JNCI: Journal of the National Cancer Institute

BackgroundThe relative risk of smoking on lung cancer have been reported to be much higher in white population than that in East Asians. However, its unknown whether genetic background underlies this disparity between ethnic groups. To assess the role of ethnic differences in genetic factors associated with this phenomenon. MethodsWe first constructed ethnic-specific polygenic risk scores (PRSs) to quantify individual genetic risk of lung cancer in Chinese and white populations. Then, we compared genetic risk and smoking as well as their interactions on lung cancer between two cohorts, including the China Kadoorie Biobank (CKB) and the UK Biobank (UKB). We also evaluated the absolute risk reduction over a 5-year period. Results19 SNPs and 23 SNPs were identified to construct the PRSs in Chinese and white populations, and smoking-related loci were only included in white populations. The PRSs were consistently associated with lung cancer risk respectively, but stronger associations were observed in smokers of the UKB (HR 1.26 versus 1.15, P=0.028). A significant interaction between genetic risk and smoking on lung cancer was observed in the UKB (RERI, 11.39 [95% CI, 7.01-17.94]), but not in the CKB. By comparing heavy smokers with nonsmokers, a greater absolute risk reduction was found in the UKB (10.95 versus 7.12 per 1000 person-years, P<0.001), especially for those at high genetic risk. ConclusionsIn China, tobacco control alone is not enough to reduce the burden of lung cancer, and comprehensive policies should be made to lower its high incidence.

BackgroundSmoking is the most common etiology for lung cancer and smoking cessation does not eliminate the risk. Mucin (MUC)1 glycoprotein is aberrantly expressed in lung carcinomas and premalignant lung lesions. We explored whether a MUC1 vaccine might be effective in halting neoplastic development and progression in individuals at high risk for lung cancer. MethodsWe conducted a multicenter trial of a MUC1 vaccine in current and former heavy smokers to evaluate immunogenicity and safety. Smoking history of [&ge;]30 pack-years and CT chest showing either no nodules or nodules < 6 mm were inclusion criteria. A vaccine containing MUC1 peptide was administered at weeks 0, 2 and 10. Blood was collected pre-vaccine administration, 2 weeks after each vaccine, and at week 24. Immunogenicity (primary endpoint) and the presence of myeloid-derived suppressor cells (MDSC) and regulatory T cells (secondary endpoints) were assessed. Adverse events and toxicities were monitored. ResultsOf 77 individuals screened, 50 were registered and 45 completed the study (27 current and 18 former smokers). The vaccine was well-tolerated. Four current (14.8%) and 2 former smokers (11.1%) developed anti-MUC1 IgG titers [&ge;]2 fold higher at week 12 as compared with baseline, with an overall immune response rate of 13.3% (95% CI 5.1-26.8%). We found high circulating levels of immunosuppressive MDSCs in both current and former smokers. ConclusionsAdministering a potentially preventive vaccine is feasible and safe in individuals at high risk for lung cancer. However, this cohort exhibited a high level of immune suppression, previously documented only in patients with advanced lung cancer. Nonetheless, a vaccine-induced immune response was noted in 13% of participants. Further work is required to refine participant selection, understand the factors driving immunosuppression, and counteract these factors to apply immunoprevention strategies in this high-risk population. Translational RelevanceVaccines targeting antigens aberrantly expressed on lung cancers and their precursors offer the potential for a relatively non-invasive prevention strategy. Worldwide, lung cancer remains the most important cause of cancer-related mortality, and an immunoprevention approach, if successful, has the potential to save many lives by prevention of lung cancer. All epithelial tumors, including lung cancer, express high levels of abnormal mucin (MUC)1 and MUC1-based therapeutic vaccines can increase this immune response to aberrant expressed MUC1 to therapeutic levels. We conducted a multicenter trial to evaluate the immunogenicity and safety of a MUC1 preventive vaccine in individuals with a significant smoking history and at high risk of developing lung cancer. The MUC1 vaccine was safe and elicited an immune response in 13%, which was lower than anticipated. Unexpectedly, we observed a high level of immune suppression in this cohort of heavy smokers, which has been previously documented in individuals who already have lung cancer. Although immunoprevention strategies are promising for reducing the risk of lung cancer in current and former heavy smokers, the immune environment induced by smoking, and the factors that drive immunosuppression are crucial barriers that must be overcome by well-designed immunoprevention strategies for lung cancer.

Melanoma develops as the result of complex interactions between sun exposure and genetic factors. Data on the relationship between sunlight and melanoma from prospective studies are scant, and the combination of ultraviolet exposure data collected before melanoma diagnosis and genetic information is rarer still. We aimed to quantify the association between ambient and personal UV exposure in relation to risk of incident melanoma (invasive; invasive+in situ) in a large population-based prospective study of men and women (n=38,833) residing in a high ambient UV setting, and to examine potential gene-environment interactions. During a median follow-up time of 4.4 years, 782 (1.5%) participants developed cutaneous melanoma (316 invasive, 466 in situ). Country of birth, age at migration and sunburns during all periods of life were significantly associated with melanoma risk. Histories of keratinocyte cancer and of other actinic lesions were both strongly associated with melanoma risk. An interaction with polygenic risk is possible; among people at low risk, markers of cumulative sun exposure were associated with melanoma. In contrast, among people at high polygenic risk, markers of high-level early life ambient exposure were associated with melanoma. Polygenic risk scores can assist in identifying individuals for whom sunlight exposure is most relevant.

PurposeExposure to Agent Orange, a known carcinogen, might increase risk of prostate cancer (PCa). We sought to investigate the association of Agent Orange exposure and PCa risk when accounting for race/ethnicity, family history, and genetic risk in a diverse population of US Vietnam War veterans. Methods & MaterialsThis study utilized the Million Veteran Program (MVP), a national, population-based cohort study of United States military veterans conducted 2011-2021 with 590,750 male participants available for analysis. Agent Orange exposure was obtained using records from the Department of Veterans Affairs (VA) using the US government definition of Agent Orange exposure: active service in Vietnam while Agent Orange was in use. Only veterans who were on active duty (anywhere in the world) during the Vietnam War were included in this analysis (211,180 participants). Genetic risk was assessed via a previously validated polygenic hazard score calculated from genotype data. Age at diagnosis of any PCa, diagnosis of metastatic PCa, and death from PCa were assessed via Cox proportional hazards models. ResultsExposure to Agent Orange was associated with increased PCa diagnosis (HR 1.04, 95% CI 1.01-1.06, p=0.003), primarily among Non-Hispanic White men (HR 1.09, 95% CI 1.06- 1.12, p<0.001). When accounting for race/ethnicity and family history, Agent Orange exposure remained an independent risk factor for PCa diagnosis (HR 1.06, 95% CI 1.04-1.09, p<0.05). Univariable associations of Agent Orange exposure with PCa metastasis (HR 1.08, 95% CI 0.99-1.17) and PCa death (HR 1.02, 95% CI 0.84-1.22) did not reach significance on multivariable analysis. Similar results were found when accounting for polygenic hazard score. ConclusionsAmong US Vietnam War veterans, Agent Orange exposure is an independent risk factor for PCa diagnosis, though associations with PCa metastasis or death are unclear when accounting for race/ethnicity, family history, and/or polygenic risk.

The increasing number of long-term survivors of childhood/adolescent cancer are at-risk for premature death resulting from cancer treatment exposures. To better understand the implications of late mortality, we estimated and characterized the magnitude and temporal patterns of annual excess deaths following childhood/adolescent cancers diagnosed in 1975-2016 in the US using SEER 9 registries. We demonstrate for several tumor types that, despite decreasing excess deaths <5.0 years from diagnosis, the total number of excess deaths is not necessarily decreasing due to the growing and aging population of survivors at risk for treatment related late effects.

The negative health consequences of acute ultraviolet (UV) exposure are evident, with reports of 30,000 emergency room visits annually to treat the effects of sunburn in the United States alone. Acute effects of sunburn include erythema, edema, and severe pain, and chronic overexposure to UV radiation can lead to skin cancer. While the pain associated with the acute effects of sunburn may be relieved by current interventions, existing post-sunburn treatments are not capable of reversing the cumulative and long-term pathological effects of UV exposure, an unmet clinical need. Here we show that activation of the vascular endothelial growth factor (VEGF) pathway is a direct and immediate consequence of acute UV exposure, and activation of VEGF signaling is necessary for the initiating the acute pathological effects of sunburn. In UV-exposed human subjects, VEGF signaling is activated within hours. Topical delivery of VEGF pathway inhibitors, targeted against the ligand VEGF-A (gold nanoparticles conjugated with anti-VEGF antibodies) and small molecule antagonists of VEGF receptor signaling, prevent the development of erythema and edema in UV-exposed mice. Collectively, these findings suggest targeting VEGF signaling may reduce the subsequent inflammation and pathology associated with UV-induced skin damage, which reveals a new post-exposure therapeutic window to potentially inhibit the known detrimental effects of UV on human skin.

Damage to the vascular endothelium is a major contributor to acute radiation injury in multiple organs that underlies acute radiation syndrome (ARS), yet there are no FDA-approved radiation countermeasures targeting endothelial cells. Use of kinome-scale CRISPR screens performed in cultured human vascular endothelial cells isolated from different organs identified CLK2 as a potential radioprotective target. Pharmacological inhibition of CLK2 using TG003 and Cirtuvivint protected these endothelial cells against radiation injury and reversed its effects across the transcriptome and phospho-proteome. Human Organ Chip models of human intestine and lung that contain organ-specific epithelium and microvascular endothelium faithfully replicated clinical features of ARS when exposed to radiation, which were prevented when treated with CLK2 inhibitors. Thus, CLK2 inhibitors may represent a new class of radiation countermeasure drugs that can protect multiple organs against radiation-induced toxicities in patients with ARS.

High pre-treatment values of the neutrophil-to-lymphocyte ratio (NLR) are strongly associated with poorer survival outcomes in cancer patients. Here, we assess heterogeneity in the magnitude of this association and the prognostic potential of the NLR between patient subgroups. We conducted a random effects meta-analysis of 228 published studies (N=75,555 patients) relating NLR with overall survival across 18 cancer types. Cochrans Q test and Higgins I2 statistic were used to assess study heterogeneity. Pooled hazard ratios were compared between groups of studies classified by cancer type, geographic region, therapy type, and cut-off for high NLR to identify study-level characteristics associated with increased prognostic potential of the NLR. Pooled hazard ratios are highest in studies of melanoma and breast cancer and lowest in studies of brain cancer and lung cancer. Radiation as primary treatment also demonstrates a large pooled effect size as compared to other therapies. The NLR has greater prognostic value in certain cancer types and therapeutic regimens. Efforts are needed to comprehensively examine populations in which NLR has maximum prognostic power. Clinically meaningful thresholds for risk stratification should be identified within these patient subgroups to permit prospective validation of the prognostic potential of the NLR.

BackgroundChildhood cancer survivors (CCS) face elevated skin cancer risk, especially after radiotherapy or hematopoietic stem cell transplantation (HSCT). We evaluated the prevalence and predictors of sun protection, sunburn, and physician skin examination (PSE) among CCS in Switzerland. MethodsWe surveyed CCS diagnosed <21 years and surviving [&ge;]5 years after diagnosis about sun protection, sunburns during last summer, and PSE within the last year. We retrieved cancer-related data from the Swiss Childhood Cancer Registry and used multivariable logistic regression, stratified by age group, to identify predictors. ResultsWe included 1,048 children (5-15 years), 572 adolescents (16-19 years), and 1,959 adults ([&ge;]20 years). Regular sun protection was reported by 89% of children, 65% of adolescents, and 77% of adults, and sunburns by 23%, 49%, and 43%. PSE prevalence among those treated with radiotherapy was 21%, 18%, and 17%, and among HSCT recipients 36%, 28%, and 28%. Radiotherapy was unrelated to sun protection and PSE, but associated with fewer sunburns (OR=0.63-0.77). HSCT recipients were more likely to have attended a PSE (OR=2.06-3.75), but not radiotherapy recipients. Across age groups, survivors born more recently were less likely to protect from sun (OR range=0.94-0.97) and more likely to report sunburn (OR=1.04-1.14). ConclusionSurvivors protect insufficiently from sun and only few who are particularly at risk for skin cancer due to their treatment history attend PSEs as recommended by the Childrens Oncology Group. Healthcare practitioners should systematically integrate yearly PSE after radiotherapy or HSCT and encourage consistent sun protection, particularly among younger generations and adolescents.

Genome-wide association studies (GWASs) have identified approximately 100 loci for lung cancer, but potential causal genes remain largely unknown. To address this, we conducted a lung tissue-specific transcriptome-wide association study (TWAS). Gene expression prediction models were constructed using data of adjacent normal lung tissues from our Vanderbilt Thoracic Biorepository (N=314) and normal lung tissues from the GTEx (N=466) and then applied to our lung cancer GWAS meta-analysis (55,174 cases and 1,294,174 controls). We identified 109 unique risk genes for lung cancer and its histological subtypes. Of them, 71 unique genes were novel discoveries, and 13 unique genes reside in novel loci. Smoking-conditional analysis revealed that 52 unique genes are unrelated to smoking behavior. Seven unique genes showed cell-type-specific colocalization within potential risk cell types, including the alveolar type I and II, dendritic, and natural killer cells. Seventeen unique genes are targeted of 58 drugs that have been approved or in Phase II or III trials. In addition, 22 unique potential causal genes were supported by both Mendelian randomization and colocalization. Functional validation identified three genes through in vitro knockdown experiments. Our study identified new lung cancer candidate risk genes and offered insights into lung cancer biology and future translational utilities.

The incidence of cutaneous malignancies is increasing worldwide, presenting an important public health burden. Cohort studies can provide high quality data on the epidemiology of these cancers, and are invaluable for deriving measures of disease burden used to inform prevention, diagnosis and treatment. We conducted a systematic review of the literature to summarise the characteristics of cohort studies that have published one or more papers describing the epidemiology of melanoma and/or keratinocyte cancers. Eligible studies were population-based cohort studies that have published findings on incidence or etiology of melanoma or keratinocyte cancer (including associations with phenotypic, environmental, and genetic factors). We excluded clinical cohorts focused on survivorship outcomes. We searched MEDLINE 1950 (U.S. National Library of Medicine, Bethesda, MD, USA), the ISI Science Citation Index (1990 to 31 July 2025) and the reference lists of retrieved articles, imposing no language restrictions. We identified 22 eligible cohort studies, 20 of which had published on melanoma, and 16 on keratinocyte cancer. Nine were conducted in the United States, eleven in Europe, and two in Australia. There was substantial variability in terms of cohort size, risk factor information recorded at baseline, and other data collected (e.g., health services, genetic). Only three studies were specifically designed to examine skin cancers as study endpoints, and only two cohorts pre-specified both melanoma and keratinocyte cancer endpoints. Our summary provides a resource for skin cancer researchers conducting investigations into the causes, burden and prevention of these important cancers.

Background: Our group previously reported that lung cancer (LC) screening history results and subsequent timing of diagnosis are associated with significant differences in survival outcomes. As a follow-up study, we sought to develop novel personalized risk models that considered screening history for incidence cancers, interval LCs, and prevalence LCs. Methods: Using data from the CT-arm of the NLST, four independent case-control analyses were conducted to develop parsimonious risk models. Controls (n=26,038) were those never diagnosed with LC. The four LC case groups were 270 prevalence LCs, 44 interval LCs, 206 screen-detected LCs (SDLCs) that had a baseline positive screen, and 164 SDLCs that had a baseline negative screen. For each case-control analysis, univariable analyses identified statistically significant covariates from 48 variables and then significant covariates were included into a stepwise backward selection approach to identify a model with the most informative covariates. Results: For prevalence LCs, the model (AUC=0.711) included age, pack-years smoked, BMI, smoking status, smoking onset age, personal history of cancer, family history of LC, alcohol consumption, and milling occupation. For interval LCs, the model (AUC=0.734) included age, smoking status, smoking onset age, cigar smoking, marital status, and asbestos occupation. For baseline positive SDLCs, the model (AUC=0.685) included age, pack-years smoked, BMI, emphysema, chemicals/plastics exposure, and milling occupation. For baseline negative SDLCs, the model (AUC=0.701) included age, pack-years smoked, BMI, smoking status, emphysema, sarcoidosis, and sandblasting occupation. Conclusions: Besides smoking and age, which are inclusion criteria for screening, these models identified other important risk factors which could be used to provide personalized LC risk assessment and screening management.

BackgroundLung cancer (LC) is the leading cause of cancer mortality, often diagnosed at advanced stages. Screening reduces mortality in high-risk individuals, but its efficiency can improve with pre- and post-screening risk stratification. With recent LC screening guideline updates in Europe and the US, numerous novel risk prediction models have emerged since the last systematic review of such models. We reviewed risk-based models for selecting candidates for CT screening, and post-CT stratification. MethodsWe systematically reviewed Embase and MEDLINE (2020-2024), identifying studies proposing new LC risk models for screening selection or nodule classification. Data extraction included study design, population, model type, risk horizon, and internal/external validation metrics. In addition, we performed an exploratory meta-regression of AUCs to assess whether sample size, model class, validation type, and biomarker use were associated with discrimination. ResultsOf 1987 records, 68 were included: 41 models were for screening selection (20 without biomarkers, 21 with), and 27 for nodule classification. Regression-based models predominated, though machine learning and deep learning approaches were increasingly common. Discrimination ranged from moderate (AUC{approx}0.70) to excellent (>0.90), with biomarker and imaging-enhanced models often outperforming traditional ones. Model calibration was inconsistently reported, and fewer than half underwent external validation. Meta-regression suggested that, among pre-screening models, larger sample sizes were modestly associated with higher AUC. Conclusion75 models had been identified prior to 2020, we found 68 models since. This reflects growing interest in personalized LC screening. While many demonstrate strong discrimination, inconsistent calibration and limited external validation hinder clinical adoption. Future efforts should prioritize improving existing models rather than developing new ones, transparent evaluation, cost-effectiveness analysis, and real-world implementation.

BackgroundDurvalumab consolidation after concurrent chemoradiotherapy (cCRT) is the standard-of-care for unresectable stage III non-small cell lung cancer (NSCLC) without actionable driver mutations. However, pneumonitis remains a dose-limiting toxicity that often precludes or interrupts immunotherapy. Conventional predictors based on lung dosimetry alone exhibit limited individual-level discrimination. We investigated whether the thymus, long considered vestigial in adults, influences post-treatment immune recovery and susceptibility to inflammatory toxicity. MethodsWe analyzed patients with locally advanced NSCLC treated with cCRT in the RTOG 0617 trial (n = 490) and with standard-of-care cCRT followed by consolidation durvalumab at Memorial Sloan Kettering Cancer Center (MSKCC, n = 230). Percent thymic tissue (pTT), a novel imaging parameter that quantifies the proportion of residual functional thymic tissue on pre-treatment CT scans, was derived using an autosegmentation and Gaussian mixture modeling framework. Logistic regression with restricted cubic splines assessed associations between pTT, mean radiation dose to the thymic region (MDTR), and volume of the lungs receiving [&ge;]20 Gy (lung V20) with high-grade ([&ge;] 3) pneumonitis. ResultsAcross both cohorts, pTT was inversely associated with severe pneumonitis independent of lung V20. Grade 3+ pneumonitis incidence in low-vs high-pTT groups was 7.3% vs 2.9% (p = 0.038) in the RTOG 0617 cohort and 13.9% vs. 5.2% (p = 0.042) in the MSKCC cohort. The combination of low pTT and high lung V20 was associated with the highest rates of severe pneumonitis with 11.5% in RTOG 0617 and 20.8% in MSKCC (compared with 3.3% and 1.9% for high pTT/low lung V20), identifying a subgroup at particularly high risk. MDTR showed a weaker, non-linear relationship with pneumonitis risk, increasing at moderate doses and declining at the highest radiation exposures. ConclusionsThis study established pTT, a quantitative marker of residual functional thymus in adults, as a novel, independent predictor of severe pneumonitis following cCRT with or without consolidation immunotherapy. Incorporating pTT into multimodal risk-stratification frameworks could improve patient selection, personalize radiation planning, and enhance safe delivery of curative-intent cCRT and immunotherapy in locally advanced NSCLC.

PurposeWe report a blinded validation study of a ten-protein marker blood test for assessing risk of developing or harboring nine common cancers in a prospective lung cancer screening cohort. Patients and MethodsThe foundation of the multi-cancer risk stratification test (MCaST), test is a 4-marker protein panel consisting of ProSFTPB, CEA, CA125, and CYFRA-21 which has been extensively validated for risk of lung cancer and which has been expanded to include six additional markers to encompass, in addition to lung cancer, prostate, colorectal, breast, ovarian, pancreatic, liver, esophageal, and stomach cancers. Blinded validation samples consisted of 1,235 plasmas collected prior to diagnosis from 171 cancer cases and 526 randomly selected non-case controls. Fixed individualized combination rules as well as cancer-specific risk thresholds predefined based on established clinical guidelines were applied. ResultsAt the subject level, the MCaST tested positive for imminent risk of lung cancer in 65 of 73 lung cancer cases, including 45 of 51 early-stage cases, with a median time of 12.7 months (interquartile range [IQR]: 1.7 - 27.8 months) between the first positive MCaST and diagnosis of lung cancer. The positive rate of MCaST for other cancers was 88.9% for prostate, 63.6% for invasive breast, 85.7% for CRC, 50% for ovarian, 50% for pancreatic, and 67% for esophagus plus stomach cancers with a median (IQR) time of 20.7 months (10.2 - 42.8 months) from the first positive MCaST to a clinical diagnosis across the cancer types. Overall accuracy for tissue-of-origin (TOO) signal was 94.6%, and as high as 98.1% for lung cancer. ConclusionMCaST has utility for assessing cancer risk for common and lethal solid cancers in this smoker population.

BackgroundLung cancer presents a significant global health challenge, with disparities in incidence and outcomes across races and ethnicities. These disparities underscore the need to explore the molecular landscapes of lung cancer in relation to ancestry. Here, we leverage data from a real-world clinico-genomic database to discover associations between molecular profiles and genetic ancestry or race/ethnicity categories. MethodsWe utilized data from a cohort of 13,196 primarily late-stage non-small cell lung adenocarcinoma (LUAD) patients, sequenced with the Tempus xT NGS 648-gene panel, of which normal tissue was also sequenced for 6,520 cases. Genetic ancestry proportions were estimated using ancestry informative markers. Race and ethnicity categories were imputed using an ancestry-backed method, resulting in the assignment of 568 Hispanic/Latino, 892 non-Hispanic (NH) Asian, 1,581 NH Black, and 10,063 NH White individuals. Multiple imputation addressed missing data on smoking status. Logistic regression models assessed associations between ancestry proportions and somatic variants in 23 LUAD-related genes, adjusting for a false discovery rate of 5%. Analyzed mutations included copy number alterations, gene fusions, protein-altering SNVs and indels, and actionable or predicted driver mutations. ResultsOur analysis confirmed previously reported associations, such as a positive correlation between East Asian (EAS) ancestry and EGFR (OR per doubling ancestry=1.1) and a negative correlation with KRAS driver mutations (OR=0.96), while European ancestry exhibited the opposite relationship (OR=0.93 and 1.08, correspondingly; all p<0.0001). We also verified a positive association with EGFR driver mutations (OR=2) and a negative one with KRAS (OR=0.46; p<0.001) among Hispanic/Latino patients and American Indigenous (AMR) genetic ancestry (OR=1.03 and 0.97, correspondingly; p<0.05). Novel associations were identified between African (AFR) and South Asian (SAS) ancestries and LUAD genes. Some associations are explained by differences in smoking status (e.g., ATM and ALK fusions), while others persist even after adjusting for smoking (e.g., EGFR, KRAS, and CDKN2A copy-number alterations). Notably, we identified a positive association between EAS ancestry and the imputed NH Asian category with driver mutations in CTNNB1 (OR=1.05 and 2.2, respectively; p<0.01), independent of smoking. These mutations are rare in NH White patients (2.4%) but are more prevalent in never-smoker NH Asian patients with predominant EAS ancestry (8.5%). ConclusionThis study underscores the value of clinico-genomic databases in revealing associations between LUAD mutational profiles and genetic ancestry, shedding light on lung cancer disparities. Identification of a previously unappreciated association between EAS with CTNNB1, a potential biomarker for spindle assembly checkpoint kinase (TTK) inhibitors effectiveness and prognosis in LUAD, emphasizes the value of studying diverse populations in cancer research, paving the way for more equitable lung cancer treatments.

PurposeHuman papillomavirus-associated (HPV+) head and neck squamous cell carcinoma (HNSCC) is the fastest rising cancer in North America. There is significant interest in treatment de-escalation for these patients given the generally favourable prognosis. However, 15-30% of patients recur after primary treatment, reflecting a need for improved risk-stratification tools. We sought to develop a molecular test to predict the survival of patients with newly diagnosed HPV+ HNSCC. MethodsWe created a prognostic score (UWO3) that was successfully validated in six independent cohorts comprising 906 patients, including blinded retrospective and prospective external validations. Transcriptomic data from two aggressive radiation de-escalation cohorts were used to assess the ability of UWO3 to identify patients who recur. Multivariate Cox models were used to assess the associations between the UWO3 immune class and outcomes. ResultsA three-gene immune score classified patients into three immune classes (immune rich, mixed, or immune desert) and was strongly associated with disease-free survival in six datasets, including large retrospective and prospective datasets. Pooled analysis demonstrated that the immune rich group had superior disease-free survival at 5 years to the immune desert (HR= 9.0, 95% CI 3.2-25.5, P=3.6x10-5) and mixed (HR=6.4, 95%CI 2.2-18.7, P=0.006) groups after adjusting for age, sex, smoking status, and AJCC8 clinical stage. Finally, UWO3 was able to identify patients from two treatment de-escalation cohorts who remain disease-free after aggressive de-escalation to 30 Gy radiation. ConclusionsThe UWO3 immune score could enable biomarker-driven clinical decision-making for patients with HPV+ HNSCC based on robust outcome prediction across six independent cohorts. The superior survival of immune rich patients supports de-intensification strategies, while the inferior outcomes of the immune desert patients suggest the potential for intensification and/or immunotherapy. Prospective de-escalation and intensification clinical trials are currently being planned.

In the United States, Black individuals have higher rates of cancer mortality than any other racial or ethnic group. The sources of these significant racial disparities are not fully understood, and may include social, environmental, and genetic factors that influence cancer onset, diagnosis, and treatment. Here, we examined genomic data from several large-scale cancer patient cohorts to search for racial associations in chromosome copy number alterations. We found that tumors from self-reported Black patients were significantly more likely to exhibit whole-genome duplications (WGDs), a genomic event that enhances metastasis and aggressive disease, compared to tumors from self-reported white patients. Among patients with WGD-positive cancers, there was no significant difference in survival between self-reported Black and white patients, suggesting that the increased incidence of WGD events could contribute to the disparities in patient outcome. We further demonstrate that combustion byproducts are capable of driving genome-duplication events in cell culture, and cancers from self-reported Black patients exhibit mutational patterns consistent with increased exposure to these carcinogens. In total, these findings identify a class of genomic alterations that are associated with environmental exposures and that may influence racial disparities in cancer patient outcome. Additionally, as cancers that have undergone WGD events exhibit unique genetic vulnerabilities, therapies that selectively target WGD-positive cancers may be particularly effective at treating aggressive malignancies in Black patients.

BackgroundAccelerometer-derived behavioral phenotype captures multidimensional aspects of human behavior extending well beyond physical activity, encompassing light exposure, step counts, physical activity patterns, sleep, and circadian rhythms. Whether these five domains constitute a unified behavioral architecture underlying cancer risk and whether circadian organization and light exposure confer incremental predictive value beyond movement volume alone remains to be comprehensively established. MethodsWe conducted an accelerometer-wide association study (AWAS) encompassing the complete accelerometer-derived behavioral exposome across five behavioral domains in UK Biobank participants with valid wrist accelerometry data. Incident solid cancers were designated as the primary endpoint, with prespecified site-specific solid cancers and hematological malignancy as secondary outcomes. Cox proportional hazards models with age as the timescale were used. The minimal covariate set served as the primary reporting tier, followed by sensitivity analyses additionally adjusting for adiposity/metabolic factors, independent activity patterns, shift work history, and accelerometry measurement quality. Nominal statistical significance was defined as two-sided P < 0.05 ResultsAmong 89,080 participants, 6,598 incident solid cancer events were observed over a median follow-up of 8.39 years. In the minimally adjusted model, the pan-solid-tumor association atlas was dominated by signals from activity volume, inactivity fragmentation, and circadian rhythm. Higher overall acceleration (HR per SD: 0.91, 95% CI: 0.89-0.94) and higher daily step counts (HR: 0.93, 95% CI: 0.90-0.95) were independently associated with reduced solid cancer risk, while inactivity fragmentation metrics were consistently linked to higher risk. Notably, circadian rhythms, most prominently cosinor mesor (Midline Estimating Statistic of Rhythm under cosinor model), emerged as leading inverse risk signals, underscoring the independent contribution of circadian behavioral architecture. Site-specific analyses revealed pronounced heterogeneity across tumor sites. Lung cancer exhibited a robust inverse activity-risk gradient, while breast cancer showed reproducible associations with MVPA. Most strikingly, nocturnal light exposure demonstrated a tumor-site-specific association confined to pancreatic cancer, a signal absent across all other sites examined. Associations for uterine cancer were predominantly inactivity-related and substantially attenuated following adjustment for adiposity and metabolic factors. ConclusionsAcross five accelerometer-derived behavioral domains, solid cancers as a whole were most consistently associated with a high-movement, low-fragmentation, and circadian-coherent behavioral profile. While site-specific heterogeneity exists, the broad cancer risk landscape is dominated by movement volume, inactivity fragmentation, and circadian rhythmicity. Light exposure, although more localized in its contribution, demonstrates a potentially novel and specific association with pancreatic cancer risk. These findings support a five-domain behavioral exposome framework for cancer epidemiology and, importantly, position circadian rhythm integrity and nocturnal light exposure as critically understudied dimensions warranting dedicated mechanistic investigation.

BackgroundObservational studies have identified patients with cancer as a potential subgroup of individuals at elevated risk of severe SARS-CoV-2 (COVID-19) disease and mortality. Early studies showed an increased risk of COVID-19 mortality for cancer patients, but it is not well understood how this association varies by cancer site, cancer treatment, and vaccination status. MethodsUsing electronic health record data from an academic medical center, we identified 259,893 individuals who were tested for or diagnosed with COVID-19 from March 10, 2020, to February 2, 2022. Of these, 41,218 tested positive for COVID-19 of whom 10,266 had a past or current cancer diagnosis. We conducted Firth-corrected, covariate-adjusted logistic regression to assess the association of cancer status, cancer type, and cancer treatment with four COVID-19 outcomes: hospitalization, intensive care unit (ICU) admission, mortality, and a composite "severe COVID-19" outcome which is the union of the first three outcomes. We examine the effect of the timing of cancer diagnosis and treatment relative to COVID diagnosis, and the effect of vaccination. ResultsCancer status was associated with higher rates of severe COVID-19 infection [OR (95% CI): 1.18 (1.08, 1.29)], hospitalization [OR (95% CI): 1.18 (1.06, 1.28)], and mortality [OR (95% CI): 1.22 (1.00, 1.48)]. These associations were driven by patients whose most recent initial cancer diagnosis was within the past three years. Chemotherapy receipt was positively associated with all four COVID-19 outcomes (e.g., severe COVID [OR (95% CI): 1.96 (1.73, 2.22)], while receipt of either radiation or surgery alone were not associated with worse COVID-19 outcomes. Among cancer types, hematologic malignancies [OR (95% CI): 1.62 (1.39, 1.88)] and lung cancer [OR (95% CI): 1.81 (1.34, 2.43)] were significantly associated with higher odds of hospitalization. Hematologic malignancies were associated with ICU admission [OR (95% CI): 1.49 (1.11, 1.97)] and mortality [OR (95% CI): 1.57 (1.15, 2.11)], while melanoma and breast cancer were not associated with worse COVID-19 outcomes. Vaccinations were found to reduce the frequency of occurrence for the four COVID-19 outcomes across cancer status but those with cancer continued to have elevated risk of severe COVID [cancer OR (95% CI) among those fully vaccinated: 1.69 (1.10, 2.62)] relative to those without cancer even among vaccinated. ConclusionOur study provides insight to the relationship between cancer diagnosis, treatment, cancer type, vaccination, and COVID-19 outcomes. Our results indicate that it is plausible that specific diagnoses (e.g., hematologic malignancies, lung cancer) and treatments (e.g., chemotherapy) are associated with worse COVID-19 outcomes. Vaccines significantly reduce the risk of severe COVID-19 outcomes in individuals with cancer and those without, but cancer patients are still at higher risk of breakthrough infections and more severe COVID outcomes even after vaccination. These findings provide actionable insights for risk identification and targeted treatment and prevention strategies.