JNCI: Journal of the National Cancer Institute

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.

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.

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.

BackgroundWith the increasing popularity of decorative tattooing, which entails the intradermal injection of inks that may contain carcinogens, investigating the related potential skin cancer risk is a public health priority. MethodsWe used data from the Cancer Risk Attributable with the Body Art of Tattooing (CRABAT) study, nested in the French national cohort Constances (adults aged 18-69 years recruited in 2012-2018). Tattoo exposure was collected in 2020-23. Skin cancers overall, cutaneous melanoma (CM), and non-melanoma skin cancer (NMSC) diagnosed during 2007-21 were retrieved from national health insurance data. As exposure information was collected after possible disease ascertainment, risks of skin cancer with prior tattoo exposure were assessed using (i) Logistic regression and (ii) retrospective cohort analyses using Cox proportional hazards model. ResultsAmong 111 074 participants, 1789 skin cancers (1.6%) were recorded (693 CM, 1096 NMSC). No association was found between binary tattoo exposure and any skin cancer type. In logistic regression, tattoo body surface >2 hand palms was associated with lower overall skin cancer risk (OR = 0.21, 95% CI: 0.05-0.83; reference no tattoos). This association was not significant in the Cox model, but the suggestive dose-response relationship remained, with HRs of 1.14, 0.60, and 0.26 for tattoo body surface of 0-1, 1-2, and >2 hand palms, respectively. ConclusionLarge tattoo surfaces were tentatively associated with reduced overall skin cancer risk. While these finding merits further research, small case numbers and the retrospectively collected data might have biased the results.

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.

BackgroundLung cancer incidence rates in Atlantic Canada significantly exceed those of other Canadian provinces, with underlying causes remaining poorly understood. This regional disparity suggests potential genetic or environmental factors unique to Atlantic Canada. Here we present for the first-time data indicating that accompanying the high lung cancer rates in Atlantic Canada is an intricate landscape of multiple malignancies. This represents a phenomenon of multiple primary cancers that is unprecedented in the literature and presents unique challenges in the diagnosis and treatment of individuals diagnosed with lung cancer in Atlantic Canada. MethodsWe performed a retrospective chart review of 1,151 patients referred to the thoracic surgeons at the Queen Elizabeth II Health Sciences Centre between 2019 and 2023 with the new diagnosis of lung cancer. The primary focus was to assess the incidence of multiple primary cancers (as documented in pathology reports) and analyze demographic, clinical, and geographical factors through Fishers exact tests and Students t-tests. ResultsForty-three precent (43.3%) of Atlantic Canadian patients presented with multiple primary cancers. Of 1,949 cancers identified, 1,440 were of primary lung origin. Sixty percent (60.0%) of our cohort was female. Thirty-one percent (31.3%) were self-reported current tobacco smokers, 50.3% were former tobacco smokers, and 18.4% reported no tobacco use. The average age and body mass index (BMI) at first diagnosis was similar between those patients with and without multiple primary cancers, averaging 67 years and 27.7 kg/m2, respectively. Thirty-nine percent (39.2%) of our study participants lived in more densely populated centers (>100,000 people), 10.2% in intermediate centers ([~]98,000 people) and 50.7% in more sparsely populated centers (<55,000 people). ConclusionsWe have uncovered an unprecedented phenomenon in Atlantic Canada of a cohort of patients with lung cancer having multiple primary cancers of different tissue origin at a rate that is four times greater than previously described. The implications of this study are that Atlantic Canadians are disproportionately burdened with cancers of multiple origins that are not explained by smoking rates or BMI. Future studies will investigate the contribution of genetic predisposition, environmental exposures, and socioeconomic factors unique to Atlantic Canada underlying the high rates of multiple primary cancers documented here in a lung cancer cohort. Such studies will be essential to develop effective cancer prevention and screening strategies in Atlantic Canada.

PurposeHigh fat mass and low muscle mass are associated with increased mortality and risk of second primary cancers in cancer survivors. This longitudinal study examined trends in body size and composition among US adults with a history of cancer from 1999 to 2018. MethodsData from self-reported cancer survivors aged [&ge;]20 years in the Continuous National Health and Nutrition Examination Survey 1999-2006 and 2011-2018 were analyzed. Outcome measurements included body mass index (BMI, n=3,544) waist circumference (WC, n=3,354), and DEXA-derived indices, including fat mass index (FMI, n=1,767), total lean mass (LM, n=1,775), and appendicular skeletal muscle mass index (ASMMI, n=1,741). Multivariate linear regressions were used to analyze across data cycle associations, adjusting for age, sex, and race/ethnicity. ResultsAcross 19 years, average BMI increased from 27.1 kg/m{superscript 2} to 30.0 kg/m{superscript 2} (p<.001) and average WC increased from 96.1 cm to 103.8 cm (p<.001) among all cancer survivors and increased in Hispanic and non-Hispanic White subgroups, but not non-Hispanic Black or other race/ethnicity subgroups. Total LM increased overall between 1999 and 2006, from 46.6 kg to 49.5 kg (p=.002), and increased in the non-Hispanic White subgroup (p=.009). FMI and ASMMI showed no significant overall changes, although FMI levels remained elevated. ConclusionUS cancer survivors experienced notable increases in BMI and WC from 1999 to 2018, with LM gains observed in some racial/ethnic groups, particularly from 1999 to 2006. Implications for Cancer SurvivorsThese findings highlight the need for targeted interventions addressing obesity and fat mass to improve long-term health outcomes among cancer survivors.

BackgroundIf lung cancer in never-smokers was a single disease entity, it would be the sixth most commonly occurring malignancy. Despite the population impact, its risk factors are poorly understood owing to a dearth of larger-scale, well-characterised studies. MethodsWe pooled individual-participant data from 18 prospective cohort studies comprising 91,588 never smokers (55,452 women) aged 16-102 years at study induction. Participants were linked to national death registries. ResultsA maximum of 17 years follow-up (mean 9.7) gave rise to 85 lung cancer deaths. Of the 19 potential determinants captured at baseline, only being older age (hazard ratio; 95% confidence interval per 10 year increase: 2.45; 2.11, 2.85), male (2.25; 1.46, 3.48), and having a high fruit and vegetable intake (2.29; 1.25, 4.17) were associated with elevated rates of lung cancer in this never-smoking group. No other substantial relationships were detected. ConclusionsDespite the number and breadth of potential risk factors featured in this multi-cohort study, there was no clear suggestion of new determinants of lung cancer in never-smokers. ImpactOur findings point to the need to explore the influence of risk factors additional to those included herein, particular in the field of genetics. Our unlikely finding for fruit and vegetable consumption warrants further testing.

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.

Tattooing, involving the injection of pigments into the skin, has become increasingly popular, with up to 40% of individuals under 40 years old tattooed in high-income countries. Despite regulatory measures, tattoo inks may contain hazardous substances such as polycyclic aromatic hydrocarbons, primary aromatic amines, and metallic impurities, many of which are classified as carcinogens. Research on systemic health risks, particularly cancer, associated with intradermal ink exposure remains limited. Complications like contact allergies and inflammatory skin reactions are more frequently reported among tattooed individuals. However, cancer risks from tattooing, especially for internal cancers like lymphoma, are challenging to assess. Existing case-control studies indicate mixed findings regarding hematologic cancers, with one large study reporting a 20% increased lymphoma risk among tattooed individuals in the first two years post-tattooing. Here, we present the Cancer Risk Associated with the Body Art of Tattooing (CRABAT) study, that is, to our knowledge, the first larger study that prospectively investigates tattoo-related cancer risks. CRABAT follows up over 110,000 participants for long-term health effects within the French Constances cohort with objective cancer data linkage. Of [~]13,000 participants that were tattooed in 2020, detailed tattoo exposure assessment via a validated tattoo exposure questionnaire was conducted in 2023 (response rate >60%). With its robust dataset through linkage to the Constances variable pool, CRABAT enables the analysis of exposure-response relationships, and addresses potential confounders such as sociodemographic and lifestyle factors, and alternative pathways such as tattoo-related infections. Body word count: 2498 words

BackgroundEmerging data suggest variability in susceptibility and outcome to Covid-19 infection. Identifying the risk-factors associated with infection and outcomes in cancer patients is necessary to develop healthcare recommendations. MethodsWe analyzed electronic health records of the US National Veterans Administration healthcare system and assessed the prevalence of Covid-19 infection in cancer patients. We evaluated the proportion of cancer patients tested for Covid-19 and their confirmed positivity, with clinical characteristics, and outcome, and stratified by demographics, comorbidities, cancer treatment and cancer type. ResultsOf 22914 cancer patients tested for Covid-19, 1794 (7.8%) were positive. The prevalence of Covid-19 was similar across all ages. Higher prevalence was observed in African-American (AA) (15%) compared to white (5.5%; P<.001), in Hispanic vs non-Hispanic population and in patients with hematologic malignancy compared to those with solid tumors (10.9% vs 7.7%; P<.001). Conversely, prevalence was lower in current smoker patients, patients with other co-morbidities and having recently received cancer therapy (< 6 months). The Covid-19 attributable mortality was 10.9%. Highest mortality rates were observed in older patients, those with renal dysfunction, higher Charlson co-morbidity score and with certain cancer types. Recent (< 6 months) or past treatment did not influence mortality. Importantly, AA patients had 3.5-fold higher Covid-19 attributable hospitalization, however had similar mortality rate as white patients. ConclusionPre-existence of cancer affects both susceptibility to Covid-19 infection and eventual outcome. The overall Covid-19 attributable mortality in cancer patients is affected by age, co-morbidity and specific cancer types, however, race or recent treatment including immunotherapy does not impact outcome. FundingsVA Office of Research and Development and National Institutes of Health.

ObjectiveTo investigate whether the higher risks of certain cancers associated with high cardiorespiratory fitness can be explained by increased detection and unobserved confounders. DesignNationwide sibling-controlled cohort study of adolescents. SettingSweden. Participants1 124 049 men of which 477 453 were full siblings, who underwent mandatory military conscription examinations between 1972 and 1995 at a mean age of 18.3 years. Main outcome measuresHazard ratios (HR) and 95% confidence intervals (CI) of overall cancer diagnosis and cancer mortality, and 14 site-specific cancers (diagnosis or death), as recorded in the Swedish National Patient Register or Cause of Death Register until 31 December 2023, modelled using flexible parametric regressions. ResultsParticipants were followed until a median (maximum) age of 55.9 (73.5) years, during which 98 410 were diagnosed with cancer and 16 789 had a cancer-related death (41 293 and 6908 among full siblings respectively). The most common cancers were non-melanoma skin (27 105 diagnoses & 227 deaths) and prostate cancer (24 211 diagnoses & 869 deaths). In cohort analysis, those in the highest quartile of cardiorespiratory fitness had a higher risk of prostate (adjusted HR 1.10; 95% CI: 1.05 to 1.16) and skin cancer (e.g., non-melanoma HR 1.44; 1.37 to 1.50) compared to those in the lowest quartile, which led to a higher risk of any type of cancer diagnosis (HR 1.08; 1.06 to 1.11). However, those in the highest quartile had a lower risk of cancer mortality (HR 0.71; 0.67 to 0.76). When comparing full siblings, and thereby controlling for all behavioural, environmental, and genetic factors they share, the excess risk of prostate (HR 1.01; 0.90 to 1.13) and skin cancer (e.g., non-melanoma HR 1.09; 0.99 to 1.20) attenuated to the null. In contrast, the lower risk of overall cancer mortality was still statistically significant after control for such shared confounders (HR 0.78; 0.68 to 0.89). For other site-specific cancers, the influence of such confounding tended to vary, but none showed the same excess risk as prostate and non-melanoma skin cancer. ConclusionsThe association between high levels of adolescent cardiorespiratory fitness and excess risk of some cancers, such as prostate and non-melanoma skin cancer, appears to be fully explained by unobserved confounders shared between full siblings. However, the protective association with cancer mortality persists even after control for such confounding. Summary boxWhat is already known on this topic O_LIAdolescent physical activity and cardiorespiratory fitness are considered important factors for the prevention of cancer based on evidence from observational studies. C_LIO_LIObservational studies are, however, vulnerable to unobserved confounders and bias processes, including health-seeking behaviours and genetic and environmental confounders. C_LIO_LIThese biases could explain why prior studies have found that high adolescent cardiorespiratory fitness is associated with higher risks of some cancers, typically low-mortality cancers such as prostate and non-melanoma skin cancer. C_LI What this study adds O_LIThis nationwide cohort study of 1.1 million male adolescents showed that while higher cardiorespiratory fitness was associated with excess risk of the most common cancers - prostate and non-melanoma skin - these associations attenuated to the null when accounting for behavioural, environmental, and genetic confounders shared between full siblings. C_LIO_LIIn contrast, high adolescent cardiorespiratory fitness was associated with a lower risk of overall cancer mortality, which remained after controlling for unobserved confounders shared between full siblings. C_LI

Prior cohort studies assessing cancer risk based on immune cell subtype profiles have predominantly focused on White populations. This limitation obscures vital insights into how cancer risk varies across race. Immune cell subtype proportions were estimated using deconvolution based on leukocyte DNA methylation markers from blood samples collected at baseline on participants without cancer in the Atherosclerosis Risk in Communities (ARIC) Study. Over a mean of 17.5 years of follow-up, 668 incident cancers were diagnosed in 2,467 Black participants. Cox proportional hazards regression was used to examine immune cell subtype proportions and overall cancer incidence and site-specific incidence (lung, breast, and prostate cancers). Higher T regulatory cell proportions were associated with statistically significantly higher lung cancer risk (hazard ratio = 1.22, 95% confidence interval = 1.06-1.41 per percent increase). Increased memory B cell proportions were associated with significantly higher risk of prostate cancer (1.17, 1.04-1.33) and all cancers (1.13, 1.05-1.22). Increased CD8+ naive cell proportions were associated with significantly lower risk of all cancers in participants [&ge;]55 years (0.91, 0.83-0.98). Other immune cell subtypes did not display statistically significant associations with cancer risk. These results in Black participants align closely with prior findings in largely White populations. Findings from this study could help identify those at high cancer risk and outline risk stratifying to target patients for cancer screening, prevention, and other interventions. Further studies should assess these relationships in other cancer types, better elucidate the interplay of B cells in cancer risk, and identify biomarkers for personalized risk stratification.

BackgroundImprovements in cancer control have led to a drastic increase in cancer survivors who may be at an elevated risk of developing a subsequent primary cancer (SPC). In this study, we assessed the risk and patterns of SPC development among 134,693 adult cancer survivors in Alberta, Canada. MethodsWe used data from the Alberta Cancer Registry to identify all first primary cancers (FPC) occurring between 2004 and 2015. A SPC was considered as the next primary cancer occurring in a different site. We estimated standardized incidence ratios (SIR) for SPC development as the observed number of SPC (O) divided by the expected number of SPC (E), where E is a weighted-sum of the population-based year-age-sex-specific incidence rates and the corresponding person-years of follow-up. ResultsThe risk of developing a SPC up to fifteen years after an initial cancer was 16.1% for males and 12.3% for females, though these estimates vary considerably by cancer site. Survivors of initial head and neck cancers had a 21.3% fifteen-year cumulative incidence and a 2.5-fold relative risk of SPC development. Overall, both males (SIR=1.50) and females (SIR=1.64) had an increased risk of a SPC. There were significant increases in SPC risk for nearly all age groups, with a greater than 5-fold increase for survivors of cancers diagnosed between ages 18-39. ConclusionsCancer survivors of nearly every FPC site had substantially increased risk of a SPC, compared to the cancer risk in the general population. Screen-detectable cancers (breast, cervical, colorectal, lung) were common SPC sites and highlights the need to investigate optimal strategies for screening the growing population of cancer survivors.

BackgroundLung cancer is the leading cause of cancer-related deaths worldwide and is one of the major diseases contributing to the loss of healthy life years. A comprehensive understanding of the burden of lung cancer is crucial for developing effective prevention and treatment strategies. However, there is still a limited comprehensive assessment of the global burden of lung cancer. This study provides the latest evaluation of lung cancer prevalence, incidence, mortality, and Disability-Adjusted Life Years (DALYs) from 1990 to 2021, systematically analyzes global lung cancer trends from 1990 to 2021, and predicts future trends for 2040, aiming to provide scientific evidence for policy-making. MethodsThe data for this study were obtained from the 2021 Global Burden of Disease Study (GBD). The estimated annual percentage changes (EAPCs) were calculated to quantify temporal patterns and assess trends in age-standardized lung cancer prevalence (ASPR), incidence (ASIR), mortality (ASDR), and DALYs; the study conducted stratified analyses by sex, twenty age categories, twenty-one GBD regions, two hundred four countries/regions, and five SDI quintiles; trends were predicted to 2040 using a Bayesian age-period-cohort model. Statistical analyses and plotting were performed using R version 4.4.3. ResultsIn 2021, the total number of lung cancer cases worldwide was approximately 3,253,729. The global ASPR was 37.3 per 100,000, the ASIR was 26.4 per 100,000, and the ASDR was 23.5 per 100,000 (95% UI: 21.2-25.8), with an age-standardized DALY rate of 533 years lost per 100,000. Regionally, higher socio-demographic index (SDI) areas had the highest ASPR, ASIR, ASDR, and age-standardized DALY rates, while lower SDI areas had relatively lower incidence rates. Geographically, the High-income Asia Pacific region had the highest ASPR, East Asia ranked first in ASIR and ASDR, and Central Europe had the highest age-standardized DALY rate. Among countries, Monaco had the highest ASPR, ASIR, and ASDR, while Greenland had the highest age-standardized DALY rate. ConclusionThis study describes the current global prevalence of lung cancer, estimates the influencing factors in different regions, utilizes scientific statistical methods to predict future trends in lung cancer development, and proposes response measures tailored to the burden of lung cancer in different regions, which will help alleviate the global burden of lung cancer.

Tobacco smoke, alone or combined with alcohol, is the predominant cause of head and neck cancer (HNC). Here, we further explore how tobacco exposure contributes to cancer development by mutational signature analysis of 265 whole-genome sequenced HNC from eight countries. Six tobacco-associated mutational signatures were detected, including some not previously reported. Differences in HNC incidence between countries corresponded with differences in mutation burdens of tobacco-associated signatures, consistent with the dominant role of tobacco in HNC causation. Differences were found in the burden of tobacco-associated signatures between anatomical subsites, suggesting that tissue-specific factors modulate mutagenesis. We identified an association between tobacco smoking and three additional alcohol-related signatures indicating synergism between the two exposures. Tobacco smoking was associated with differences in the mutational spectra and repertoire of driver mutations in cancer genes, and in patterns of copy number change. Together, the results demonstrate the multiple pathways by which tobacco smoke can influence the evolution of cancer cell clones.

BackgroundSubsequent primary malignancies following human papillomavirus (HPV)-related cancers represent an important survivorship concern. However, evidence remains limited regarding sociodemographic and clinical factors associated with registry-defined subsequent cancers among children, adolescents, and young adults in U.S. population-based cohorts. MethodsWe conducted a retrospective population-based analysis of 1,326 individuals diagnosed with HPV-related cancers using Surveillance, Epidemiology, and End Results (SEER) data. Registry-defined subsequent cancer was operationalized as the occurrence of additional primary HPV-related malignancies according to SEER multiple primary rules. Multivariable logistic regression models estimated associations with sex, age group, area-level socioeconomic status (Yost Index quintiles), persistent poverty census tract status, and primary cancer site. Sex-stratified analyses by cancer site were performed. ResultsRegistry-defined subsequent cancers were significantly associated with female sex and young adult age (20-29 years). Females had higher odds of subsequent cancer compared with males (OR = 1.06, 95% CI: 1.03-1.10), and individuals aged 20-29 years had higher odds than those aged 0-9 years (OR = 1.10, 95% CI: 1.05-1.16). Associations persisted after adjustment for socioeconomic indicators. No significant associations were observed with Yost Index quintiles or persistent poverty. Sex-stratified analyses showed higher odds of subsequent cancer for anal cancer among males and vulvar cancer among females relative to oropharyngeal cancer. ConclusionsSex and age are key determinants of registry-defined subsequent cancers following HPV-related malignancies, independent of area-level socioeconomic context. These findings support age- and sex-specific survivorship surveillance strategies across early life-course stages.

Structured SummaryO_ST_ABSBackgroundC_ST_ABSProteins have an integral role in cancer aetiology and inform cancer detection, treatment, and prognosis. While published data from prospective proteomic studies identifying early detection cancer risk markers have rapidly increased in the past five years, the landscape of evidence remains unclear. We aim to synthesize the evidence on circulating proteins and cancer risk. MethodsWe conducted a systematic review and meta-analysis. We searched Embase and Medline up to December-2023 with reference-list screening and hand-searching up to June-2024. Prospective cohort studies were eligible if they used multiplex panels, included adults without cancer diagnosis at baseline, and reported associations between circulating proteins at baseline and risk of incident cancer. Based on highest global incidence, we included esophageal, stomach, colorectal, liver, lung, breast, cervical, prostate, bladder, thyroid cancer. We conducted exome-protein-score and Mendelian randomisation analyses and integrated exome-gene-burden results for protein associations that passed false-discovery-rate correction to assess protein roles in cancer aetiology. FindingsOf 4,949 articles, we included 26 unique studies comprising 84,129 participants and 14,326 cases. The studies profiled 2,434 unique proteins and reported 19,130 total protein-cancer-associations. We conducted 3,448 meta-analyses and detected 216 associations (131 novel) that passed false-discovery-rate correction for stomach (n=2), colorectal (n=27), lung (n=172), breast (n=14), and prostate (n=1) cancer. No significant associations were observed for bladder cancer. Meta-analyses were not possible for esophageal, liver, cervical, or thyroid cancer, due to limited data. Supporting genetic evidence was found for 39 protein-cancer-associations. InterpretationWe identified 131 novel protein-cancer-associations with strong evidence across meta-analyses of which some may be cancer markers and others may have a role in aetiology, indicated by supporting genetic analyses, including ITGA11 and lung cancer. Our findings highlight the need for large, diverse, and mature prospective proteomic cohort studies of cancer risk to ensure the equity and generalisability of insights into cancer risk.

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.

BackgroundcSCC (cutaneous squameous cell carcinom) and its precursors are a major cause of morbidity especially in immunosuppressed patients and are frequently associated with human papilloma virus (HPV) infections. ObjectiveThe purpose of this study is to investigate the therapeutically potential of alpha-HPV vaccination for immunosuppressed patients with established cSCC and its precursors. MethodsIn this retrospective study, all patients who received Gardasil-9(R), a nonavalent HPV vaccine, as secondary prophylaxis were examined. Dermatologic interventions in both the pre- and post-vaccination periods were analyzed with zero-inflated poisson regression and a proportional intensity model for repeated events with consideration of the clinically relevant cofactors. ResultsThe hazard ratio for major dermatologic interventions was 0.27 (CI 0.14-0.51, p <0.001) between pre- and post Gardasil-9(R) intervention. Gardasil-9(R) vaccination showed good efficacy in reducing major dermatologic interventions even after correction of relevant cofactors and national COVID-19 case loads during the observational period. LimitationThe retrospective study design and the rather low number of patients may influence study results. Furthermore, analysis of HPV types and data collection on vaccine-specific HPV antibody measurements was not possible. ConclusionAlpha-HPV vaccination may potentially cause a significant decrease in dermatologic interventions in immunosuppressed patients with high skin tumor burden. Capsule summaryO_LILittle is known about a possible immunizing effect of alpha-vaccines in immunosuppressed patients with high skin tumor burden C_LIO_LIAlpha-HPV vaccination such as Gardasil-9(R) may potentially cause a significant decrease in dermatologic interventions in IS patients with high skin tumor burden. C_LI