SEARCH · Search PubMed

Results for “Cancer drivers”

Search indexed PubMed citations on genomics, clinical trials, systematic reviews and public health. Explore titles, authors and supplied subject terms, then open the PubMed record.

SourceResearch connectionFrom yearThrough year

Quote a phrase for an exact phrase match. Source license links do not imply unrestricted reuse.

At least 451 records · Page 25Linked to original sources

PubMed2026

Trop-1/EpCAM Thr115 is a driver of hyperproliferative cell repair and of severe lung damage in COVID-19.

SARS-CoV-2 lung infection triggers an acute reaction that can severely impair oxygen exchange. However, the underlying molecular processes are poorly understood. The TROP1/EPCAM p.M115T polymorphism was found associated with COVID-19 severity. We discovered here that the T115 Trop-1/EpCAM is a driver of cell growth, whereas M115 Trop-1/EpCAM has little, if any, cell growth induction capacity. TROP1/EPCAM knockout mice showed altered proliferation of embryonic stem cells. The Trop-1/EpCAM T115 allele was then found to drive hyperproliferative capacity in murine fibrosarcoma cells. Corresponding growth stimulation was shown in human colon cancer cells, through CRISPR-Cas9 ablation of the endogenous TROP1/EPCAM and comparative transfection of TROP1/EPCAM p.T115 (T-mod) or p.M115 (M-mod) alleles. In COVID-19 patients, T115 Trop-1/EpCAM was shown to cause aberrant, hyperproliferative wound repair in SARS-CoV-2-damaged lung alveoli that led to critical oxygen-exchange impairment. Analysis of COVID-19 patient lungs at autopsy showed hyperproliferation of T115 Trop-1/EpCAM+ epithelial cells over the alveolar epithelium damaged by the infection. This correlated with T115 Trop-1/EpCAM+ inflammatory cells hyperproliferation and alveolar hyaline membrane formation. These multi-layered barriers were computed to reduce oxygen diffusion by up to 100-fold. Our findings indicate an unanticipated mechanism for lung damage by T115 Trop-1/EpCAM, and suggest a potential target for corresponding therapeutic approaches.

COVID-19↗

PubMed2002

Identification of genes induced by BRCA1 in breast cancer cells.

Inherited mutations of the BRCA1 gene predispose to breast, ovarian, and other cancers. The role of the BRCA1 gene in the maintenance of chromosomal integrity is linked to a number of biological properties of its protein product, including transcriptional regulation. In the present study, we have used suppression subtractive hybridisation (SSH) to identify genes induced by BRCA1 by comparing control MCF7 breast carcinoma cells (driver) with MCF7 cells ectopically expressing BRCA1 (tester) and generated a forward subtracted cDNA library. We screened 500 putative positive clones from this library. Two hundred and ten of these clones were positive by differential screening with forward and reverse subtracted probes and the 65 cDNA clones which showed more than fivefold increase were selected for sequencing analysis. We clustered 46 different genes that share high homology with sequences in the GenBank/EMBL databases. Among these, 30 were genes whose function had been previously identified while the remaining 16 clones were genes with unknown functions. Of particular interest, BRCA1 gene induces the expression of genes encoding DNA repair proteins RAD21 and MSH2, ERBB2/HER2 interacting protein ERBIN, meningioma-associated protein MAC30, and a candidate ovarian tumour-suppressor OVCA1. Northern and Western blot analyses confirmed that the expression of these five genes are up-regulated following BRCA1 overexpression in MCF7 and UBR60-bcl2 cells. This is the first study reporting a set of BRCA1-induced genes in breast carcinoma cells by the SSH technique. We suggest that some known genes identified in this study may provide new insights into the tumour-suppressor function of BRCA1.

BRCA1 Protein↗

PubMed1997

Lifestyles and health risks of collegiate athletes: a multi-center study.

OBJECTIVE: To determine whether college athletes are at greater risk for maladaptive lifestyle and health-risk behaviors than their nonathletic peers and to identify high risk taking groups by gender, sport, and other identifiers. DESIGN: Multicenter, cross-sectional study. SETTING: Seven major geographically represented collegiate institutions in the United States. PARTICIPANTS: A total of 2,298 college athletes and 683 randomized nonathlete controls completed a confidential survey questionnaire between the summer of 1993 and winter of 1994, assessing lifestyle and health-risk behaviors over the previous 12 months. MAIN OUTCOME MEASURES: Self-reports of lifestyle behaviors and health risks in the following areas: motor-vehicle safety, substance abuse, sexually transmitted diseases and contraception, mental health, cancer prevention, nutrition, exercise and general preventive health issues. RESULTS: Athletes demonstrated significantly higher risk-taking behaviors (p < 0.05) than their nonathlete peers in the following areas: less likely always to use seatbelts; less likely always to use helmets with motorcycles, mopeds, and bicycles; more often drive as a passenger with a driver under the influence of alcohol or drugs; greater quantity and frequency of alcoholic beverages; greater frequency of smokeless tobacco and anabolic steroid use; less-safe sex; greater number of sexual partners; less contraceptive use; and more involvement in physical fights. Female athletes reported a higher prevalence of irregular menses, amenorrhea, and stress fractures compared with female nonathletes. Male athletes had more risk-taking behaviors than did female athletes (p < 0.05), and athletes in contact sports demonstrated more risk-taking behaviors than did athletes in noncontact sports (p < 0.05). Athletes with one risk-taking behavior were likely to have multiple risk-taking behaviors (p < 0.05). CONCLUSIONS: College athletes appear to be at higher risk than their nonathletic peers for certain maladaptive lifestyle behaviors. Athlete subgroups at highest risk include male athletes and athletes participating in contact sports. Athletes at risk for one high-risk behavior demonstrated an increased risk for multiple risk-taking behaviors. Preventive health interventions deserve further study to determine strategies for risk reduction in high-risk groups.

Adolescent↗

PubMed2026

NTRK-positive collision tumor of the gastrointestinal tract: a rare entity case report.

Neurotrophic receptor tyrosine kinase (NTRK) fusion-positive colorectal cancer (CRC) represents a rare molecular subset of CRC. We report an exceptional case of a collision tumor composed of two anatomically adjacent but histologically and genomically distinct primary colorectal carcinomas, each giving rise to a corresponding metastasis. Comprehensive histopathologic and molecular analyses demonstrated that one primary tumor and its matched metastasis consisted predominantly (> 90%) of a solid carcinoma harboring a TPR::NTRK fusion, high microsatellite instability (MSI-H), elevated tumor mutational burden (TMB), and loss of MLH1 and PMS2 expression by immunohistochemistry. In contrast, the second primary tumor and its corresponding metastasis exhibited conventional adenocarcinoma morphology with mucinous differentiation, lacked an NTRK fusion, and carried canonical driver mutations in KRAS, APC, SMAD4, and TP53. This case underscores the importance of integrated histopathologic and molecular evaluation in CRCs with heterogeneous morphology, as the identification of multiple, genomically distinct tumor components may have significant diagnostic, prognostic, and therapeutic implications.

NTRK gene fusion↗

PubMed2026

MET-Aberrant non-small cell lung cancer: from kinase dependence to cell-surface targetability-mechanistic basis and biomarker framework for bispecific antibodies and antibody-drug conjugates.

MET-aberrant non-small cell lung cancer (NSCLC) is not a uniform therapeutic entity. Its biology, diagnostic pathways, and treatment sensitivity differ across MET exon 14 skipping alteration (METex14), MET amplification, and MET overexpression. This heterogeneity cannot be fully explained by conventional event-based classification and is reflected in the distinct clinical activity of MET tyrosine kinase inhibitors (MET-TKIs), bispecific antibodies (BsAbs), and antibody-drug conjugates (ADCs). With the emergence of antibody-based therapies, MET has evolved from a signaling driver to a cell-surface target for receptor modulation and payload delivery. We therefore propose a clinically anchored two-dimensional framework for interpreting therapeutic relevance in MET-aberrant NSCLC: kinase dependence and cell-surface targetability. Neither dimension should be regarded as a directly measurable binary variable. Kinase dependence is inferred from genomic and treatment-contextual proxies, most strongly METex14 and, more conditionally, high-level focal MET amplification. Cell-surface targetability is approximated by drug-specific IHC assessment of assay-defined c-MET protein expression; however, receptor internalization, intracellular trafficking, and payload delivery capacity remain incompletely measurable in routine clinical practice. Within this framework, MET-TKIs have the most evidence-supported established role in tumors with evidence of MET-driven kinase dependence. EGFR × MET BsAbs have demonstrated clinical activity in broad post-osimertinib EGFR-mutant NSCLC, while EGFR/MET co-dependence or MET-mediated bypass activation provides a mechanistic rationale for their use; MET-defined preferential benefit remains to be prospectively established. MET-directed antibody-drug conjugates (MET-ADCs) are supported in drug- and assay-defined populations with high c-MET protein overexpression, although the predictive relevance of delivery-related factors remains hypothesis-generating. Accordingly, MET testing should shift from single-event detection to platform-oriented stratification: next-generation sequencing (NGS) for driver alterations and resistance profiles, fluorescence in situ hybridization (FISH) for high-level focal amplification, and immunohistochemistry (IHC) for surface expression relevant to antibody-based therapies. This framework is intended to organize current biological and clinical evidence rather than to replace drug-specific companion diagnostics, regulatory indications, or prospectively validated treatment-selection algorithms. Precision treatment of MET-aberrant NSCLC is thus moving from event-based drug selection toward mechanism-based therapeutic matching. Future priorities include standardizing biomarkers, defining optimal target populations, and aligning biological subtypes, diagnostic strategies, and therapeutic platforms.

Antibody-drug conjugate↗

PubMed1996

State- and sex-specific prevalence of selected characteristics--Behavioral Risk Factor Surveillance System, 1992 and 1993.

PROBLEM/CONDITION: Much chronic disease and injury morbidity and mortality is associated with high-risk behaviors (e.g., cigarette smoking, excessive alcohol consumption, and physical inactivity) and with lack of preventive health care (e.g., screening for cancer). States use the Behavioral Risk Factor Surveillance System (BRFSS) to collect data about these modifiable health behaviors and to monitor trends and significant changes in their populations over time. REPORTING PERIOD: 1992 and 1993. DESCRIPTION OF SYSTEM: The BRFSS is a state-based telephone survey of the civilian, noninstitutionalized, adult (persons > or = 18 years of age) population. In 1992, 48 states and the District of Columbia participated in the BRFSS; in 1993, 49 states and the District of Columbia participated. Several questions were added to the BRFSS in 1993. RESULTS: As in previous years, state-specific variations occurred in the prevalence of high-risk behaviors, awareness of certain medical conditions, use of preventive health services, and health-care coverage. In 1993, 4.0% (range: 1.4% - 6.4%) of adults reported riding with a driver who had had too much alcohol to drink. The percentage of persons > or = 50 years of age who had ever had a proctoscopic examination ranged from 25.6% to 51.5% (median: 36.8%). Among adults > or = 65 years of age, 27.4% (range: 18.5 % - 40.0%) had ever had a pneumococcal vaccination, and 49.9% (range: 28.7% - 66.2%) had had an influenza vaccination within the past 1 year. INTERPRETATION: The variations in prevalence across states likely reflect socioeconomic differences, differences in state laws enacted to discourage risky behaviors, different levels of effort to screen for certain types of cancer or risk factors for other diseases, and other factors. ACTION TAKEN: States will continue to use the BRFSS to collect data about health behaviors. Analysis of these data will enable states to monitor factors that may affect the rate of chronic disease and injury mortality and morbidity and to develop public health policies to address these problems.

Adult↗

PubMed2026

Network based approach identifies miR-145-3p as a central regulatory hub associated to the progression from localized to metastatic medullary thyroid carcinoma.

Medullary thyroid carcinoma (MTC) is a neuroendocrine tumor originating from calcitonin producing C-cells and accounts for 1-5% of thyroid cancers. Total thyroidectomy is curative in localized disease (N0), whereas lymph node metastases (N1) are associated with poorer prognosis. However, the molecular mechanisms driving the metastatic shift remain poorly understood. This study aimed to identify miRNA features linked to metastatic spread in MTC, focusing on the transition from N0 to N1. Co-expression networks were constructed for N0 and N1 tumors, and differential connectivity analysis was used to identify key miRNAs acting as regulatory hubs. Functional annotation of their target genes was performed using the Kyoto Encyclopedia of Genes and Genomes (KEGG), Gene Ontology (GO), and Reactome pathway analyses. Validation experiments were carried out in MTC cells to evaluate the effects of selected miRNAs on cell proliferation, survival, and MAPK pathway activation. Network analysis revealed distinct miRNA co-expression patterns between N0 and N1 tumors. Differential network analysis highlighted miR-145-3p as a central regulatory hub, exhibiting 29 altered co-expression changes and a marked loss of connectivity in N1. Target enrichment identified 59 validated genes, including key oncogenic drivers such as MYC, PTEN, BCL2, PIK3CA, AKT1, and MAPK7. In MTC cells, simultaneous inhibition of miR-145-3p together with its top co-expressed miRNAs increased proliferation and survival, and enhanced ERK phosphorylation, indicating MAPK pathway activation and a shift toward a more aggressive phenotype. In conclusion, this study identifies a miRNA regulatory hub centered on miR-145-3p that is associated with metastatic progression and highlights the value of network-based approaches in uncovering mechanisms of cancer dissemination. © 2026 The Author(s). The Journal of Pathology published by John Wiley & Sons Ltd on behalf of The Pathological Society of Great Britain and Ireland.

MAPK signaling↗

PubMed2026

The mechanism of malignant progression in extramammary Paget's disease (EMPD): hallmarks of EMPD.

The pathogenesis of cancer is characterized by the acceleration of tumor growth, inhibition of tumor suppression, genetic and epigenetic alteration, lubricative transformation and tumor microenvironment. Extramammary Paget's disease (EMPD) is a rare skin cancer that originates from apocrine glands in genital and axillary area. Although the pathogenesis of EMPD is still poorly understood, increasing evidence reveals that the mechanism of EMPD progression is regulated by the acquired ability of EMPD cells and tumor microenvironment. HER2/PI3K/AKT signaling and hormone receptor pathways are activated. Whereas tumor mutation burden is low, numerous driver genes such as ERBB2 and PIK3CA are detected. Tumor evolution in EMPD is characterized by high genetic intratumor heterogeneity with shared background factors. Tumor microenvironment in EMPD promotes immune evasion through the reduction of reduced CD4 + and CD8 + T cells and the increase of Treg cells and CD163 + macrophages. Enhanced Warburg effect and S. aureus contribute to the suppression of antitumor immunity. This review focuses on the mechanism of malignant progression in EMPD (hallmarks of EMPD).

Genome mutation↗

PubMed2024

ASXL1 truncating variants in BOS and myeloid leukemia drive shared disruption of Wnt-signaling pathways but have differential isoform usage of RUNX3.

BACKGROUND: Rare variants in epigenes (a.k.a. chromatin modifiers), a class of genes that control epigenetic regulation, are commonly identified in both pediatric neurodevelopmental syndromes and as somatic variants in cancer. However, little is known about the extent of the shared disruption of signaling pathways by the same epigene across different diseases. To address this, we study an epigene, Additional Sex Combs-like 1 (ASXL1), where truncating heterozygous variants cause Bohring-Opitz syndrome (BOS, OMIM #605039), a germline neurodevelopmental disorder, while somatic variants are driver events in acute myeloid leukemia (AML). No BOS patients have been reported to have AML. METHODS: This study explores common pathways dysregulated by ASXL1 variants in patients with BOS and AML. We analyzed whole blood transcriptomic and DNA methylation data from patients with BOS and AML with ASXL1-variant (AML-ASXL1) and examined differential exon usage and cell proportions. RESULTS: Our analyses identified common molecular signatures between BOS and AML-ASXL1 and highlighted key biomarkers, including VANGL2, GRIK5 and GREM2, that are dysregulated across samples with ASXL1 variants, regardless of disease type. Notably, our data revealed significant de-repression of posterior homeobox A (HOXA) genes and upregulation of Wnt-signaling and hematopoietic regulator HOXB4. While we discovered many shared epigenetic and transcriptomic features, we also identified differential splice isoforms in RUNX3 where the long isoform, p46, is preferentially expressed in BOS, while the shorter p44 isoform is expressed in AML-ASXL1. CONCLUSION: Our findings highlight the strong effects of ASXL1 variants that supersede cell-type and even disease states. This is the first direct comparison of transcriptomic and methylation profiles driven by pathogenic variants in a chromatin modifier gene in distinct diseases. Similar to RASopathies, in which pathogenic variants in many genes lead to overlapping phenotypes that can be treated by inhibiting a common pathway, our data identifies common pathways for ASXL1 variants that can be targeted for both disease states. Comparative approaches of high-penetrance genetic variants across cell types and disease states can identify targetable pathways to treat multiple diseases. Finally, our work highlights the connections of epigenes, such as ASXL1, to an underlying stem-cell state in both early development and in malignancy.

Humans↗

PubMedDate not supplied

When deep venous thrombosis fails to respond to therapy.

BACKGROUND: Deep venous thrombosis in primary care is usually treated with rest, analgesics, intravenous or low-molecular-weight heparin, and coumadin. In some cases, however, a less familiar course of diagnosis and management is required. METHODS: We describe the case of a 53-year-old truck driver who had an acute deep venous thrombosis of his right lower extremity, which failed to respond to routine therapy with heparin and warfarin. A literature search was undertaken to research the differential diagnosis and management of deep venous thrombosis and to review specifically the role of venal caval filters and inherited thrombotic disorders and occult cancer in this context. RESULTS AND CONCLUSION: The ultimate diagnosis in our patient appeared to be signet ring cell cancer of the colon that had metastasized to the right thigh. This case is an example of the inherent limitations of even an aggressive diagnostic and therapeutic approach to the entity of refractory deep venous thrombosis.

Anticoagulants↗

PubMed1998

Occupational risk factors for cancer of the gastric cardia. Analysis of death certificates from 24 US states.

We evaluated the risk of gastric cardia cancer by occupation and industry in a case-control study using information from death certificates for 24 US states in 1984-1992. One thousand fifty-six cases of gastric cardia cancer were identified among men aged 20 years or more, including 1,023 whites and 33 blacks. Controls were 5,280 subjects who died of nonmalignant diseases, 5:1 matched to cases by geographic region, race, gender, and 5-year age group. Among white men, occupations with elevated risk included financial managers (odds ratio [OR] = 6.1; 95% confidence interval [CI], 1.3-28.8), janitors and cleaners (OR = 1.7; 95% CI, 1.0-2.9), production inspectors (OR = 3.2; 95% CI, 1.5-6.9), and truck drivers (OR = 1.5; 95% CI, 1.0-2.2). Industries with elevated risk included pulp and paper mills (OR = 2.0; 95% CI, 1.0-37), newspaper publishing and printing (OR = 2.6; 95% CI, 1.0-6.3), industrial and miscellaneous chemicals (OR = 2.0; 95% CI, 1.0-3.9), water supply and irrigation (OR = 5.6; 95% CI, 1.6-19.9). Among black men, risks were nonsignificantly increased for subjects employed in railroads (3 cases, 2 controls) and for carpenters (3 cases, 0 controls). We created job-exposure matrices for asbestos, inorganic dust, metal dust, lead, polycyclic aromatic hydrocarbons, nitrogen oxides, nitrosamines, sulfuric acid, fertilizers, herbicides, other pesticides, and wood dust. Among white men, a consistent pattern of risk increase by level and probability of exposure was observed only for sulfuric acid mists, with a twofold excess (95% CI, 0.6-7.3) associated with high probability of high intensity exposure. A significant 30% increase in risk was observed for those subjects with a high probability of exposure (all levels combined) to lead, and a 60% increase was observed for subjects with high-level exposure to lead (all probabilities combined). However, crosstabulation of gastric cardia cancer risk by probability and level of exposure to lead did not show consistent trends. Asbestos exposure also showed an overall 50% increase but no consistent trends among white men. None of the 12 occupational hazards showed an association with risk for black men.

Adult↗

PubMed2005

The economic burden of lung cancer and the associated costs of treatment failure in the United States.

The economic burden of lung cancer was examined with a retrospective case-control cohort study on a database containing inpatient, outpatient and drug claims for employees, dependents and retirees of multiple large US employers with wide geographic distribution. Patients were followed for maximum of 2 years from first cancer diagnosis until death, health benefits dis-enrollment or study end (31 December 2000). Compared with controls (subjects without any cancer), patients with lung cancer (n = 2040) had greater health care service utilization and costs for hospitalization, emergency room visits, outpatient office visits, radiology procedures, laboratory procedures and pharmacy-dispensed drugs (all P < 0.05). Regression-adjusted mean monthly total costs were US dollar 6520 for patients versus US dollar 339 for controls (P < 0.0001), and overall costs across the study period (from diagnosis to death or maximum of 2 years) were US dollar 45,897 for patients and US dollar 2907 for controls (P < 0.0001). The main cost drivers were hospitalization (49.0% of costs) and outpatient office visits (35.2% of costs). Monthly initial treatment phase costs (US dollar 11,496 per patient) were higher than costs during the secondary treatment phase (US dollar 3733) or terminal care phase (US dollar 9399). Failure of initial treatment was associated with markedly increased costs. Compared with patients requiring only initial treatment, patients experiencing treatment failure accrued an additional US dollar 10,370 per month in initial treatment phase costs and US dollar 8779 more per month after starting the secondary and/or terminal care phase. Over the course of the study period, these patients had total costs of US dollar 120,650, compared with US dollar 45,953 for those receiving initial treatment only. Thus, the incremental costs associated with treatment failure were US dollar 19,149 per month and US dollar 74,697 across the study period. Other types of clinical and epidemiological analysis are needed to identify risks for treatment failure. The economic burden of lung cancer on the US health care system is significant and increased prevention, new therapies or adjuvant chemotherapy may reduce both resource use and healthcare costs. New strategies for lung cancer that reduce hospitalizations and/or prevent or delay treatment failure could offset some of the economic burden associated with the disease.

Adolescent↗

PubMed2005

The impact of provider volume on outcomes from urological cancer therapy.

PURPOSE: Growing evidence suggests an association between higher hospital and surgeon volumes, and better outcomes after high risk surgical procedures. We reviewed the literature on volume and outcomes, specifically in urological cancer therapy. MATERIALS AND METHODS: We searched the literature from 1966 to 2004 using MEDLINE with the keywords outcomes, urology, neoplasms, volume, hospital volume, surgeon volume, prostatectomy, cystectomy, nephrectomy, prostate cancer, bladder cancer, kidney cancer and testis cancer. Relevant articles were reviewed and results were compared for each urological cancer. RESULTS: Several studies demonstrated that higher hospital volume is associated with better outcomes for all urological cancer surgeries. We found that long-term morbidity associated with radical prostatectomy is significantly associated with individual surgeon volume. There were variations in outcome even among high volume surgeons, suggesting that surgical technique can independently impact outcome. Hospitals with a high volume of cystectomies and nephrectomies had decreased overall mortality rates compared with low volume hospitals. Patients undergoing retroperitoneal lymph node dissection for metastatic germ cell tumor had statistically significantly improved survival when treated at larger oncology centers. CONCLUSIONS: Evidence that high volume hospitals have better outcomes is increasing for urological cancer surgeries. Whether volume affects quality or better clinicians and services attract more patients can be debated. Centralizing health care will have major health policy implications, ie high volume hospitals may be overwhelmed and low volume hospitals may be at a disadvantage. An alternative would be to attempt to improve outcomes at low volume hospitals by identifying drivers of high quality care at high volume hospitals and transferring some of these characteristics.

Clinical Competence↗

PubMed1993

non-Hodgkin's lymphoma and occupation in Sweden: a registry based analysis.

Incidence of non-Hodgkin's lymphoma in different employment categories was evaluated from the Swedish Cancer-Environment Registry, which links cancer incidence during 1961 to 1979 with occupational information from the 1960 census. New associations were found for men employed in shoemaking and shoe repair, porcelain and earthenware industries, education, and other white collar occupations. Several findings supported associations found in other countries, including excesses among woodworkers, furniture makers, electric power plant workers, farmers, dairy workers, lorry drivers, and other land transport workers. Risks were not increased among chemists, chemical or rubber manufacturing workers, or petrochemical refinery workers. Caution must be used in drawing causal inferences from these linked registry data because information on exposure and duration of employment is not available. Nevertheless, this study has suggested new clues to possible occupational determinants of non-Hodgkin's lymphoma.

Humans↗

PubMed2026

Detection of House Dust Mite-derived DNA in Human Lung Tumors by Whole-Genome Sequencing.

Lung cancer in never-smokers (LCINS) accounts for an increasing proportion of lung cancer cases, yet its risk factors remain poorly understood. House dust mites (HDM) are common aeroallergens that induce airway inflammation, but their potential contribution to lung cancer is unknown. We analyzed unmapped whole-genome sequencing reads from 783 lung cancers from the Sherlock-Lung (n = 621 never-smokers) and EAGLE (n = 162 smokers) cohorts, including 328 matched adjacent normal lung tissues. After removal of human sequences, reads were aligned to reference genomes from the two major HDM species and confirmed by BLAST. Samples with top BLAST matches were classified as HDM-detected. Associations between HDM detection and genomic, microbiome, and bulk RNA-seq-derived immune features were evaluated. HDM-derived DNA was detected at low abundance in a subset of tumors and adjacent normal tissues, with higher detection frequencies in tumors than matched normal tissues and in smokers than never-smokers. In LCINS tumors, HDM detection was not associated with tumor mutational burden or recurrent driver alterations but was associated with modest differences in immune cell composition and a limited but reproducible bacterial co-detection pattern. These findings provide a foundation for investigating aeroallergen-derived DNA signatures and their potential relationship to the lung tumor microenvironment.

Environmental exposure↗

PubMed2026

Genomic profiling by circulating tumor DNA in patients with hormone receptor-positive/HER2-negative advanced breast cancer: Prevalence of actionable mutations across treatment lines.

INTRODUCTION: Plasma next-generation sequencing (NGS) is endorsed by ESMO as an alternative to tissue testing in advanced hormone receptor-positive, HER2-negative metastatic breast cancer (HR+/HER2- mBC), particularly after progression on endocrine therapy plus CDK4/6 inhibitors. However, prospective real-world data across distinct therapeutic contexts remain limited. PATIENTS AND METHODS: In this prospective observational study conducted within a nationwide cancer network in Brazil, centralized plasma NGS, and tissue NGS when available, was performed in two independent cohorts: prior to initiation of first-line endocrine therapy in the metastatic setting (Cohort 1) and at progression on endocrine therapy plus a CDK4/6 inhibitor (Cohort 2). The primary objective was to evaluate plasma-detected ESR1 mutation prevalence across these therapeutic contexts, and secondarily to assess other actionable drivers detected by plasma or tissue NGS. RESULTS: Among 86 collected plasma samples, 72 (84%) had evaluable NGS results (Cohort 1, n = 37; Cohort 2, n = 35). ESR1 mutations were identified in 18.9% of patients in Cohort 1 and 40.0% in Cohort 2, mostly at low variant allele fractions (<0.5%), corresponding to an absolute prevalence difference of 21.1 percentage points (95% CI, -0.2 to 40.3; P value=0.07). When considering any actionable alteration detected by plasma, including ESR1, PIK3CA, AKT1, PTEN, BRCA1, BRCA2, and ERBB2, prevalences were 43.2% and 68.6%, respectively (P value=0.04). Only four patients had ESR1 mutations identified in tissue, three in metastatic samples. Plasma-tissue concordance was higher for PIK3CA mutations (85.1%). CONCLUSION: Plasma NGS identified clinically meaningful ESR1 mutation rates across both contexts, supporting guideline-endorsed plasma-based genomic profiling in HR+/HER2- mBC.

CDK4/6 inhibitors↗

PubMed2024

Molecular and Clinical Determinants of Acquired Resistance and Treatment Duration for Targeted Therapies in Colorectal Cancer.

PURPOSE: Targeted therapies have improved outcomes for patients with metastatic colorectal cancer, but their impact is limited by rapid emergence of resistance. We hypothesized that an understanding of the underlying genetic mechanisms and intrinsic tumor features that mediate resistance to therapy will guide new therapeutic strategies and ultimately allow the prevention of resistance. EXPERIMENTAL DESIGN: We assembled a series of 52 patients with paired pretreatment and progression samples who received therapy targeting EGFR (n = 17), BRAF V600E (n = 17), KRAS G12C (n = 15), or amplified HER2 (n = 3) to identify molecular and clinical factors associated with time on treatment (TOT). RESULTS: All patients stopped treatment for progression and TOT did not vary by oncogenic driver (P = 0.5). Baseline disease burden (≥3 vs. <3 sites, P = 0.02), the presence of hepatic metastases (P = 0.02), and gene amplification on baseline tissue (P = 0.03) were each associated with shorter TOT. We found evidence of chromosomal instability (CIN) at progression in patients with baseline MAPK pathway amplifications and those with acquired gene amplifications. At resistance, copy-number changes (P = 0.008) and high number (≥5) of acquired alterations (P = 0.04) were associated with shorter TOT. Patients with hepatic metastases demonstrated both higher number of emergent alterations at resistance and enrichment of mutations involving receptor tyrosine kinases. CONCLUSIONS: Our genomic analysis suggests that high baseline CIN or effective induction of enhanced mutagenesis on targeted therapy underlies rapid progression. Longer response appears to result from a progressive acquisition of genomic or chromosomal instability in the underlying cancer or from the chance event of a new resistance alteration.

Humans↗

PubMed1994

Use of ketorolac by continuous subcutaneous infusion for the control of cancer-related pain.

Ketorolac tromethamine is a newly available non-steroidal anti-inflammatory drug which is suitable for parenteral administration. We have given it by continuous subcutaneous infusion to 36 patients with pain due to advanced cancer. Improvement in pain control occurred in 29 (80%). A reduction in the dose of concomitant opioid analgesia was possible in 22 (76%) and a reduction in opioid-related adverse effects occurred in 16 (73%) of these. Ketorolac was most effective in patients who had bone or visceral pain. It was mixed safely with diamorphine in a syringe driver at concentrations up to 4 g diamorphine/10 ml and 120 mg ketorolac/10 ml. Infusion was well tolerated for periods of up to 115 days (mean 21 days; median 15 days; range 3-115 days). Four patients experienced gastrointestinal bleeding and one colonic perforation to which treatment with ketorolac may have been a contributory factor. No other clinically significant adverse effects were observed.

Adult↗