Molecular evolution--who is in the driver's seat?
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Aging↗
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Results for “driver mutations”
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STK11 Mutations and Deletions Define an Aggressive Molecular Subgroup of Cervical Adenocarcinoma.
Cervical adenocarcinoma accounts for 15%-20% of cervical cancers and is associated with poorer survival and reduced response to screening and immunotherapy compared with squamous cell carcinoma (SCC). The genomic drivers underlying this molecular subgroup remain incompletely characterized. Whole-exome sequencing was performed on 302 invasive cervical cancers from Guatemala and Venezuela. Structural variation analysis was conducted using SNP-array and whole-genome sequencing data. Findings were replicated in more than 4600 additional cervical cancer samples from TCGA, AACR Project GENIE, MSKCC, and Caris datasets. TP53 mutations were more frequent in adenocarcinoma than SCC, particularly in HPV-negative tumors. STK11 alterations, including mutations and focal deletions, were significantly enriched in HPV-positive adenocarcinomas compared with SCC and affected 23% of adenocarcinomas overall. Whole-genome analyses identified recurrent focal deletions, inversions, chromosomal rearrangements, and breakage-fusion-bridge events involving chromosome 19p and STK11 that were not detected by exome sequencing alone. STK11 alterations were associated with younger age at diagnosis, poorer overall survival, and inferior outcomes following immune checkpoint inhibitor (ICI) therapy. STK11 alterations significantly co-occurred with YAP1 amplification but were largely mutually exclusive with PIK3CA mutation. Cervical adenocarcinomas also demonstrated significantly lower CD274 (PD-L1) expression than SCC. STK11 alterations define a distinct molecular subgroup of cervical adenocarcinoma characterized by structural disruption of chromosome 19p, younger age at onset, and poorer clinical outcomes. These findings have implications for molecular classification and future targeted therapeutic approaches in cervical cancer.
Humans↗
NOTCH1 acts as a tumor suppressor that induces early differentiation in head and neck cancer.
Inactivating NOTCH1 mutations in head and neck squamous cell carcinoma (HNSCC) were described over a decade ago, suggesting a tumor suppressor function - unlike its oncogenic role in other tumors. Today, much debate persists regarding a putative oncogenic role in HNSCC as well, with reports that NOTCH1 signaling drives tumor growth and a cancer stem cell (CSC) phenotype. In this work, comprehensive experiments unequivocally demonstrate that NOTCH1 is a tumor suppressor in HNSCC regardless of mutation or activation status and that it reduces CSC frequency. We developed a signature of NOTCH1 activation showing the pathway is associated with very early differentiation, an altered tumor microenvironment, and better prognosis. Clarifying whether NOTCH1 occasionally functions as an oncogenic driver in HNSCC is crucial to prognosis and personalized therapy. The results presented unify the field, reconcile conflicting data, and provide critical insights into the biological and clinical significance of NOTCH1, with broader implications in other squamous carcinomas with NOTCH1 mutations.
Receptor, Notch1↗
Maternal age as a driver of genome instability: mechanisms linking aneuploidy, mutagenesis and mitochondrial dysfunction.
Advanced maternal age is a well-established risk factor for adverse reproductive outcomes due to increased rates of aneuploidy. However, emerging evidence indicates that the genetic consequences of maternal aging extend well beyond chromosome mis-segregation. Aging oocytes acquire a broad spectrum of genetic abnormalities, including maternally derived nuclear de novo mutations (DNMs) and mitochondrial DNA mutations, together with epigenetic dysregulation of DNA methylation and post-translational modification levels. These changes reflect the unique biology of the female germline in which oocytes remain arrested in meiotic prophase I for decades. Age-related deterioration of key processes, such as erosion of cohesion complexes, altered meiotic recombination, and weakened spindle assembly checkpoint surveillance collectively destabilize meiotic chromosome architecture, directly driving chromosome mis-segregation. At the same time, accumulation of endogenous DNA damage and declining DNA damage and repair processes increase the chances of transmitting lesions that can be converted into sequence-level mutations during the earliest embryonic divisions, when genome maintenance relies exclusively on maternal factors. High-resolution sequencing studies further demonstrate that maternal aging is associated with increased DNMs burden in both nuclear and mitochondrial DNA. Together, these findings support a model in which maternal aging is a driver of genome-wide instability that links aneuploidy and mutagenesis through shared defects in meiotic surveillance, declining DNA repair efficiency, and mitochondrial function. This framework positions delayed childbearing as a multifaceted genetic risk factor that extend beyond aneuploidy to include mutations and other genomic alterations that can impact intergenerational genetic risk.
Aneuploidy↗
DNA sequence of the Doc retroposon in the white-one mutant of Drosophila melanogaster and of secondary insertions in the phenotypically altered derivatives white-honey and white-eosin.
We analysed the structure of the white locus of Drosophila melanogaster in a family of related white mutants. The white-one mutant has bleach white eyes, and a Doc transposable element is inserted into the promotor region of the white locus. The DNA sequence of this Doc insertion was determined, and showed it to be closely related to other Drosophila melanogaster retroposons such as the I factor and the F, G and jockey elements. There are two long open reading frames, which encode a putative nucleic acid binding protein and a putative reverse transcriptase, respectively. Two independent, partially pigmented derivatives were analysed by cloning sequences from this region. In white-honey a transposable element of the retroviral class, B104, is inserted within the Doc element. In white-eosin there is an insertion within the Doc element of a 190 bp sequence that appears to be a member of a novel family of transposable elements. This pogo element is of the same structural class as the Drosophila melanogaster P and hobo elements. These data are consistent with the hypothesis that the Doc retroposon cannot excise, and that, for the white-one mutation, flies with altered phenotypes are most often generated by the insertion of additional transposable elements.
Amino Acid Sequence↗
Disassembly of the TRIM56-ATR complex promotes cytoDNA/cGAS/STING axis-dependent intervertebral disc inflammatory degeneration.
As the leading cause of disability worldwide, low back pain (LBP) is recognized as a pivotal socioeconomic challenge to the aging population and is largely attributed to intervertebral disc degeneration (IVDD). Elastic nucleus pulposus (NP) tissue is essential for the maintenance of IVD structural and functional integrity. The accumulation of senescent NP cells with an inflammatory hypersecretory phenotype due to aging and other damaging factors is a distinctive hallmark of IVDD initiation and progression. In this study, we reveal a mechanism of IVDD progression in which aberrant genomic DNA damage promoted NP cell inflammatory senescence via activation of the cyclic GMP-AMP synthase/stimulator of IFN genes (cGAS/STING) axis but not of absent in melanoma 2 (AIM2) inflammasome assembly. Ataxia-telangiectasia-mutated and Rad3-related protein (ATR) deficiency destroyed genomic integrity and led to cytosolic mislocalization of genomic DNA, which acted as a powerful driver of cGAS/STING axis-dependent inflammatory phenotype acquisition during NP cell senescence. Mechanistically, disassembly of the ATR-tripartite motif-containing 56 (ATR-TRIM56) complex with the enzymatic liberation of ubiquitin-specific peptidase 5 (USP5) and TRIM25 drove changes in ATR ubiquitination, with ATR switching from K63- to K48-linked modification, c thereby promoting ubiquitin-proteasome-dependent dynamic instability of ATR protein during NP cell senescence progression. Importantly, an engineered extracellular vesicle-based strategy for delivering ATR-overexpressing plasmid cargo efficiently diminished DNA damage-associated NP cell senescence and substantially mitigated IVDD progression, indicating promising targets and effective approaches to ameliorate the chronic pain and disabling effects of IVDD.
Humans↗
BMP receptor signaling is required for postnatal maintenance of articular cartilage.
Articular cartilage plays an essential role in health and mobility, but is frequently damaged or lost in millions of people that develop arthritis. The molecular mechanisms that create and maintain this thin layer of cartilage that covers the surface of bones in joint regions are poorly understood, in part because tools to manipulate gene expression specifically in this tissue have not been available. Here we use regulatory information from the mouse Gdf5 gene (a bone morphogenetic protein [BMP] family member) to develop new mouse lines that can be used to either activate or inactivate genes specifically in developing joints. Expression of Cre recombinase from Gdf5 bacterial artificial chromosome clones leads to specific activation or inactivation of floxed target genes in developing joints, including early joint interzones, adult articular cartilage, and the joint capsule. We have used this system to test the role of BMP receptor signaling in joint development. Mice with null mutations in Bmpr1a are known to die early in embryogenesis with multiple defects. However, combining a floxed Bmpr1a allele with the Gdf5-Cre driver bypasses this embryonic lethality, and leads to birth and postnatal development of mice missing the Bmpr1a gene in articular regions. Most joints in the body form normally in the absence of Bmpr1a receptor function. However, articular cartilage within the joints gradually wears away in receptor-deficient mice after birth in a process resembling human osteoarthritis. Gdf5-Cre mice provide a general system that can be used to test the role of genes in articular regions. BMP receptor signaling is required not only for early development and creation of multiple tissues, but also for ongoing maintenance of articular cartilage after birth. Genetic variation in the strength of BMP receptor signaling may be an important risk factor in human osteoarthritis, and treatments that mimic or augment BMP receptor signaling should be investigated as a possible therapeutic strategy for maintaining the health of joint linings.
Alleles↗
A gene-environment interaction between occupation and BRCA1/BRCA2 mutations in male breast cancer?
The association of male breast cancer (MBC) with a positive breast cancer (BC) family history and with BRCA1/2 germ-line mutations points to a genetic component; a relationship with occupation has also been reported. Recently, we identified pathogenetic BRCA1/2 mutations in a population-based series of Italian MBC patients: here in, we investigated interactions between a carrier status for BRCA1/2 mutations and occupation using a case-case design and estimating case-only odds ratios (CORs). Truck-driving was the most frequent occupation (3/4 BRCA-related cases and 2/19 unrelated cases). An interaction between carrier status and working as a truck-driver emerged, when we classified MBC cases as "ever/never-held" this job title (COR 25.5; 95% Confidence Limits (CL): 1.1-1,412.5) or according to truck-driving as the "longest-held" work (COR 54.0; 95% CL: 1.6-2,997.5). The possible modifying effect on MBC risk in subjects carrying BRCA1/2 germ-line mutations of an occupation characterised by exposure to chemicals such as polycyclic aromatic hydrocarbons (PAH) that are capable of inducing DNA damage, may provide clues to the role of environmental exposures in modifying BC risk in mutation carriers in both genders.
Adult↗
Marked response to dabrafenib plus trametinib in a patient with BRAF V600E-mutant pancreatic hepatoid carcinoma: a case report and systematic analysis of 57 cases.
BACKGROUND: Pancreatic hepatoid carcinoma (PHC) is an extremely rare pancreatic malignancy characterized pathologically by hepatocellular-like differentiation. Some patients may present with elevated serum alpha-fetoprotein (AFP). Owing to the limited number of reported cases, the clinical features, molecular characteristics, and systemic treatment strategies for PHC remain poorly defined. BRAF V600E is an actionable alteration with established therapeutic value in several solid tumors; however, its clinical significance in PHC remains unclear. CASE PRESENTATION: We report the case of a 64-year-old man with advanced PHC who presented with painless jaundice, dark urine, and recent weight loss. Laboratory tests showed marked cholestatic liver injury and significantly elevated AFP. Imaging revealed a pancreatic head-neck mass with portal vein tumor thrombus and regional lymph node metastases, corresponding to cT4N1M1, stage IV disease. Percutaneous transhepatic biliary drainage was first performed to relieve obstructive jaundice. Biopsy of the pancreatic lesion showed poorly differentiated carcinoma. Based on hepatoid morphology, immunophenotype, elevated serum AFP, imaging findings, and exclusion of primary hepatocellular carcinoma, the patient was diagnosed with PHC. Comprehensive genomic profiling identified a BRAF V600E mutation with a variant allele frequency of 31.89%, together with MDM2 and MYC amplification. The molecular profile was characterized by microsatellite stability, low tumor mutational burden, MGMT promoter methylation, and low PD-L1 expression. After two cycles of pembrolizumab-based first-line therapy combined with paclitaxel, S-1, and lenvatinib, AFP continued to increase and imaging showed rapid tumor enlargement, consistent with immune checkpoint inhibitor-related hyperprogressive disease. The treatment was then switched to dabrafenib plus trametinib. AFP declined rapidly and returned to the normal range within approximately two months. Imaging showed marked regression of the pancreatic primary lesion, disappearance of the portal vein tumor thrombus and metastatic lymph nodes, and conversion of peripheral blood minimal residual disease to negative. The best response was partial response. After approximately six months of targeted therapy, occult disease progression emerged. Subsequent addition of cetuximab, replacement of the MEK inhibitor, and dose escalation of targeted therapy did not restore sustained systemic disease control, although local disease remained manageable with subsequent treatment adjustments. Proton radiotherapy was then delivered to the residual pancreatic lesion, followed by CyberKnife radiotherapy for a newly detected 2.3-cm metastasis in the caudate lobe of the liver. As of April 2026, the patient's AFP level remained close to normal at 14 ng/mL, local lesions were well controlled, peripheral blood minimal residual disease had turned positive, and the patient remained in a stable tumor-bearing state. SYSTEMATIC ANALYSIS: We further summarized 57 previously reported cases of PHC. The median age was 54 years, and 66.7% of patients were male. Tumors occurred at different pancreatic sites, including the pancreatic head in 21 cases, body in 8 cases, tail in 13 cases, and multifocal lesions in 15 cases. More than half of the patients had metastatic disease at initial diagnosis. The immunophenotype of PHC was highly heterogeneous. Regarding treatment, 47 patients underwent surgery, 20 received chemotherapy, and 6 received targeted therapy. The 1-year and 3-year overall survival rates were 70.7% and 43.1%, respectively, indicating an overall poor prognosis. CONCLUSION: This case suggests that BRAF V600E may represent a clinically actionable driver alteration in PHC. Dabrafenib plus trametinib induced a rapid and deep response in this patient with advanced BRAF V600E-mutant PHC. Microsatellite stability, low tumor mutational burden, low PD-L1 expression, and MDM2 amplification may be associated with limited benefit from immunotherapy and a risk of hyperprogression. After resistance to targeted therapy, local radiotherapy may serve as an important strategy for controlling oligoresidual and oligometastatic lesions. Together with the literature review, this case supports early comprehensive molecular profiling and individualized multidisciplinary management for advanced PHC.
BRAF V600E↗
Steroid hormone-dependent transformation of polyhomeotic mutant neurons in the Drosophila brain.
Polyhomeotic (Ph), which forms complexes with other Polycomb-group (PcG) proteins, is widely required for maintenance of cell identity by ensuring differential gene expression patterns in distinct types of cells. Genetic mosaic screens in adult fly brains allow for recovery of a mutation that simultaneously disrupts the tandemly duplicated Drosophila ph transcriptional units. Distinct clones of neurons normally acquire different characteristic projection patterns and can be differentially labeled using various subtype-specific drivers in mosaic brains. Such neuronal diversity is lost without Ph. In response to ecdysone, ph mutant neurons are transformed into cells with unidentifiable projection patterns and indistinguishable gene expression profiles during early metamorphosis. Some subtype-specific neuronal drivers become constitutively activated, while others are constantly suppressed. By contrast, loss of other PcG proteins, including Pc and E(z), causes different neuronal developmental defects; and, consistent with these phenomena, distinct Hox genes are differentially misexpressed in different PcG mutant clones. Taken together, Drosophila Ph is essential for governing neuronal diversity, especially during steroid hormone signaling.
Animals↗
Nucleotide sequence and expression of ribosomal protein S3 mRNA during embryogenesis in the Mexican axolotl (Ambystoma mexicanum).
We have isolated and sequenced a full-length (0.9 kb) cDNA clone of ribosomal protein S3 by subtraction hybridization using a single-stranded cDNA library from stage 25-27 (tracer) and the mRNA from stage 15-17 (driver) of embryonic Mexican axolotl (Ambystoma mexicanum). The axolotl is a unique animal model for studying heart development as well as myofibrillogenesis because it carries a mutation in gene c. The deduced amino acid sequence of axolotl S3 protein shows about 93.9% identity with human S3 protein over a 243 amino acid residue overlap. When compared with mouse and Xenopus laevis ribosomal S3 proteins, the axolotl sequenc shows 94.3 and 93.9% identity respectively. Interestingly, the axolotl S3 sequence shows higher identity at the nucleic acid level with human and/or other mammals than with Xenopus. The S3 transcript, as determined by RT-PCR, is present at stage 2-4 in a lower amount and the onset of transcription is most likely at the beginning of gastrulation (10-12). The expression level of S3 transcripts reaches a maximum by mid gastrulation (stages 13-14) and then follows a biphasic pattern being lower at stages 16-17 with subsequently steady increases until the mid tailbud stages (25-27).
Ambystoma mexicanum↗
Exploring genetic adaptation and microbial dynamics in engineered anaerobic ecosystems via strain-level metagenomics.
Genetic heterogeneity exists within all microbial populations, with sympatric cells of the same species often exhibiting single-nucleotide variations that influence phenotypic traits, including metabolic efficiency. However, the evolutionary dynamics of these strain-level differences in response to environmental stress remain poorly understood. Here, we present a first-of-its-kind study tracking the adaptive evolution of an anaerobic, carbon-fixing microbiota under a controlled engineered ecosystem focused on carbon dioxide bioconversion into methane. Leveraging strain-resolved metagenomics with an ad hoc variant calling and phasing approach, we mapped mutation trajectories and observed that the two dominant Methanothermobacter species maintained distinct sweeping haplotypes over time, most likely due to niche-specific metabolic roles. By combining population genetic statistics and peptide reconstruction, mer and mcrB genes emerged as potential drivers of archaeal strain-level competition. These findings pave the way for targeted engineering of microbial communities to enhance bioconversion efficiency, with significant implications for sustainable energy and carbon management in anaerobic systems.
Metagenomics↗
What the papers say: where is the somatic mutation that causes aging?
It has been proposed that somatic mutations make major contributions to aging. The first paper, based on a gene knock-in mouse, supports a contributory role for mutation in mtDNA in aging, but does not support a damaged-mtDNA-producing-more-damaged-mtDNA hypothesis. The second paper indicates some GC-rich sequences in the nuclear DNA are more sensitive to oxidative damage than mtDNA. As a result, key genes involved in brain function and mitochondrial function are progressively inactivated with age. Failure in these nucleus-encoded mitochondrial genes may be a primary reason for mitochondrial failure in old age.
Aging↗
Physical analysis of deletion mutations in the ilvGEDA operon of Escherichia coli K-12.
DNA-DNA hybridization of cloned segments of the Escherichia coli K-12 ilvGEDA operon to genomic blots was used to determine the physical dimensions of a series of deletion mutations of the ilvGEDA operon. The smallest mutation resulted from the deletion of approximately 200 base pairs from within ilvD, whereas the largest mutation resulted from the deletion of 17 kilobases including the rep gene. The structure of three of these mutants indicates that formation of the deletions was mediated by Tn5 (or Tn5-131) that is retained in the chromosome. This is the first observation of this type of Tn5-mediated event. Our analysis of the total acetohydroxy acid synthase activity of strains containing deletions of ilvG indicates that the truncated ilvG polypeptide of wild-type E. coli K-12 lacks enzyme activity. The small 200-base-pair deletion of ilvD confirms the presence of a strong polar site 5' to ilvA. The detailed structure of these deletions should prove useful for the investigation of other genes in this region. This genomic analysis demonstrates that the ilv restriction site map that was established previously by the analysis of recombinant bacteriophage and plasmids is identical to that on the genome.
Chromosome Deletion↗
Targeting CD44 reverses sphingomyelin-induced oligodendrocyte maturation arrest in acid sphingomyelinase deficiency.
Loss-of-function mutations in the smpd1 gene cause acid sphingomyelinase deficiency (ASMD). Early neurodegeneration and lethality characterize its infantile neurovisceral form (type A). While neuronal dysfunction was traditionally considered the primary driver of the pathology, recent evidence suggests that dysmyelination and microgliosis are not merely secondary features. Specifically, myelin debris undermines the protective role of microglia, contributing to neuroinflammation and neuronal death. Herein, we examined central myelin and oligodendrocyte lineage progression in ASM knockout mice. We show that early-onset dysmyelination results from compromised oligodendrocyte maturation driven by aberrant sphingomyelin-mediated signaling. Transcriptomic profiling revealed that mature oligodendrocytes in these mice retain a gene expression signature similar to oligodendrocyte precursor cells, indicating a differentiation arrest. The cell adhesion molecule CD44 remained significantly upregulated in mature ASMko oligodendrocytes. Pharmacological inhibition of CD44 with verbascoside rescued oligodendroglial maturation in primary culture. Verbascoside administration in vivo restored myelin integrity and improved motor behavior. These findings establish that sphingomyelin homeostasis is critical for oligodendrocyte maturation and identify myelin defects as both primary pathological triggers and therapeutic targets for ASMD with neurologic symptoms.
Animals↗
CMAtlas: a comprehensive DNA methylation atlas for exploring epigenetic alterations in 34 human cancer types.
MOTIVATION: Aberrant DNA methylation is a fundamental epigenetic hallmark of cancer. However, existing resources often lack technological diversity and comprehensive cancer coverage. Furthermore, most platforms fail to achieve deep multi-omics integration and tend to ignore cancer-type-specific methylation features, limiting their utility in precision oncology and drug discovery. RESULTS: We developed Cancer Methylation Atlas (CMAtlas), a comprehensive platform integrating 13 753 samples across 34 cancer types. By applying technology-tailored pipelines to data from various profiling technologies, we identified 830 725 tumor-specific differentially methylated elements (DMEs) and 1 480 098 differentially methylated regions (DMRs), alongside 1 154 256 cancer-type-specific DMEs and 329 154 DMRs. The platform demonstrates high cross-platform consistency and strong concordance between tumor tissues and cell lines, ensuring the robustness of our findings. All DMEs and DMRs are annotated with multi-omics data (RNA expression, somatic mutations, and chromatin accessibility) and clinical relevance (survival associations and cell-free DNA profiling). We further demonstrate the utility of CMAtlas by identifying prognostic aberrant methylation in colorectal cancer driver genes. AVAILABILITY AND IMPLEMENTATION: CMAtlas is freely accessible at {{https://cmatlas.renlab.cn/}}. The platform offers an intuitive web interface supporting gene-centric and cancer-centric queries, alongside customizable analysis modules designed to facilitate user-specific research needs.
Humans↗
In-depth assessment of BRAF, NRAS, KRAS, EGFR, and PIK3CA mutations on cell-free DNA in the blood of melanoma patients receiving immune checkpoint inhibition.
INTRODUCTION: Circulating tumor DNA (ctDNA) holds promise for guiding immune checkpoint inhibitor (ICI) therapy and stratifying responders from non-responders. While tumor-informed ctDNA detection approaches are sensitive and mutation-inclusive, they require tumor tissue, which limits applicability in real-world settings. Conversely, tumor-agnostic methods often have limited genomic coverage. In this study, we evaluated a tumor-agnostic, broad-panel ctDNA assay in patients with advanced melanoma treated with ICI. METHODS: We conducted a prospective analysis of 241 longitudinal samples from 39 patients with unresectable stage III/IV melanoma using a SYSMEX targeted NGS panel covering 1,114 COSMIC mutations. Plasma samples were collected at baseline and during ICI therapy. The assay's sensitivity reached seven mutant molecules, corresponding to a 0.07% mutation allele frequency (MAF). ctDNA profiles were compared with matched tumor tissue and correlated with clinical features and survival. RESULTS: At baseline, ctDNA was detected in 64.5% of patients. Common mutations included BRAFV600E (43.8%) and NRASG12D (36.4%), followed by KRAS, EGFR, and PIK3CA variants. Overall tissue-plasma concordance was 51.6%, with more extended biopsy-plasma intervals associated with discordance (p = 0.0105). Notably, 12.2% of cases exhibited partial concordance, characterized by shared mutations and additional plasma-only alterations, underscoring the complementary value of blood-based profiling. Persistent or re-emerging ctDNA positivity post-therapy correlated with shorter progression-free survival (PFS, p = 0.003), while ctDNA-negative patients showed significantly improved outcomes. Patients that remained ctDNA-negative had significantly longer progression-free survival (median not reached) compared to those with persistent ctDNA positivity (median 3 months) or those converting to positive (median 7.5 months; p = 0.0073). Early NRAS and KRAS ctDNA levels strongly predicted poor response (p = 0.0069 and p = 0.028). The prognostic impact extended beyond canonical drivers, as non-hotspot variants also correlated with the outcome. Notably, even low-level ctDNA persistence (5-10 MM/mL) carried adverse prognostic implications (p = 0.0054). Concerning a shorter PFS, ctDNA positivity was also associated with elevated S100 levels (p = 0.047). Organ-specific mutation enrichment (e.g., KRASG12D in brain, EGFRG719A in lymph nodes) suggested possible metastatic tropism. CONCLUSION: Broad tumor-agnostic ctDNA analysis effectively identified clinically relevant mutations and predicted outcomes in ICI-treated melanoma patients. This approach enables tissue-independent and real-time ctDNA monitoring and may inform patient selection and therapeutic strategies in future interventional trials.
Humans↗
Cyclin D does not provide essential Cdk4-independent functions in Drosophila.
The three mammalian D-type cyclins are thought to promote progression through the G1 phase of the cell cycle as regulatory subunits of cyclin-dependent kinase 4 and 6. In addition, they have been proposed to control the activity of various transcription factors without a partner kinase. Here we describe phenotypic consequences of null mutations in Cyclin D, the single D-type cyclin gene in Drosophila. As previously observed with null mutations in the single Drosophila Cdk4 gene, these mutations do not primarily affect progression through the G1 phase. Moreover, the apparently indistinguishable phenotypes of double (CycD and Cdk4) and single mutants (CycD or Cdk4) argue against major independent functions of Cyclin D and Cdk4. The reduced cellular and organismal growth rates observed in both mutants indicate that Cyclin D-Cdk4 acts as a growth driver.
Animals↗