Independent evaluation of melanoma polygenic risk scores in UK and Australian prospective cohorts

Abstract

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.

Figure 1

Calibration of polygenic risk score (PRS)‐adjusted and unadjusted (based on age and sex only) absolute melanoma risks in the UK Biobank (UKB) and the Melbourne Collaborative Cohort Study (MCCS), by risk quintile. (a) Calibration of absolute melanoma risks in the UKB based on population‐wide data for 2011–2015. (b) Calibration of absolute melanoma risks in the MCCS based on population‐wide data for 2009–2013. Bars show 95% confidence intervals (CIs). E/O, expected/observed. [Colour figure can be viewed at wileyonlinelibrary.com]

Figure 2

Calibration of absolute melanoma risks after rescaling to expected/observed (E/O) = 1 in (a) the UK Biobank (UKB) and (b) the Melbourne Collaborative Cohort Study (MCCS), by risk quintile. Bars show 95% confidence intervals (CIs). [Colour figure can be viewed at wileyonlinelibrary.com]

Figure 3

Polygenic risk score (PRS) adjustment improves the discriminative ability of absolute melanoma risks in (a) the UK Biobank (UKB) and (b) the Melbourne Collaborative Cohort Study (MCCS). Shaded areas indicate 95% confidence intervals. Absolute risks were calculated based on population‐level cancer registry data, age and sex, with and without PRS adjustment. The straight diagonal line (grey) represents the line of no discrimination. AUC, area under the receiver operating characteristic curve (with 95% confidence interval). ns, P > 0·05; **P < 0·001; ***P < 0·0001; ****P < 10⁻¹⁰. [Colour figure can be viewed at wileyonlinelibrary.com]

Figure 4

Estimated 10‐year absolute melanoma risks and 95% confidence intervals (CIs) by the top or bottom PRS50 quintile and age based on data from (a) the UK Biobank and population‐wide data for England/Wales, and (b) the Melbourne Collaborative Cohort Study and population‐wide data for Victoria, Australia. (a) The estimated population‐average 10‐year risk of invasive melanoma for 50‐year old men in England/Wales was 0·28%, which is estimated to be reached 15 years earlier and 15 years later for men in the top and bottom PRS50 quintiles, respectively. Similarly, the estimated population‐average 10‐year risk of melanoma for 50‐year‐old women in England/Wales was 0·31%, estimated to be reached more than 20 years earlier for those in the top PRS50 quintile, and not before age 80 years for those in the bottom quintile. The results were similar for Scotland. (b) For Victoria, the estimated population‐average 10‐year risk for 50‐year‐old men was 0·67%, estimated to be reached about 10 years earlier and 10 years later for those in the top and bottom quintiles, respectively. For women, the population‐average 10‐year risk at age 50 years was 0·52%, estimated to be reached 10 years earlier and not before age 80 years for those in the top and bottom PRS50 quintiles, respectively. [Colour figure can be viewed at wileyonlinelibrary.com]