Louise Wang

Purpose: Genome-wide association studies have identified many common variants associated at low effect sizes with various cancers. Summing the effects of these variants into polygenic risk scores (PRS) can improve cancer risk prediction. However, cross-cancer and cross-phenotype pleiotropic associations of cancer-specific PRS are limited. Methods: Using logistic regression models, we tested the association of 13 cancer-specific PRS with curated phenotypes representing the same 13 cancers and 340 cancer and cardiometabolic phecodes in 560,287 individuals (114,255 African ancestry [AFR] and 446,032 European ancestry [EUR]) from the Million Veteran Program. Models were stratified by ancestry and used age, principal components, and cancer-specific PRS per standard deviation as independent variables, and correction was applied for multiple comparisons. Results: All 13 cancer-specific PRS were significantly associated with their respective cancers among EUR individuals with odds ratios per standard deviation of PRS (odds ratio [OR]) 1.05-1.70. Among AFR individuals, the effect sizes of the cancer PRS were lower, with OR 1.01-1.48, and cancer-specific PRS were significantly associated with their respective cancers for five of 13 cancers (bladder, breast in female patients, colorectal, prostate, and thyroid). In cancer-cancer pleiotropy studies, only the renal cancer-specific PRS was significantly associated with skin cancer (OR = 1.04, P = 4.5 × 10 ^–06 ) among EUR individuals. PheWAS demonstrated five positive pleotropic associations with cardiometabolic conditions (thyroid cancer PRS with thyroid goiter, oral cancer PRS with diabetes phenotypes, and hypothyroidism) and two negative associations (oral and lung cancer PRS separately with coronary artery disease). Conclusion: Cancer PRS have stronger associations per cancer among EUR versus AFR individuals. In contrast to PRS of other chronic diseases, the majority of cancer-related PRS are highly specific and pleiotropic associations with other cancers and cardiometabolic traits are uncommon.

Background: Integrating genetic and lifestyle information has the potential to greatly improve the prediction of colorectal cancer (CRC) risk. However, racial and ethnic minorities are generally underrepresented in gene-environment studies of CRC risk. Methods: We investigated the interplay of genetics and lifestyle on CRC risk in a prospective analysis of 68 397 African American, Japanese American, Latino, Native Hawaiian, and White individuals from the Multiethnic Cohort Study. Genetic predisposition was assessed using a 205-variant polygenic risk score. Lifestyle was assessed using a lifestyle risk score based on smoking, alcohol consumption, body mass index, physical activity, and diet. The independent and joint associations of the polygenic risk score and lifestyle risk score on CRC risk were evaluated using Cox regression. Results: We identified 1303 incident CRC cases (median 15.1-year follow-up). The highest quintile of the polygenic risk score was associated with a 2.4-fold increase in CRC risk compared with the lowest quintile (Q5 vs Q1: hazard ratio [HR] = 2.40, 95% confidence interval [CI] = 1.99 to 2.89). The highest quintile of the lifestyle risk score was associated with a 54% increased risk (Q5 vs Q1: HR = 1.54, 95% CI = 1.26 to 1.88). This association was stronger among those with high genetic risk (polygenic risk score ≥ 50%; Q5 vs Q1: HR = 1.82, 95% CI = 1.41 to 2.35) and statistically nonsignificant among those with low genetic risk (polygenic risk score < 50%; Q5 vs Q1: HR = 1.20, 95% CI = 0.88 to 1.64; P for interaction = 0.01). Results were similar across race and ethnicity. Conclusions: Our study suggests that lifestyle modification may offer greater risk reduction among those at higher genetic risk. Future research is warranted to enhance the integration of genetics and lifestyle in CRC risk stratification and screening approaches across populations.

Individual-level social determinants of health are associated with pancreatic ductal adenocarcinoma; however, it is currently unknown whether neighborhood-level socioeconomic disadvantage is related to the risk of pancreatic ductal adenocarcinoma diagnosis. Area deprivation index is a validated tool to measure neighborhood-level disadvantage. We conducted a retrospective cohort study of 5 069 429 patients in the Veterans Health Administration between October 1, 2001, and December 31, 2021. Area deprivation index percentiles were grouped using national area deprivation index decile cutoffs. In multivariable analysis, the lowest area deprivation index group, representing the highest neighborhood-level socioeconomic status, was associated with increased hazards for pancreatic ductal adenocarcinoma (adjusted hazard ratio [HR] = 1.13, 95% confidence interval [CI] = 1.06 to 1.21) compared with those with median area deprivation index percentiles. Differences in pancreatic ductal adenocarcinoma hazards were not seen in the other area deprivation index percentiles. These results suggest that within the Veterans Health Administration, a relatively equal access health-care system, there is limited contribution of neighborhood-level socioeconomic deprivation to pancreatic ductal adenocarcinoma, except for patients with the highest neighborhood-level socioeconomic status (lowest area deprivation index).

INTRODUCTION: Early detection of pancreatic ductal adenocarcinoma (PDAC) improves survival. However, screening recommendations are limited to individuals with hereditary risk, accounting for only 10% of PDAC. We explore the feasibility of developing and validating an electronic health record-based model to identify high-risk individuals for PDAC screening within the asymptomatic general population. METHODS: Using multivariable Cox regression, we developed a diagnostic model to predict time to PDAC within 3 years in the Veterans Health Administration. We evaluated the final model using internal and temporally separate data sets using Akaike Information Criterion, Harrell c statistic, calibration curves, and sensitivity/specificity corresponding to a 3-year risk screening threshold of 1%. RESULTS: Among 9,351,261 individuals, 26,119 (0.3%) developed PDAC (107.6 cases per 100,000 person-years) within 3 years. The final model included age, pancreatic cyst, pancreatitis, smoking status, history of a localized solid tumor, race/ethnicity, and body mass index. Glucose and albumin values were highly important, in addition to other metabolic, inflammatory, and liver-related laboratory values. The c statistic (95% CI) was 0.75 (0.75–0.76) in development, 0.75 (0.75–0.76) in internal validation, and 0.74 (0.73–0.75) in temporal validation. At a 3-year risk threshold of 1.0%, 11% of the population would undergo screening, capturing 30% of the PDAC cases. DISCUSSION: We demonstrate good model discrimination in independent data. Compared with current screening practices targeting only genetically predisposed individuals, its implementation could identify 3 times as many PDAC cases. However, predictors beyond the electronic health record (EHR) may be needed to further improve the feasibility of generalized screening.

Supplementary Table 3 shows the studies excluded from this review

Supplementary Table 2 shows the search strategies employed for the scoping review.

Supplementary Table 1 shows the preferred reporting items for systematic reviews and meta-analyses extension for scoping reviews (PRISMA-ScR) checklist

Supplementary Table 4 shows additional information on the studies included in the scoping review

Background:Polygenic risk scores (PRS) summarize an individual's germline genetic risk, but it is unclear whether PRS offer independent information for pancreatic cancer risk prediction beyond routine clinical data.Methods:We searched 8 databases from database inception to March 10, 2023 to identify studies evaluating the independent performance of pancreatic cancer–specific PRS for pancreatic cancer beyond clinical risk factors.Results:Twenty-one studies examined associations between a pancreatic cancer–specific PRS and pancreatic cancer. Seven studies evaluated risk factors beyond age and sex. Three studies evaluated the change in discrimination associated with the addition of PRS to routine risk factors and reported improvements (AUCs: 0.715 to 0.745; AUC 0.791 to 0.830; AUC from 0.694 to 0.711). Limitations to clinical applicability included using source populations younger/healthier than those at risk for pancreatic cancer (n = 10), exclusively of European ancestry (n = 13), or controls without relevant exposures (n = 1).Conclusions:While most studies of pancreatic cancer–specific PRS did not evaluate the independent discrimination of PRS for pancreatic cancer beyond routine risk factors, three that did showed improvements in discrimination.Impact:For pancreatic cancer PRS to be clinically useful, they must demonstrate substantial improvements in discrimination beyond established risk factors, apply to diverse ancestral populations representative of those at risk for pancreatic cancer, and use appropriate controls.

Importance: Although hepatitis C virus (HCV) is an oncovirus, its association with the risk of pancreatic ductal adenocarcinoma (PDAC) is unclear. In addition, it is unknown whether there is differential risk for PDAC across HCV genotypes. Objective: To assess the association between chronic HCV and PDAC. Design, Setting, and Participants: This retrospective, national, population-based cohort study was conducted across Veterans Health Administration (VA) sites. The study included veterans with HCV testing documented in the VA or VA-linked Medicare with at least 1 inpatient or outpatient visit between October 1, 2001, and September 30, 2020. Patients were followed-up for at least 18 months after this visit. Data were analyzed from October 2023 to September 2025. Exposure: HCV status was categorized as chronic HCV, exposure to HCV, or no chronic HCV infection. Main Outcomes and Measures: The association of HCV status with PDAC was evaluated using Cox proportional hazards regression, adjusting for demographic and clinical confounders. Analysis was substratified by HCV genotype. Results: Of 6 330 856 people tested for HCV (5 841 571 men [92.3%]; median [IQR] age, 61.6 years [49.9-70.1]), 246 218 (3.9%) had chronic HCV and 209 492 (3.3%) were exposed. Of the 33 451 individuals (0.5%) who developed PDAC, age at diagnosis was younger among those with vs those without HCV (median [IQR] age, 65.0 [59.9-69.6] years vs 72.4 [66.7-79.0] years). Compared with no HCV infection, chronic HCV infection (adjusted hazard ratio [aHR], 1.76; 95% CI, 1.67-1.86) and HCV exposure (aHR, 1.18; 95% CI; 1.11-1.25) were associated with increased risk of incident PDAC. Hazards for PDAC were greater for HCV genotype 3 (aHR, 2.02; 95% CI, 1.67-2.45) and genotype 1 (aHR, 1.75; 95% CI, 1.64-1.87) than for genotype 2 (aHR, 1.35; 95% CI, 1.14-1.60) compared with no HCV infection. Conclusions and Relevance: In this cohort study of veterans, chronic HCV infection was associated with a 1.8-fold higher risk of PDAC diagnosis, and HCV genotypes 3 and 1 had greater PDAC risk than genotype 2. These findings prompt future research on the mechanisms underlying this association and the impact of HCV treatment on PDAC risk.