JNCI: Journal of the National Cancer Institute

BackgroundThe U.S. Department of Health and Human Services recently announced plans to curtail investment in messenger RNA (mRNA) vaccine development, despite the central role played by the platform in preventing millions of deaths during the COVID-19 pandemic. Beyond infectious diseases, mRNA vaccines are showing promise in oncology, where early-phase clinical trials report meaningful improvements in overall and recurrence-free survival. Evaluating the potential public health and economic value of these therapies is critical for informing funding decisions. MethodsWe reviewed ongoing mRNA cancer vaccine clinical trials and extracted available survival outcomes. To project potential impact of mRNA vaccination on overall survival, we combined trial-based improvements in survival with incidence and demographic-adjusted survival rates from the Surveillance, Epidemiology, and End Results (SEER) program of National Cancer Institute. A logistic regression framework estimated one- and three-year survival gains. We then applied the Value of a Statistical Life Year (VSLY, $604,000; 3% discount rate) provided by the U.S. Department of Health and Human Services to quantify the economic implications of forgoing mRNA investment. ResultsIn a single annual U.S. cohort of patients newly diagnosed with non-small cell lung cancer, pancreatic cancer, renal cell carcinoma, or melanoma, mRNA vaccination could potentially avert approximately 49,000 deaths within three years of diagnosis. These projected survival gains translate to an estimated economic value of $75 billion. ConclusionsOur findings underscore the substantial public health opportunity provided by mRNA cancer vaccines. Curtailing federal investment risks forfeiting these benefits, while sustained support could accelerate clinical translation and preserve infrastructure essential for future pandemic preparedness.

IntroductionChronic inflammation has been implicated in lung carcinogenesis. Prospective studies have linked higher circulating C-reactive protein (CRP), an acute-phase inflammation marker, to higher lung cancer risk in predominantly smoking populations but lower risk in never smokers. We evaluated DNA methylation-based inflammation risk scores (DNAm-IRSs), which may capture longer-term immune-inflammatory and exposure-related biology, with lung cancer risk among never smokers. MethodsWe evaluated six DNAm-IRSs, including four CRP-based scores (IRSLigthart, IRSWielscher, IRSLinear_Hillary, IRSElnet_Hillary), in 683 risk-set-sampled case-control pairs nested in the Shanghai Womens Health Study (n=74,941). We estimated hazard ratios (HRs) and 95% confidence intervals (CIs) using conditional logistic regression. We examined DNAm-derived leukocyte composition and circulating immune-inflammatory proteins to characterize DNAm-IRS biology. ResultsCirculating CRP correlated positively with IRSLigthart (r=0.19), IRSWielscher (r=0.13), and IRSElnet_Hillary (r=0.30), but inversely with IRSLinear_Hillary (r=-0.02). Per standard deviation increase, IRSLigthart was associated with lower lung cancer risk (HR=0.85, 95% CI: 0.76-0.95), and IRSWielscher with lower risks of lung cancer (HR=0.87, 95% CI: 0.77-0.97) and adenocarcinoma (HR=0.83, 95% CI: 0.71-0.97). Associations persisted after adjustment for leukocyte composition and strengthened after adjustment for DNAm pack-years, an epigenetic smoking index that may capture combustion-related exposures beyond active smoking. Inverse associations were more evident among women with lower DNAm pack-years, although formal interaction tests were not statistically significant. Both scores were positively associated with acute-phase inflammation, IFN-{gamma}/effector trafficking, and higher CD8+ T-cell proportions. ConclusionsAmong never smokers, selected CRP-related DNAm-IRSs were associated with lower lung cancer risk and were linked to immune features consistent with antitumor activity.

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.

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.

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.

The relative contributions of genetic and shared environmental influences to cancer risk and cross-cancer associations remain poorly understood. We analyzed data from 222,530 same-sex twins from Denmark, Finland, Norway, and Sweden in the Nordic Twin Study of Cancer, including 43,060 incident cancers over a median follow-up of 41.6 years. Using a target trial framework, biometric modeling, and competing-risk adjustment, we estimated familial risk, heritability, and shared environmental contributions across 35 cancer sites. Lifetime cancer risk was 36.5%, increasing to 51.4% in monozygotic (MZ) twins and 45.3% in dizygotic (DZ) twins with an affected co-twin. Overall cancer risk was explained by heritable (28%) and shared environmental (40%) influences. Heritability was highest for prostate (42%), non-melanoma skin (24%), and breast (18%) cancers. Cross-cancer analyses revealed extensive overlap in the genetic and shared environmental factors across sites, consistent with widespread pleiotropy and shared environmental susceptibility. Prostate cancer exhibited the strongest genetic overlap with rectum/anus (12%) and kidney (11%) cancers, whereas co-shared environmental influences were most pronounced for breast-lung (11%), prostate-bladder (11%), and prostate-lung (12%) cancers. These findings show pervasive genetic overlap across cancers at different sites and emphasize the importance of incorporating familial shared environmental exposures into cancer risk prediction and prevention strategies.

PURPOSERandomized controlled trials have failed to validate that neutralizing oxidative stress (OxS) through antioxidant supplementation reduces cancer risk. This study aims to prospectively investigate whether the relationship between systemic OxS and colorectal cancer (CRC) risk changes over the course of cancer development. METHODSThis study utilized a nested case-control design in two Shanghai cohorts for primary analysis and one US cohort for replication analysis. During a median follow-up of 15.1 years in the Shanghai cohorts, 1938 incident CRC cases were identified and matched to one control each. In the US cohort, 285 incident CRC cases were included with two matched controls per case. Systemic OxS was assessed by urinary markers of DNA oxidation (8-oxo-7,8-dihydro-2-deoxyguanosine [8-oxo-dG]) and RNA oxidation (7,8-dihydro-8-oxo-guanosine [8-oxo-Guo]) using UPLC-MS/MS assays. Multivariable-adjusted odds ratios (ORs) for CRC risk were calculated. RESULTSAfter adjusting for potential confounders, we observed an inversion association between OxS markers and CRC risk in the Shanghai cohorts, which was independently replicated in the US cohort. Moreover, the inverse association was time-dependent, manifesting only for CRC cases diagnosed within 5 years of enrollment. ORs (95% CI) for CRC at the 10th and 90th percentiles of 8-oxo-dG levels, relative to the median, were 1.87 (1.39 to 2.53) and 0.48 (0.37 to 0.63), respectively, demonstrating an approximate 4-fold difference in risk between the two groups, with P for overall association of < 0.001. A similar pattern was observed for 8-oxo-Guo. No significant association was found for CRC diagnosed beyond 5 years of enrollment. CONCLUSIONThis novel finding of an inverse and time-dependent relationship between systemic OxS and CRC risk, if further confirmed, may provide a new perspective for revisiting redox-based chemoprevention. CONTEXTO_ST_ABSBackgroundC_ST_ABSAlmost all large randomized controlled trials have failed to validate the hypothesis that neutralizing oxidative stress through antioxidant supplementation can lower cancer risk, which has puzzled the public and researchers for decades. Key FindingsA reduced risk for colorectal cancer (CRC) with increasing systemic oxidative stress, measured by two urinary biomarkers of DNA and RNA oxidation, was observed in two large prospective cohort studies in Shanghai, China, and was replicated in an independent cohort in the United States. This association was time-dependent, with the inverse relationship strengthening as the biomarker assessment neared the time of CRC diagnosis. RelevanceOur study, for the first time, suggests an inverse and time-dependent relationship between systemic oxidative stress and CRC development, which, if further confirmed, may provide a new perspective for revisiting redox-based chemoprevention.

Background: Colorectal cancer (CRC) disproportionately affects non-Hispanic Black (NHB) Americans compared to Non-Hispanic White (NHW), with more cases arising before age 50. Racial disparities in outcomes reflect complex interactions among healthcare access, socioeconomic factors, and structural racism, yet analyses linking individual-level data for these factors to survival remain limited. Methods: We examined overall and CRC-specific survival among NHB and NHW patients diagnosed between 2013 and 2022 enrolled in the Disparities and Cancer Epidemiology (DANCE) cohort, a population-based study of CRC in metropolitan Detroit and Louisiana. Multivariable Cox regression and competing-risks models were used to assess the roles of race, age of onset, neighborhood deprivation, and stage on survival outcomes. Results: Among 1,019 CRC cases (57% NHB, 43% NHW), NHB patients were more likely to reside in high-deprivation neighborhoods, report lower household incomes, and present with right-sided tumors, though stage at diagnosis did not differ by race. In multivariable analysis, stage was the strongest predictor of survival, while neighborhood deprivation (per 10-unit ADI increase: HR = 1.14) was independently associated with worse survival; NHB race was not significantly associated with survival after adjustment. Younger age at diagnosis was associated with a survival advantage in regional-stage disease but paradoxically with worse survival in distant-stage disease, and higher deprivation predicted worse survival in both local and distant but not regional stage. Conclusion: Our study shows that socioeconomic factors, as measured by ADI and household income, accounts for some, but not all, of the disparities in survival between NHB and NHW CRC cases.

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.

BackgroundTo measure the aging process before a cancer diagnosis, we developed the first cancer-specific proteomic aging clock (CaPAC) and examined its association with cancer risk in the Atherosclerosis Risk in Communities (ARIC) and Multi-Ethnic Study of Atherosclerosis (MESA) studies. MethodsUsing the SomaScan assay, ARIC measured 4,712 proteins in plasma samples collected in 1990-92 from 3,347 participants who developed cancer over follow-up until 2015 and 7,487 who remained cancer-free, all aged 46-70. We constructed CaPAC0 using elastic net regression among two-thirds randomly selected cancer-free participants (N=4,991, training set) and calculated age acceleration for CaPAC0 (CaPAA0) as residuals of CaPAC0 on chronological age in all remaining ARIC participants. We used multivariable-adjusted Cox proportional hazards regression to calculate hazard ratios (HRs) for the risk of overall, obesity-related, smoking-related, and the most common cancers (prostate, lung, breast, colorectal) with CaPAA0 using a case-cohort design. We replicated the analysis in 3,893 MESA participants aged 46-70 at Exam 1 (456 incident cancer). ResultsCaPAC0 was correlated with chronological age in ARIC and MESA (r=0.82 and 0.86, respectively). In both ARIC and MESA, CaPAA0 was significantly (p<0.05) associated with the risk of overall [HRs per 5-years=1.08 and 1.23, respectively], smoking-related [HRs=1.30 and 1.54, respectively], and lung cancers [HRs=1.54 and 1.94, respectively]. CaPAA0 was also significantly associated with colorectal cancer risk in ARIC [HR=1.31], but not in MESA. CaPAA0 was not associated with obesity-related, breast, or prostate cancers. ConclusionCaPAA0 was associated with several types of cancer with the strongest association observed for lung cancer risk.

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.

Head and neck cancer (HNC) is the sixth most common cancer globally. Incidence and survival rates vary significantly across geographic regions and tumor subsites. This is partly due to differences in risk factor exposure, which includes tobacco smoking, alcohol consumption and human papillomavirus (HPV) infection, alongside detection and treatment strategies. The VOYAGER (human papillomaVirus, Oral and oropharYngeal cAncer GEnomic Research) consortium is a collaboration between five large North American and European studies which generated data on 10,530 participants (7,233 cases and 3,297 controls). The primary goal of the collaboration was to improve understanding of the role of HPV and genetic factors in oral cavity and oropharyngeal cancer risk and outcome. Demographic and clinical data collected by the five studies were harmonized, and HPV status was determined for the majority of cases. In addition, 999 tumors were sequenced to define somatic mutations. These activities generated a comprehensive biomedical resource that can be utilized to answer critical outstanding research questions to help improve HNC prevention, early detection, treatment, and surveillance.

ObjectiveTo develop the Mexico Smoking and Vaping Model (Mexico SAVM) to estimate cigarette and electronic nicotine delivery systems (ENDS) prevalence and the public health impact of legalizing ENDS use. MethodsSAVM, a cohort-based discrete-time simulation model, compares two scenarios. The ENDS-Restricted Scenario estimates smoking prevalence and associated mortality outcomes under the current policy of an ENDS ban, using Mexico-specific population projections, death rates, life expectancy, and smoking and e-cigarette prevalence. The ENDS-Unrestricted Scenario projects smoking and vaping prevalence under a hypothetical scenario where ENDS use is allowed. The impact of legalizing ENDS use is estimated as the difference in smoking- and vaping-attributable deaths (SVADs) and life-years lost (LYLs) between the ENDS-Restricted and Unrestricted scenarios. ResultsCompared to a national ENDS ban, The Mexico SAVM projects that legalizing ENDS use could decrease smoking prevalence by 40.1% in males and 30.9% in females by 2049 compared to continuing the national ENDS ban. This reduction in prevalence would save 2.9 (2.5 males and 0.4 females) million life-years and avert almost 106 (91.0 males and 15.5 females) thousand deaths between 2025 and 2049. Public health gains decline by 43% to 59,748 SVADs averted when the switching rate is reduced by half and by 24.3% (92,806 SVADs averted) with a 25% ENDS risk level from that of cigarettes but increased by 24.3% (121,375 SVADs averted) with the 5% ENDS risk. ConclusionsMexico SAVM suggests that greater access to ENDS and a more permissive ENDS regulation, simultaneous with strong cigarette policies, would reduce smoking prevalence and decrease smoking-related mortality. The unanticipated effects of an ENDS ban merit closer scrutiny, with further consideration of how specific ENDS restrictions may maximize public health benefits.

ImportanceWe recently observed an inverse and time-dependent association between systemic oxidative stress (OxS), measured by urinary biomarkers of nucleic acid oxidation, and colorectal cancer (CRC) risk. Further investigations into other types of OxS markers are warranted. ObjectiveTo extend the investigation into systemic lipid peroxidation and CRC risk. Design, Setting, and ParticipantsUtilizing a nested case-control design, this studys primary analysis was performed in two large prospective cohorts in Shanghai, China, and replicated in an independent cohort in the US. ExposuresSystemic lipid peroxidation was assessed by urinary F2-isoprostanes (F2-IsoPs) using UPLC-MS/MS assays. Main Outcomes and MeasuresDuring 15.1-year follow-up in the Shanghai cohorts, 1938 incident CRC cases were identified and matched to one control each through incidence-density sampling. In the US cohort, 285 incident CRC cases were included, each matched to two controls. Odds ratios (ORs) for CRC were calculated using multivariable conditional logistic regression models. ResultsElevated levels of urinary 5-F2t-IsoP (5-iPF2-VI), a major isomer of F2-IsoPs induced solely by free radicals, were associated with reduced risk of CRC in the Shanghai cohorts. This finding was replicated in the US cohort. Moreover, this inverse association was time-dependent, manifesting only in the later years of cancer development. Multivariable-adjusted ORs (95% CI) for CRC diagnosed within 5 years of enrollment at the 10th and 90th percentiles of 5-F2t-IsoP levels, relative to the median, were 1.57 (1.26-1.96) and 0.61 (0.42-0.89), respectively, indicating a 2.2-fold difference in risk between the two groups. A stronger association was observed when using the composite index of DNA, RNA and lipid OxS markers, showing a 3.9-fold difference in risk between the two groups. No significant association was found for CRC diagnosed beyond 5 years of enrollment. ConclusionsThis study provides new evidence that systemic OxS is inversely and time-dependently associated with CRC risk in humans. Key PointsO_ST_ABSQuestionC_ST_ABSIs the time-dependent relationship between oxidative stress and tumorigenesis observed at the cellular level in experimental models also present at the systemic level in a population-based setting? FindingsElevated systemic lipid peroxidation, measured by urinary F2-isoprostanes, was associated with a reduced risk of colorectal cancer (CRC) in two large prospective cohort studies in Shanghai, China, which was replicated in an independent cohort in the United States. This association varied over time, showing a stronger effect as cancer advanced. MeaningThis study provides new evidence that systemic oxidative stress is inversely and time-dependently associated with CRC risk in humans.

BackgroundOur 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. MethodsUsing 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. ResultsFor 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. ConclusionsBesides 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.

This study investigated potential pre-diagnostic proteomic risk markers for 7 solid cancers independent of known risk factors within a multi-center, prospective cohort study. Using the SomaScan(R) 5K assay, we analyzed 4,712 unique plasma proteins (4,955 aptamers) in the Atherosclerosis Risk in Communities (ARIC) study among 9,391 middle-aged and older Black (23%) and White (77%) men and women. Over a maximum follow-up of 25.9 years, incident cases included 136 bladder, 271 colorectal, 96 kidney, 22 liver, 416 lung, 88 pancreatic, and 588 prostate cancers. After false discovery rate (FDR) correction, we identified 144 unique protein-cancer associations in common risk-factor adjusted models, and 41 protein-cancer associations in both common and cancer site-specific risk-factor adjusted models. Associations included several novel circulating proteins related to liver (33 proteins) and lung (4 proteins) cancer risk, and confirmed previously established proteins associated with kidney (HAVCR1 and MMP7) and prostate (KLK3 and ACP3) cancer risk. External validation in the European Prospective Investigation into Cancer and Nutrition cohort (SomaScan 7K) confirmed that the majority of FDR-significant proteins showed consistent effect directions and nominal significance, with the proportion of confirmed proteins varying between 75% and 100% depending on the cancer site. Time-lagged analysis demonstrated that 90% of the identified cancer-associated proteins are markers for long-term cancer risk, with observed associations more than 5 years pre-diagnosis after multiple-testing correction. These findings underscore the potential of circulating proteomic markers beyond known risk factors for elucidating etiologic mechanisms and improving risk stratification across cancers.

BackgroundUltra-processed foods (UPF) account for >50% of calories consumed by US adults. Strong evidence links whole grain, fiber, calcium, and dairy intake to lower and processed meat intake to higher colorectal (CRC) risk. UPF, include some whole grain and dairy products and most processed meats. Studies of UPF intake and CRC risk are inconsistent. ObjectiveTo estimate the association between UPF intake and CRC risk as well as to evaluate the joint effect of UPF intake and diet quality with CRC risk and to estimate associations of select food groups and nutrients with CRC risk by UPF and non-UPF source . MethodsUS adults, aged 50-71, who participated in the NIH-AARP Diet and Health Study self-reported dietary intake using a validated food frequency questionnaire (FFQ). We assigned disaggregated FFQ items to Nova classification and categorized UPF intake (g/1000 kcal/day) into sex-specific quintiles. We used multivariable-adjusted Cox proportional hazards regression models to estimate hazard ratios (HR) and 95% confidence intervals (CI) for CRC. ResultsOver 20 years of follow-up, 10,075 colorectal adenocarcinoma cases were diagnosed among 461,682 participants who were cancer-free at baseline. Median UPF intake was 293 g/1000 kcal/day or 43% of daily energy intake. UPF intake was not associated with incident CRC (HRQ5vs.Q1=0.97; 95% CI, 0.91-1.03; Ptrend=.55) overall or by anatomic location (all Ptrend>.05). Whole grain, dairy, and calcium intake were inversely but meat intake was positively associated with CRC risk regardless of processing level. ConclusionsTotal UPF intake was not associated with incident CRC in this cohort of older, US adults. This may be explained, in part, by opposing effects of some UPF on CRC etiology. Our findings support current dietary guidance to consume whole grains, fiber, dairy, and calcium and avoid processed meat for CRC prevention.

Background: Proteins directly impact disease development and act as drug targets. Therefore, we integrated genomic and lung tissue proteomics data to identify lung cancer susceptibility proteins, elucidating genetic mechanisms and candidate drug targets. Method: We profiled the proteome and genome in non-neoplastic lung tissue from 200 lung cancer patients. Using this data, we constructed genetic models to predict abundance across the proteome in lung tissue. We applied these models to genome-wide association study (GWAS) data from 55,174 lung cancer cases and 1,294,174 controls to evaluate their associations with the risk of lung cancer, overall and by major histological subtypes. Bayesian colocalization and Mendelian randomization (MR) analyses were used to prioritize putative causal proteins, which were cross-referenced with three main drug-protein databases to identify potential therapeutic targets. Results: We identified 29 proteins associated with lung cancer risk at a false discovery rate < 5%, including 25 for overall lung cancer, two (AQP3 and IL18) specifically for adenocarcinoma, and another two (HMGN2 and HLA-DMB) for squamous cell carcinoma. Of them, genes encoding 17 proteins reside at least 2Mb away from any known GWAS risk loci, including 14 for overall lung cancer (HYI, GPX1, GMPPB, DSP, HDDC2, MTCH2, SUOX, JMJD7, PDIA3, IL16, IQGAP1, SULT1A2, ARHGAP27, and TYMP) and three for subtypes (AQP3, IL18, and HMGN2). Among the 12 proteins located within the known risk loci, EPHX2, CLDN18, PSMD5, and CYP2S1 proteins showed an association independent of the proximal GWAS-identified lead variant. Colocalization and/or MR analysis suggested 11 potential causal proteins. Five of these candidate causal proteins (DSP, CLDN18, IQGAP1, IL18 and TYMP) are targeted by nine drugs already approved by the FDA or in phase III trials. Conclusion: Our study identified novel lung cancer susceptibility proteins and potential drug targets, offering valuable insights into lung cancer biology and future translational utilities.

The incidence of colorectal cancer (CRC) among individuals under age 50, or early-onset CRC (EOCRC), has been rising over the past few decades for unclear reasons, and the etiology of the disease remains largely unknown. Known genetic risk factors do not explain this increase, pointing to possible environmental and as-yet unidentified genetic contributors and their interactions. Previous research linked genetic variation on chromosome 6 to increased CRC risk. This region harbors multiple immune genes, including the gene encoding Major Histocompatibility Complex (MHC) class I polypeptide-related sequence A (MICA). MICA is a polygenic ligand for the Natural Killer Group 2D receptor (NKG2D), a receptor expressed on Natural Killer (NK) cells and other lymphocytes. Given that intra-tumoral NK cell infiltration correlates with favorable CRC outcomes, we hypothesized that germline genetic variation in MICA could influence CRC risk. In a discovery set of 40,125 cases and controls, we show that the minor G allele at Chr6:31373718C>G (hg19) is associated with increased risk for CRC (odds ratio (OR) = 1.09, 95% confidence interval (CI) 1.04 - 1.15, p = 0.0009). The effect is stronger in EOCRC (OR = 1.26, 95% CI 1.08 - 1.44, p = 0.0023) than in those 50 and over (OR = 1.07, 95% CI 1.02 - 1.13; p = 0.012) (Ratio of ORs = 1.32, 95% CI 1.14 - 1.52, p = 0.0002). In an independent validation set of 77,983 cases and controls, the adjusted interaction by age-of-onset was significant at OR = 1.15 (95% CI 1.03 - 1.34, p = 0.0150) with a higher risk in EOCRC. Expression quantitative trait locus analysis in normal colonic epithelia showed that MICA RNA expression decreases linearly with each additional copy of the minor G allele (p = 3.345 x 10e-18). Bulk RNA analysis of the tumor immune microenvironment revealed that tumors from patients with CG or GG genotypes have lower resting and activated NK cell infiltration as compared to tumors from patients with CC genotype. Multiplex immunofluorescence analysis demonstrated that patients with a G allele (i.e. CG or GG genotype, but not CC genotype) have a statistically significant decrease in the number of NK cells in tumor compared to adjacent normal colonic mucosa. Taken together, population-based epidemiologic, molecular, genetic, cellular and immunologic evidence demonstrate that MICA genotype is associated with increased risk of EOCRC and reduced number of NK cells in colorectal tumors, suggesting that patients with a G allele have altered NK cell-mediated immunosurveillance. These novel findings suggest that EOCRC may have a previously unrecognized innate immune-mediated etiology which merits further investigation.

BackgroundMeningioma risk factors include older age, female sex, and African-American race. There are limited data exploring how meningioma risk in African-Americans varies across the lifespan, interacts with sex, and differs by tumor grade. MethodsThe Central Brain Tumor Registry of the United States (CBTRUS) is a population-based registry covering the entire U.S. population. Meningioma diagnoses from 2004-2019 were used to calculate incidence rate ratios (IRRs) for non-Hispanic Black individuals (NHB) compared to non-Hispanic white individuals (NHW) across 10-year age intervals, and stratified by sex and by WHO tumor grade. Results53,890 NHB individuals and 322,373 NHW individuals with an intracranial meningioma diagnosis were included in analyses. Beginning in young adulthood, the NHB-to-NHW IRR was elevated for both grade 1 and grade 2/3 tumors. The IRR peaked in the seventh decade of life regardless of grade, and was higher for grade 2/3 tumors (IRR=1.57; 95% CI: 1.46-1.69) than grade 1 tumors (IRR=1.27; 95% CI: 1.25-1.30) in this age group. The NHB-to-NHW IRR was elevated in females (IRR=1.17; 95% CI: 1.16-1.18) and further elevated in males (IRR=1.28; 95% CI: 1.26-1.30), revealing synergistic interaction between NHB race/ethnicity and male sex (PInteraction=0.001). ConclusionsRelative to NHW individuals, NHB individuals are at elevated risk of meningioma from young adulthood through old age. NHB race/ethnicity conferred higher risk of meningioma among men than women, and higher risk of developing WHO grade 2/3 tumors. Results identify meningioma as a significant source of racial disparities in neuro-oncology and may help to improve preoperative predictions of meningioma grade.