Background Genome-wide association studies have identified common genetic risk variants in many loci associated with multiple cancers. We sought to systematically evaluate the utility of these risk variants in identifying high-risk individuals for eight common cancers. Methods We constructed polygenic risk scores (PRS) using genome-wide association studies–identified risk variants for each cancer. Using data from 400 812 participants of European descent in a population-based cohort study, UK Biobank, we estimated hazard ratios associated with PRS using Cox proportional hazard models and evaluated the performance of the PRS in cancer risk prediction and their ability to identify individuals at more than a twofold elevated risk, a risk level comparable to a moderate-penetrance mutation in known cancer predisposition genes. Results During a median follow-up of 5.8 years, 14 584 incident case patients of cancers were identified (ranging from 358 epithelial ovarian cancer case patients to 4430 prostate cancer case patients). Compared with those at an average risk, individuals among the highest 5% of the PRS had a two- to threefold elevated risk for cancer of the prostate, breast, pancreas, colorectal, or ovary, and an approximately 1.5-fold elevated risk of cancer of the lung, bladder, or kidney. The areas under the curve ranged from 0.567 to 0.662. Using PRS, 40.4% of the study participants can be classified as having more than a twofold elevated risk for at least one site-specific cancer. Conclusions A large proportion of the general population can be identified at an elevated cancer risk by PRS, supporting the potential clinical utility of PRS for personalized cancer risk prediction.
Background Both genetic and lifestyle factors play an etiologic role in colorectal cancer (CRC). Objectives We evaluated potential gene–environment interactions in CRC risk. Methods We used data from 346,297 participants in the UK Biobank cohort. Healthy lifestyle scores (HLSs) were constructed using 8 lifestyle factors, primarily according to the American Cancer Society guidelines, and were categorized into unhealthy, intermediate, and healthy groups. A polygenic risk score (PRS) was created using 95 genetic risk variants identified by genome-wide association studies of CRC and was categorized by tertile. Cox models were used to estimate the HRs and 95% CIs of CRC risk associated with the HLS and PRS. Results During a median follow-up of 5.8 y, 2066 incident cases of CRC were identified. Healthier HLSs were associated with reduced risk of CRC in a dose–response manner. The risk reduction was more apparent among those with high PRS (HRhealthy vs. unhealthy HLS1: 0.58; 95% CI: 0.43, 0.79 for men and 0.71; 0.58, 0.85 for men and women combined) than those with low PRS. Although no multiplicative interactions were identified, the HLS1 and PRS showed a significant additive interaction (P = 0.02 for all participants combined, 0.04 for men). In analyses including all participants, the adjusted CRC cumulative risk from age 40 to 75 y was 6.40% for those with high PRS/unhealthy HLS1, with a relative excess risk due to interaction of 0.58 (95% CI: 0.06, 1.10), compared with 2.09% among those with low PRS/healthy HLS1. This pattern was more apparent among those who reported not having received any bowel screening before baseline. Conclusions Although the observational nature of the study precludes proof of causality, our findings suggest that individuals with a high genetic susceptibility could benefit more substantially than those with a low genetic risk from lifestyle modification in reducing CRC risk.
IMPORTANCEThe association of weight gain from early to middle adulthood with disease risk has not been adequately studied. OBJECTIVE To investigate the association of adult weight gain with major health outcomes in a Chinese population with low body weight in early adulthood. DESIGN, SETTING, AND PARTICIPANTS This population-based cohort study assessed data from 48 377 women and 35 989 men aged 40 to 59 years at recruitment in 2 prospective cohort studies in
Most women with epithelial ovarian cancer (EOC) are diagnosed after the disease has metastasized and survival in this group remains poor. Circulating proteins associated with the risk of developing EOC have the potential to serve as biomarkers for early detection and diagnosis. We integrated largescale genomic and proteomic data to identify novel plasma proteins associated with EOC risk. MethodsWe used the germline genetic variants most strongly associated (P<1.5×10 −11 ) with plasma levels of 1,329 proteins in 3,301 healthy individuals from the INTERVAL study to predict circulating levels of these proteins in 22,406 EOC cases and 40,941 controls from the Ovarian Cancer Association Consortium (OCAC). Association testing was performed by weighting the beta coefficients and standard errors for EOC risk from the OCAC study by the inverse of the beta coefficients from INTERVAL. ResultsWe identified 26 proteins whose genetically predicted circulating levels were associated with EOC risk at false discovery rate<0.05. The 26 proteins included MFAP2, SEMG2, DLK1, and NTNG1 and a group of 22 proteins whose plasma levels were predicted by variants at chromosome 9q34.2. All 26 protein association signals identified were driven by association with the high-grade serous histotype that comprised 58% of the EOC cases in OCAC. Regional genomic plots confirmed overlap of the genetic association signal underlying both plasma protein level and EOC risk for the 26 proteins. Pathway analysis identified enrichment of seven biological pathways among the 26 proteins (Padjusted<0.05), highlighting roles for Focal Adhesion-PI3K-Akt-mTOR and Notch signaling. ConclusionThe identified proteins further illuminate the etiology of EOC and represent promising new EOC biomarkers for targeted validation by studies involving direct measurement of plasma proteins in EOC patient cohorts.
Genome-wide association studies (GWAS) have identified many genetic risk variants for cancers. The utility of these variants in assessing risk of esophageal, gastric and endometrial cancers, as well as melanoma, glioma, diffuse large B-cell lymphoma, follicular lymphoma, chronic lymphoid leukemia and multiple myeloma, has not been adequately investigated. We constructed a site-specific polygenic risk score (PRS) for each of these nine cancers using their GWAS-identified risk variants. Using data from 400 807 participants of European descent in the UK Biobank, a population-based cohort study, we estimated the hazard ratios of each cancer associated with its PRS using Cox proportional hazard models. During a median follow-up of 5.8 years, 3905 incident cases of these nine cancers were identified in the cohort. The area under the receiver operating characteristic curve ranged from 0.53 to 0.69 for these cancers. Except for esophageal cancer, significant dose-response associations were observed between PRS and cancer risk. Compared to individuals in the middle quintile (40%-60%) at an average risk, those among the highest 5% of the PRS had a twofold elevated risk of melanoma, glioma, follicular lymphoma or multiple myeloma, and a fourfold elevated risk of chronic lymphoid leukemia. Using PRS, 63.0% of the participants could be classified as having an over twofold elevated risk for at least one cancer. The PRS derived using risk variants identified to date by GWAS showed the potential in identifying individuals at a significantly elevated risk of cancer for prevention.
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