International Journal of Cancer

ObjectivesTo evaluate the benefit of combining polygenic risk scores (PRS) with the QCancer-10 (colorectal cancer) non-genetic risk prediction model to identify those at highest risk of colorectal cancer (CRC). DesignPopulation based cohort study. Six different PRS for CRC were developed (using LDpred2 PRS software, clumping and thresholding approaches, and genome-wide significant models). The top-performing genome-wide and GWAS-significant PRS were then combined with QCancer-10 and performance compared to QCancer-10 alone. Case-control (logistic regression) and time-to-event (Cox proportional hazards) analyses were used to evaluate risk model performance in men and women. Setting and participantsUK Biobank Study. A total of 434587 individuals with complete genetic and QCancer-10 predictor data were included in the QCancer-10+PRS modelling cohorts. Main outcome measuresPrediction of colorectal cancer diagnosis by genetic, non-genetic and combined risk models. FindingsPRS derived using the LDpred2 program performed best, with an odds-ratio per standard deviation of 1.58, and top age- and sex-adjusted C-statistic of 0.733 (95% confidence interval 0.710 to 0.753) in logistic regression models in the validation cohort. Integrated QCancer-10+PRS models out-performed QCancer-10 alone. In men, the integrated LDpred2 (QCancer-10+LDP) model produced a C-statistic of 0.730 (0.720 to 0.741) and explained variation of 28.1% (26.3% to 30.0%), compared with 0.693 (0.682 to 0.704) and 21.0% (18.9% to 23.1%) for QCancer-10 alone. Performance improvements in women were similar. In the top 20% of individuals at highest absolute risk, the sensitivity of QCancer-10+LDP models for predicting CRC diagnosis within 5 years was 47.6% in men and 42.5% in women, with respective 3.49-fold and 2.75-fold absolute increases in the top 5% of risk compared to average. Decision curve analysis showed that adding PRS to QCancer-10 improved net-benefit and interventions avoided, across most probability thresholds. ConclusionsIntegrating PRS with QCancer-10 significantly improves risk prediction over QCancer-10 alone. Evaluation of risk stratified population screening using this approach is warranted. Summary BoxO_ST_ABSWhat is already known on this topicC_ST_ABSO_LIRisk stratification based on genetic or environmental risk factors could improve cancer screening outcomes C_LIO_LINo previously published study has examined integrated models combining genome-wide PRS and non-genetic risk factors beyond age C_LIO_LIQCancer-10 (colorectal cancer) is the top-performing non-genetic risk prediction model for CRC C_LI What this study addsO_LIAdding PRS to the QCancer-10 (colorectal cancer) risk prediction model improves performance and clinical benefit, with greatest gain from the LDpred2 genome-wide PRS, to a level that suggests utility in stratifying CRC screening and prevention C_LI

ObjectiveMutational profiles of primary and metastatic thyroid cancer (THCA) have been examined by comparison of somatic mutation prevalences in the two stages, using P values to identify significant differences. However, prevalences and P values for mutations do not directly quantify the cancer effects of somatic variants. MethodsWe calculated cancer effect sizes accounting for substantial gene- and site-specific mutation rates, to quantify somatic selection across stages. This approach provides a direct measure of cancer-driving impact of new mutations and reveals the genes that drive tumorigenesis and progression, and whether mutations have greater effects in primary or metastatic THCA. ResultsTrinucleotide mutation profiles were similar between primary and metastatic THCA. Most canonical driver genes (BRAF, NRAS, TP53, ATM, EIF1AX, KMT2C, NF1, RBM10, ARID1A, PIK3CA, and NKX2-1) exhibited stronger selection during initial tumorigenesis (from organogenesis to primary THCA) than during progression (from primary to metastatic THCA). Notably, TERT mutations have been shown to be at higher prevalence in metastatic tumors, yet their strongest selection occurred earlier, during tumor initiation. In contrast, RET mutations exhibited the opposite trajectory, experiencing weaker selection during tumorigenesis but stronger selection during metastatic progression. ConclusionCancer effect size analysis revealed dynamic shifts in selective pressures across THCA evolution, distinguishing genes that drive initiation from those that promote metastatic progression. This evolutionary framework provides a quantitative basis for understanding THCA pathogenesis and provides guidance for stage-specific precision-medicine therapeutic strategies.

BackgroundProstate cancer (PCa) is one of the most common cancers globally. The potential for polygenic risk scores (PRSs) to improve risk stratification for early detection of PCA in screening interventions is of considerable interest. We evaluated the cost- effectiveness of PRS-guided screening strategies. MethodsThe Prostata microsimulation model, calibrated to UK-specific epidemiological and clinical data, simulated individual life histories, including disease onset and progression, tumour characteristics by Gleason score, and metastatic status. The model incorporated both measured and unmeasured components of polygenic risk for incident PCa, and included ancestry-specific strata. Screening strategies were compared against a no-screening baseline. We modelled one-off, age-based prostate specific antigen screening at 50, 60, or 70 years, as well as repeated uniform screening every 4 or 2 years from age 50 to 69 with and without PRS stratification. ResultsQuality-adjusted life years were similar across all screening strategies, while differences in costs were more pronounced. A "no screening" strategy had the lowest lifetime cost of all strategies and (very marginally) the shortest life expectancy. Realistic PRS implementations were dominated (less effective and more expensive) in all scenarios, and may not provide greater cost-effectiveness than a single PSA screen at age 50 or compared to no screening at all. ConclusionOur study found little evidence that PRSs would be cost-effective in pragmatic PCa screening settings.

Patients with metastatic, Estrogen Receptor (ER) positive, HER2-negative, breast cancer, before initiating CDK4/6 inhibitors, receive either single agent endocrine- or chemotherapy based on their clinical risk. In this first-ever trial-based economic evaluation of Circulating Tumor Cells (CTCs), the cost-effectiveness of standardizing the prescription of endocrine- or chemotherapy using a CTC count threshold (with >5 CTCs/7.5mL indicative of unfavorable disease outcomes) was compared to current clinical practice. N=755 ER+ HER2-patients, enrolled in 17 French centres, were randomized to CTC guided or standard of care and were treated according to either through the CTC score or clinical examination. Health state utilities were calculated by mapping the QLQ-C30 to EQ-5D utilities and used to calculate Quality-Adjusted Life Years (QALY) over a 2-year time horizon. Bootstrapping and additional sensitivity analyses were performed to quantify the impact of uncertainty. Health outcomes in both arms were similar, but costs were higher in the CTC guided arm ({euro}19,403) compared to the usual care ({euro}18,254), resulting in an ICER of {euro}104,078/QALY in favor of usual care. However, when the analysis was performed for the clinically high- and low-risk groups separately, CTC enumeration could be a dominant strategy (cost saving) if treatment is de-escalated in clinically high-risk patients as indicated by CTC scores. However, the current analysis was based on the PFS and OS data reported in 2021 and long-term Overall Survival data is collected since then (JCO, 2023 in press). A further analysis of the health economic impact of CTC enumeration in clinically low and high-risk groups is therefore indicated.

BackgroundApproximately thirty thousand people in Scotland are diagnosed with cancer annually, of whom a third live less than one year. The timing, nature and value of hospital-based healthcare for patients with advanced cancer are not well understood. The aim of this study was to describe patterns of hospital-based healthcare use and associated costs in the last year of life for patients with a cancer diagnosis. MethodsWe undertook a Scottish population-wide administrative data linkage study of hospital-based healthcare use for individuals with a cancer diagnosis aged 60 years and over on their date of death, who died between 2012 and 2017. Hospital admissions, length of stay (LOS), number and nature of outpatient and day case appointments were analysed for all cancer types. Generalised linear models were used to adjust costs for age, gender, socioeconomic deprivation status, rural-urban (RU) status and comorbidity. ResultsThe study included 85,732 decedents with a cancer diagnosis, for whom 64,553 (75.3%) cancer was the primary cause of death. Mean age at death was 80.01 (SD 8.15) years. The mean number of inpatient stays in the last year of life was 5.88 (SD 5.68), with a mean LOS of 7 days. Mean total inpatient, outpatient and daycase costs per patient were {pound}10261, {pound}1275 and {pound}977 respectively. Admission rates rose sharply in the last month of life. One year adjusted and unadjusted costs decreased with increasing age. A higher comorbidity burden was associated with higher costs and major cost differences between cancer types were also observed. ConclusionsPeople in Scotland in their last year of life with cancer are high users of secondary care. Hospitalisation accounts for a high proportion of costs, particularly in the last month of life. Further research is needed to examine triggers for unplanned hospitalisation and to identify modifiable reasons for variation in hospital use among different cancer cohorts.

BackgroundCancer control initiatives are informed by quantifying the capacity to reduce cancer burden through effective interventions. Burden measures using health administrative data are a sustainable way to support monitoring and evaluating of outcomes among patients and populations. The PREmature Mortality to IncidencE Ratio (PREMIER) is one such burden measure. We use data on Aboriginal and non-Aboriginal South Australians from 1990 to 2010 to show how PREMIER quantifies disparities in cancer burden: between populations; between sub-population cohorts where stage at diagnosis is available; and when follow-up is constrained to 24-months after diagnosis. MethodPREMIERcancer is the ratio of years of life expectancy lost due to cancer (YLLcancer) to life expectancy years at risk at time of cancer diagnosis (LYAR) for each person. The Global Burden of Disease standard life table provides referent life expectancies. PREMIERcancer was estimated for the population of cancer cases diagnosed in South Australia from 1990 to 2010. Cancer stage at diagnosis was also available for cancers diagnosed in Aboriginal people and a cohort of non-Aboriginal people matched by sex, year of birth, primary cancer site and year of diagnosis. ResultsCancers diagnoses (N=144,891) included 777 among Aboriginal people. Cancer burden described by PREMIERcancer was higher among Aboriginal than non-Aboriginal (0.55, 95%CIs 0.52-0.59 versus 0.39, 95%CIs 0.39-0.40). Diagnoses at younger ages among Aboriginal people, 7 year higher LYAR (31.0, 95%CIs 30.0-32.0 versus 24.1, 95%CIs 24.1-24.2) and higher premature cancer mortality (YLLcancer=16.3, 95%CIs 15.1-17.5 versus YLLcancer=8.2, 95%CIs 8.2-8.3) influenced this. Disparities in cancer burden between the matched Aboriginal and non-Aboriginal cohorts manifested 24-months after diagnosis with PREMIERcancer 0.44, 95%CIs 0.40-0.47 and 0.28, 95%CIs 0.25-0.31 respectively. ConclusionPREMIER described disproportionately higher cancer burden among Aboriginal people in comparisons involving: all people diagnosed with cancer; the matched cohorts; and, within groups diagnosed with same staged disease. The extent of disparities were evident 24-months after diagnosis. This is evidence of Aboriginal peoples substantial capacity to benefit from cancer control initiatives, particularly those leading to earlier detection and treatment of cancers. PREMIERs use of readily available, person-level administrative records can help evaluate health care initiatives addressing this need.

Withdrawal statementThe authors have withdrawn this manuscript due to a conflict of interest among the authors. Therefore, the authors do not wish this work to be cited as reference for the project. If you have any questions, please contact the corresponding author.

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

BackgroundThe reduced risk of breast cancer (BC) following increasing parity has been known for decades. Most prospective studies have presented the relative risk as the percentage decrease for each child during follow-up. Since the risk reduction is up to ten percent for each child, the overall lifelong BC risk reduction could be under communicated. In this study we use cumulative incidence rates (CIR) to calculate and describe the lifelong risk of BC in relation to parity. MethodsNOWAC is a prospective cohort study with 172,000 women recruited between 1991 and 2007 with follow-up through questionnaires and national registers of cancer and death. For the present analyses, we included 165 238 women with follow-up from 01.01.2000 until 31.12. 2018. We calculated CIR of BC by parity, stratified by other established BC risk factors (maternal age at first birth, breastfeeding, body mass index (BMI), smoking and alcohol consumption). ResultsAfter 17.3 years of average follow-up, 8120 women aged 35-84 years developed breast cancer. Age-specific incidence rates increased for each age group up to 60-64 years, decreased for the age group 75-79 years, and increased again among the oldest women aged 80-84. CIR for all participants up to 84 years was 11 700 per 100 000 person years (PY). In analyses stratified by parity, the CIR of BC for nullipara was 12 600 per 100 000 PY, for 1-2 children: 12 100, 3-4 children: 10 200, and 5-6 children: 8 700 per 100 000 PY. The parity-specific CIR of BC had the same pattern of decrease in analyses stratified for other BC risk factors. ConclusionCumulative incidence rates showed a consistent decrease in BC risk for each additional child. The decrease was consistent in strata of other established BC risk factors.

Background: Rectal cancer (RC) is traditionally grouped within colorectal cancer (CRC), despite growing evidence of distinct epidemiologic features. However, global comparative assessments of lifetime risks of RC relative to CRC remain limited. We aimed to estimate lifetime risks of developing and dying from RC and CRC worldwide and to examine geographic, socioeconomic, and temporal variations in the proportional contribution of RC within CRC. Methods: Age-specific incidence and mortality estimates for RC and CRC across 185 countries were obtained from GLOBOCAN 2022, together with population and all-cause mortality data from the United Nations. Lifetime risks of incidence (LRI) and mortality (LRM) were calculated using the adjusted-for-multiple-primaries (AMP) method by sex, country, region, and Human Development Index (HDI). The RC-to-CRC lifetime risk ratio quantified the proportional contribution of RC. Temporal trends were assessed in 42 countries using Cancer Incidence in Five Continents Plus (CI5plus) data and average annual percent change (AAPC). Results: In 2022, the global lifetime risk of developing RC was 1.61% and dying from RC was 0.95%, accounting for approximately 35% of the corresponding CRC lifetime burden (4.61% and 2.68%). Absolute lifetime risks of both RC and CRC increased with HDI. In contrast, the proportional contribution of RC varied markedly, peaking at 41%-43% in Central and South-Eastern Asia but falling below 20% in the Caribbean and Central America, and showed a negative association with HDI. The LRI/LRM ratio increased with socioeconomic development. Temporal analyses showed increasing LRI trends in 17 of 42 countries for CRC versus 9 for RC, while declines occurred in 14 countries for RC and 11 for CRC. Conclusions: RC constitutes a substantial yet epidemiologically distinct component of the global CRC burden. Its proportional contribution varies across regions and does not parallel absolute risk patterns, supporting the need for subsite-specific surveillance and prevention strategies.

Triple-negative breast cancer (TNBC), an aggressive subtype with poor prognosis, is of higher frequency in African-American women and women of Sub-Saharan African origin. In France, legal constraints on obtaining health data on race, ethnicity, or nationality in cancer registries and medical records make it difficult to estimate the prevalence of TNBC according to womens origins. These constraints result from a historical "universalist" approach to French citizenship which prohibits the routine collection of ethno-racial data. An anonymous, statistical survey we conducted from the medical records of 780 women with breast cancer followed in a university hospital in Paris showed that TNBCs were at least 3 times more common in women born in Sub-Saharan Africa than in women born in France. The former consulted at a more advanced stage of the disease than the latter. The results of an ethnographic study of African women in the Paris region with breast cancer, conducted for several years, highlighted some explanatory factors: low breast cancer awareness, perceived causes far from biomedical etiology, the weight of shame and secrecy, prior recourse to local healing, difficulties in communicating with health professionals and navigating the healthcare system. Considered a public health priority, TNBCs are an emblematic example of the limits produced by French race and ethnicity blindness in public health, epidemiology, prevention and health care.

ObjectivePolygenic risk scores (PRSs) derived from genome-wide association studies are strong predictors of colorectal cancer (CRC) risk. We applied the straightforward approach of risk advancement periods (RAPs) to derive risk-adapted starting ages of CRC screening according to sex and PRS in the UK Biobank. MethodsAmong 242,779 participants (40-69 years; no previous CRC screening; no family history of CRC), we assessed associations of sex and a PRS with CRC risk and mortality using Cox regression models. Hazard ratios (HRs) were translated to RAPs to quantify how many years of age earlier men and women in defined PRS deciles reach comparable risks as those in the reference group (5th and 6th PRS deciles). ResultsDuring a median follow-up of 11.2 and 12.8 years, 2,714 participants were diagnosed with CRC and 758 died from CRC, respectively. HRs (95% CIs) of CRC risk were 1.57 (1.46, 1.70) for men versus women and ranged from 0.51 (0.41, 0.62) to 2.29 (2.01, 2.62) across PRS deciles compared to the reference. RAPs (95% CI) were 5.6 (4.6, 6.6) years for men versus women, and ranged from -8.4 (-11.0, -5.9) to 10.3 (8.5, 12.1) years across PRS deciles compared to the reference. Risk-adapted starting ages would vary by 24 years between men in the highest PRS decile and women in the lowest PRS decile. Very similar results were obtained regarding CRC mortality. ConclusionConsideration of sex and a standard PRS alone could have far-reaching implications for starting ages of CRC screening in the "average risk population". SUMMARY BOXO_ST_ABSWhat is already known on this topicC_ST_ABSO_LIPolygenic risk scores (PRSs) are strong predictors of colorectal cancer (CRC) risk. C_LIO_LIMen have substantially higher CRC incidence and mortality than women. C_LIO_LICRC risk information from the combination of PRS and genetically determined sex, which are constant factors over lifetime, is so far not used for risk-adapted CRC screening in the "average risk population". C_LI What this study addsO_LIRisk advancement periods (RAPs) of CRC by PRS and sex were derived at high levels of precision from the large database of the UK Biobank. C_LIO_LIBy joint consideration of PRS and genetically defined sex, risk-adapted starting ages would vary by as much as 24 years between men in the highest PRS decile and women in the lowest PRS decile. C_LI How this study might affect research, practice or policyO_LIOur study demonstrates a straightforward way to translate CRC risk information from a large population-based cohort into risk-adapted starting ages of screening. C_LIO_LIPersonalized, risk-adapted starting ages of CRC screening could be derived from a single blood test performed in middle adulthood. C_LIO_LIThe RAP approach could be easily extended for defining personalized starting ages by incorporating additional risk factors in the regression models. C_LI

Introduction Pathogenic germline variants in the BRCA1 and BRCA2 genes confer a markedly increased risk of breast and ovarian cancer, for which effective preventive strategies are available. Although national and international guidelines recommend BRCA testing and cascade screening of relatives, implementation in Italy remains highly heterogeneous across regions. This study estimates the potential population health and cost impact of achieving full nationwide implementation of BRCA1/2 cascade screening in Italy and identifies key organisational barriers and priority actions for implementation. Methods We conducted a Health Impact Assessment integrating literature review, simulation modelling, and stakeholder consultation. A decision tree and Markov model compared the current heterogeneous implementation of BRCA screening in Italy with an ideal scenario reflecting full adherence to national guidelines, optimal cascade screening, and uptake of preventive strategies. Outcomes included breast and ovarian cancer incidence and mortality, healthcare costs over a lifetime horizon (80 years). Key barriers affecting organisational feasibility, acceptability, and patient well-being were assessed, and a set of priority action recommendations was developed. Results In the ideal scenario, 25,626 eligible cancer patients would undergo BRCA testing annually, identifying 4,254 mutation carriers and enabling cascade testing of 27,650 relatives, of whom 8,682 would be BRCA-positive. Under the current implementation, only 8,807 patients and 2,168 relatives are tested, identifying 948 carriers. Over 30 years, full implementation would prevent 821 cancer cases (- 27.9%) and 1,282 deaths (- 49.7%) compared with the current scenario. While initial expenditures increase due to expanded testing and preventive interventions, cumulative costs decrease over time, resulting in net savings of 5.8 million euros at 30 years and a saving per event avoided (- 2,779 euros). Major implementation barriers include fragmented governance, limited access to genetic counselling, heterogeneous laboratory practices, insufficient professional training, and weak referral pathways. Conclusion Full implementation of BRCA1/2 cascade screening in Italy would yield substantial population health benefits and long-term cost savings. Coordinated national governance, standardised pathways, investment in counselling and workforce capacity, and robust monitoring systems are essential to ensure equitable access and sustainable delivery of personalised cancer prevention. This study demonstrates the value of the HIA methodology for evaluating and guiding genomic prevention policies.

Differentiated thyroid cancers (DTCs) are malignancies with ill-defined hereditary predisposition. Some germline variants influencing the risk of DTCs localize in disrupted in renal carcinoma 3 (DIRC3), a poorly characterized long non-coding RNA (lncRNA) gene. Here, we characterized the function of DIRC3 in DTCs. We established that DIRC3 is downregulated in DTCs, and its high expression may reduce the risk of cancer recurrence in patients. DIRC3 transcripts were enriched in cell nuclei in vitro, where they upregulated insulin-like growth factor binding protein 5 (IGFBP5), a gene known to modulate the cellular response to insulin-like growth factor 1 (IGF-1). Silencing of DIRC3 in thyroid cancer cell lines produced a phenotypic dichotomy: it augmented cell migration and invasiveness, reduced apoptosis, but abrogated the MTT reduction rate. We demonstrated that the pro-migratory phenotype was produced by the downregulation of IGFBP5. Transcriptomic profiling confirmed a functional redundancy in the activities of DIRC3 and IGFBP5. Moreover, downregulation of DIRC3 enhanced the susceptibility of cancer cells to IGF-1 stimulation and promoted Akt signaling. In conclusion, DIRC3 expression alters the phenotype of thyroid cancer cells and modulates the activity of IGFBP5/IGF-1/Akt axis. We propose an interplay between DIRC3 and IGF signaling as a mechanism that promotes thyroid carcinogenesis.

BackgroundMetastasis significantly contributes to cancer-related mortality and therapeutic failure. Cancer cells acquire metastatic potential by losing epithelial characteristics and gaining mesenchymal properties through the epithelial-mesenchymal transition (EMT). Differential poly(A) site (PAS) usage, known as alternative polyadenylation (APA), generates mRNA isoforms differing in coding sequence, subcellular localization, stability, or translation efficiency. In cancer, 3'UTR shortening increases expression of proto-oncogenes by escaping miRNA-mediated repression. High expression of CPSF73, which cleaves mRNA precursors at PASs, is associated with unfavorable prognoses in cancer patients. However, the role of APA in regulating EMT remains poorly understood. MethodsIn this study, to investigate the role of APA in EMT, we employed JTE-607, a small-molecule inhibitor of CPSF73 activity, to examine the impact of catalytic inhibition of CPSF73 on proliferation and EMT in MDA-MB-231, MCF7, A549, and HepG2 cancer cells. To identify differential usage of PASs, global profiling of APA changes, and differential gene expression analysis were performed in MDA-MB-231 cells. Additionally, antisense oligonucleotides were used to block the use of a specific PAS whose APA change may be a driver of EMT reversal. ResultsOur findings showed that catalytic inhibition of CPSF73 not only attenuates cancer cell proliferation but also moves the cells away from the mesenchymal state across all four cell lines tested. Global profiling of APA changes following CPSF73 inhibition revealed widespread 3'UTR lengthening and suppression of intronic PASs in MDA-MB-231 cells. APA shifts were observed in key EMT-related genes, accompanied by decreased expression of corresponding proteins across all four cell lines. We used antisense morpholino oligonucleotides to block the proximal PAS of AKT2, shifting the balance of AKT2 mRNA isoforms toward the long isoform. This shift caused EMT reversal, marked by reduced AKT2 protein expression, changes in EMT-related markers, and impaired invasion by MDA-MB-231 cells. ConclusionTogether, these findings identify APA-mediated 3UTR lengthening, with functional consequences in EMT-related genes, as a coordinated mechanism leading to an attenuated EMT phenotype, highlighting a significant connection between APA and the EMT process. Interfering with these APA changes may offer a promising therapeutic strategy to suppress metastasis, with potential efficacy across multiple pathways. Statement of SignificanceOur findings highlight APA-mediated 3 UTR lengthening as a coordinated mechanism that promotes EMT reversal and support CPSF73 inhibition or APA-targeting strategies as potential therapeutic approaches to suppress metastasis across multiple pathways.

ObjectivesNon-communicable diseases (NCDs) account for almost 90% of deaths in Europe, yet comparative estimates of the productivity costs associated with premature NCD mortality across diseases and countries remain limited. This study estimates and compares productivity losses attributable to cardiovascular disease (CVD) and cancer mortality among working-age populations across Europe. Population-based data were used to estimate productivity costs for CVD and cancer deaths across 30 European countries. Sex- and age-specific mortality data for 2021 were obtained from the World Health Organization Mortality Database. Economic data, including wages, unemployment rates, and labour force participation rates, were sourced from Eurostat. Productivity losses were valued using a human capital approach incorporating an age-transition lifecycle simulation model that adjusts for lifetime wage trajectories and labour market dynamics. Costs were discounted at 3.5%. Total productivity losses from cancer and CVD mortality in working-age populations were estimated at {euro}195.7 billion, equivalent to 1.24% of European GDP. Cancer accounted for 62.5% ({euro}122.2 billion) of total productivity losses, while CVD accounted for 37.5% ({euro}73.5 billion). Total CVD-related productivity costs exceeded cancer-related costs in Central and Eastern Europe, whereas cancer productivity costs were higher in Western, Northern, and Southern Europe. Mean productivity costs per death were higher for CVD ({euro}219,848; 95% CI 165,241-270,247) than for cancer ({euro}217,744; 95% CI 166,554-273,144). A larger gender gap was observed for CVD mortality, with a male-to-female cost ratio of 2.5 compared with 1.6 for cancer. Productivity losses associated with premature cancer and CVD mortality represent a substantial economic burden across Europe, with pronounced variation by disease, region, and sex. These findings provide comparative, cross-country estimates of the human capital costs associated with major NCD causes of death.

BACKGROUNDCancer is associated with significant economic impacts. Quantifying the scale of these impacts is challenged by confounding variables that jointly influence both cancer status and economic outcomes such as healthcare costs and quality of life. Moreover, the increasing costs attributed to cancer drug development complicate the cost-effective provision of cancer care. METHODSWe address both challenges in this paper by using germline genetic variation in the risk of incident cancer as instrumental variables in Mendelian Randomization analyses of eight cancers. We developed causal estimates of the genetically predicted effect of bladder, breast, colorectal, lung, multiple myeloma, ovarian, prostate and thyroid cancers on healthcare costs and quality adjusted life years (QALYs) using outcome data drawn from the UK Biobank cohort. We then used Mendelian Randomization to model a hypothetical population-wide preventative intervention based on a repurposed class of anti-diabetic drugs known as sodium-glucose co-transporter-2 (SGLT2) inhibitors very recently shown to reduce the odds of incident prostate cancer. RESULTSGenetic liability to prostate cancer and to breast cancer had material causal impacts on healthcare costs and QALYs. Mendelian Randomization results for the less common cancers were associated with considerable uncertainty. SGLT2 inhibition was unlikely to be a cost-effective preventative intervention for prostate cancer, although this conclusion depended on the price at which these drugs would be offered for a novel anti-cancer indication. IMPLICATIONSOur new causal estimates of cancer exposures on health economic outcomes may be used as inputs into decision analytic models of cancer interventions such as screening programmes or simulations of longer-term outcomes associated with therapies investigated in RCTs with short follow-ups. Our new method allows us to rapidly and efficiently estimate the cost-effectiveness of a hypothetical population-scale anti-cancer intervention to inform and complement other means of assessing long-term intervention cost-effectiveness.

PurposeEpithelial-to-mesenchymal transition (EMT) in cancer cells confers migratory ability, a crucial aspect of tumor metastasis that frequently leads to death. In multiple studies, authors proposed gene expression signatures for EMT, stemness, and mesenchymality (EMT-related) characteristics of tumors based on bulk tumor expression profiling. However, recent studies have suggested that non-cancerous cells in the tumor micro- or macroenvironment heavily influence individual signature profiles. Experimental DesignWe analyzed scores of 11 published and frequently referenced gene expression signatures in bulk, single cell, and pseudo bulk expression data across multiple cancer types. ResultsOur study strengthens and extends the influence of non-cancerous cells on signatures that were proposed to describe EMT-related (EMT, mesenchymal, or stemness) characteristics in various cancer types. The cell type composition, especially the amount of tumor cells, of a tumor sample frequently dominates EMT-related signature scores. Additionally, our analyses revealed that stromal cells, most often fibroblasts, are the main drivers of the EMT-related signature scores. ConclusionsWe call attention to the risk of false conclusions about tumor properties when interpreting EMT-related signatures, especially in a clinical setting: high patient scores of EMT-related signatures or calls of "stemness subtypes" often result from low tumor cell content in tumor biopsies rather than cancer cell-specific stemness or mesenchymality/EMT characteristics.

BackgroundThe tumor immune microenvironment likely plays a central role in progression of thyroid cancer. As for most other solid tumors, it is unknown if immune dysregulation contributes to earlier, subclinical stages of thyroid tumor development, or whether thyroid tumor heterogeneity might involve differential expression of pro-inflammatory mediators. MethodsThe time course of tumor-associated inflammation was studied in Tg-CreERT2;Braf CA/+ mice representing a model of BRAFV600E-driven papillary thyroid carcinoma (PTC). Tumor growth was estimated by histological examination and magnetic resonance imaging. Cytokine expression was monitored by quantitative RT-PCR, RNAScope and Western blot analyses. ResultsBased on spontaneous BrafCA activation due to leaky Cre activity in a minority of targeted cells tumors developed within a preserved thyroid tissue architecture to multifocal papillary thyroid carcinoma (PTC) over a period of 12 months. Tumorigenesis was accompanied by a gradually increased mRNA and protein expression of interleukin-1beta (IL-1{beta}), interleukin-6 and tumor necrosis factor-alpha (TNF-) starting already before Braf mutant cells commenced neoplastic growth. RNAScope revealed that both follicular cells and stromal cells expressed Il1b whereas Il6 and Tnfa transcripts were mostly confined to neoplastic epithelia. Early cytokine expression was associated with oncogene-induced senescence, whereas during tumor development (3-6 months) and in advanced tumor stages (at 12 months) the cytokine expression pattern differed among glands and tumor foci of the same gland accompanied by a highly variable locoregional lymphocytic infiltration. Oral treatment of mutant mice for 1 month with PLX4720, a vemurafenib prodrug, partially reduced cytokine expression along with inhibited tumor growth and redifferentiation of thyroid function. The magnitude of reduced cytokine expression differed much between glands and among mice of both sexes. ConclusionsThese findings indicate that oncogenic BRAFV600E targeted to the thyroid both stimulates endogenous production of IL-1{beta}, IL-6 and TNF- and recruits inflammatory cells to foci of early tumor development. PTCs of different clonal origin are distinguished by differential expression of pro-inflammatory cytokines. The anti-inflammatory effect of mutant Braf kinase inhibition varies presumably related to heterogeneous tumor development, which evolves from stochastic BrafCA activation suggesting there are clonally different probabilities of acquiring drug resistance among Braf mutant thyroid follicular cells.

AO_SCPLOWBSTRACTC_SCPLOWO_ST_ABSImportanceC_ST_ABSThe causality of the association between physical activity and risk of breast and endometrial cancers is uncertain because available evidence is based exclusively on observational studies, which are potentially susceptible to confounding and reverse causation. ObjectiveTo investigate whether increased physical activity is causally associated with decreased risk of breast and endometrial cancers, using a two-sample Mendelian randomization study design. Design, Setting, and ParticipantsGenome-wide association studies of physical activity, breast cancer, and endometrial cancer, published up to April 31, 2019, were identified using PubMed and the GWAS catalog. Twelve single nucleotide polymorphisms (SNP) known at P < 5 x 10-8 to be associated with accelerometer-assessed or self-reported physical activity served as instrumental variables. Genetic summary data from four large consortia provided SNP-outcome associations [Breast Cancer Association Consortium; Discovery, Biology and Risk of Inherited Variants in Breast Cancer Consortium; Endometrial Cancer Association Consortium]. Main Outcomes and MeasuresThe primary outcomes were risk of breast cancer and risk of endometrial cancer. Secondary outcomes were estrogen receptor positive (ER+) and ER-breast cancers. Odds ratios (ORs) and 95% confidence intervals (CIs) per mean acceleration in milli-gravities of accelerometer-assessed physical activity and per one standard deviation (1-SD) increase in metabolic-equivalent (MET)-minutes/week of self-reported moderate-to-vigorous physical activity were computed using the inverse variance weighted method. A series of sensitivity analyses addressed the potential impact of heterogeneity, pleiotropy, and outliers. ResultsSummary data were available for 122,977 breast cancers and 12,270 endometrial cancers. Genetic predisposition to increased accelerometer-assessed physical activity was associated with lower risk of breast and endometrial cancers. The associations (ORs [95% CI] per 1-SD increase in mean acceleration) were 0.88 (0.85-0.91) for breast cancer and 0.90 (0.83-0.97) for endometrial cancer. In addition, genetic predisposition to increased accelerometer-assessed physical activity was associated with lower risk of ER+ breast cancer. We found no evidence for an association between genetic predisposition to self-reported physical activity and risk of total breast cancer, breast cancer subtypes, or endometrial cancer. Conclusion and RelevanceThis first Mendelian randomization study shows that objectively-assessed physical activity plays a causal role in protecting against breast and endometrial cancers.