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Summary: Background: Previous studies suggest that polygenic risk scores (PRSs) may improve melanoma risk stratification. However, there has been limited independent validation of PRS‐based risk prediction, particularly assessment of calibration (comparing predicted to observed risks). Objectives: To evaluate PRS‐based melanoma risk prediction in prospective UK and Australian cohorts with European ancestry. Methods: We analysed invasive melanoma incidence in the UK Biobank (UKB; n = 395 647, 1651 cases) and a case‐cohort nested within the Melbourne Collaborative Cohort Study (MCCS, Australia; n = 4765, 303 cases). Three PRSs were evaluated: 68 single‐nucleotide polymorphisms (SNPs) at 54 loci from a 2020 meta‐analysis (PRS68), 50 SNPs significant in the 2020 meta‐analysis excluding UKB (PRS50) and 45 SNPs at 21 loci known in 2018 (PRS45). Ten‐year melanoma risks were calculated from population‐level cancer registry data by age group and sex, with and without PRS adjustment. Results: Predicted absolute melanoma risks based on age and sex alone underestimated melanoma incidence in the UKB [ratio of expected/observed cases: E/O = 0·65, 95% confidence interval (CI) 0·62–0·68] and MCCS (E/O = 0·63, 95% CI 0·56–0·72). For UKB, calibration was improved by PRS adjustment, with PRS50‐adjusted risks E/O = 0·91, 95% CI 0·87–0·95. The discriminative ability for PRS68‐ and PRS50‐adjusted absolute risks was higher than for risks based on age and sex alone (Δ area under the curve 0·07–0·10, P < 0·0001), and higher than for PRS45‐adjusted risks (Δ area under the curve 0·02–0·04, P < 0·001). Conclusions: A PRS derived from a larger, more diverse meta‐analysis improves risk prediction compared with an earlier PRS, and might help tailor melanoma prevention and early detection strategies to different risk levels. Recalibration of absolute risks may be necessary for application to specific populations. [ABSTRACT FROM AUTHOR]

This article aims to provide a detailed description of the Singapore Breast Cancer Cohort (SGBCC), an ongoing multi-ethnic cohort established with the overarching goal to identify genetic markers for breast cancer risk, prognosis and treatment response, as well as to understand the ethnic differences in disease risk and outcome in an Asian setting. The cohort comprises of breast cancer patients aged 21 years and above from six public hospitals which diagnose and treat nearly 76% breast cancer cases in Singapore. Self-reported data on sociodemographic and lifestyle, reproductive risk factors, medical history and family history of breast or ovarian cancer is collected using a structured questionnaire. Clinical data on tumour characteristics, and treatment modalities are obtained through medical record. Bio-specimens (blood or saliva) is collected at recruitment. Follow-up on survival information is done through routine linkage with the Registry of Births and Deaths. As of 31 December 2016, 7,768 subjects have been recruited to the study with 76% subjects contributed bio-specimens. The SGBCC provides a valuable platform which offers a unique, large and rich resource for new research ideas on breast cancer related phenotypic risk factors and genetic markers. [ABSTRACT FROM AUTHOR]

Background To improve melanoma early detection, tools to predict personal risk based on genetic information (polygenic risk scores, PRS) have been developed, but require external validation. Methods We analysed invasive melanoma incidence in UK Biobank (UKB; n = 395,647; 1,651 cases) and the Melbourne Collaborative Cohort Study (MCCS, Australia; n = 4,765; 303 cases). Three PRS were evaluated: 68 genetic variants (SNPs) at 54 loci from a 2020 meta-analysis (PRS68); 50 SNPs significant in the 2020 meta-analysis excluding UKB (PRS50); 45 SNPs at 21 loci known pre-2020 (PRS45). 10-year melanoma risks were calculated from population-level cancer registry data by age group and sex, with and without PRS adjustment. Results All PRS were strongly associated with melanoma incidence, including after adjustment for age, sex, ethnicity, and ease of tanning. Predicted absolute melanoma risks based on age and sex alone underestimated melanoma incidence in UKB (ratio expected/observed cases E/O=0.65, 95% confidence interval 0.62-0.68) and MCCS (E/O=0.65, 0.57-0.73). For UKB, this was reduced by PRS-adjustment, e.g. PRS50-adjusted risks E/O=0.91 (0.87-0.95). Discriminative ability for PRS68- and PRS50-adjusted absolute risks was higher than for risks based on age and sex alone (deltaAUC 0.07-0.1, p < 0.0001), and higher than for PRS45-adjusted risks (deltaAUC 0.02-0.04, p < 0.001). Conclusions A PRS derived from a larger, more diverse meta-analysis improves melanoma risk prediction compared to an earlier PRS. Re-calibration of absolute risks may be necessary for application to specific populations. Key messages A genetic score can improve prediction of melanoma risk and might help tailor melanoma prevention and early detection strategies to different risk levels. [ABSTRACT FROM AUTHOR]