angle and age (r = −.799, P < .001). Compared with the Ballistometer® measurements, the elastic angle was negatively correlated with alpha (r = −.570, P < .001); it was positively correlated with the mean coefficient of restitution and area (r = .602, P < .001 and r = .535, P < .001, respectively).
Conclusion
The elastic angle is a useful parameter for reflecting skin elasticity, both quantitatively and visually. Our method can help subjects understand their skin elasticity status. Therefore, we expect the device will be utilized in various fields within the cosmetic industry.
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