Clinical Pathology - Research Publications

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    Older age should not be a barrier to testing for somatic variants in homologous recombination DNA repair-related genes in patients with high-grade serous ovarian carcinoma
    Pitiyarachchi, O ; Lee, YC ; Sim, H-W ; Srirangan, S ; Mapagu, C ; Kirk, J ; Harnett, PR ; Balleine, RL ; Bowtell, DDL ; Samimi, G ; Brand, AH ; Marsh, DJ ; Beale, P ; Anderson, L ; Bouantoun, N ; Provan, P ; Ramus, SJ ; DeFazio, A ; Friedlander, M ; INOVATe, I (ELSEVIER SCIENCE INC, 2023-02-18)
    BACKGROUND: Somatic pathogenic variants (PVs) in homologous recombination DNA repair (HR)-related genes found in high-grade serous ovarian carcinomas (HGSC) are not well-characterised in older patients (≥70 years). This may reflect low testing rates in older patients. METHODS: Data from 1210 HGSC patients in AACR Project GENIE and 324 patients in an independent dataset INOVATe were analysed. Cases where somatic variants could be distinguished from germline variants were included, and analysis was restricted to those with a somatic TP53 variant, to ensure cases were HGSC. RESULTS: Of 1210 patients in GENIE, 27% (n = 325) were aged ≥70 years at testing. Patients with somatic-only PVs in BRCA2 were older compared with BRCA1 (median 71 vs 60 years, p = 0.002). Median age for 21 patients with somatic-only PVs in 11 other HR-related genes ranged from 40 to 67 years. In older patients, 7% (n = 22) had somatic BRCA1/2 PVs, and 1% (n = 2) had PVs other HR-related genes; this rate was not significantly different to younger patients (<70 years), 7% (n = 62) BRCA1/2 and 2% (n = 19) other HR-related genes (p = 0.36). The overall frequency of somatic BRCA1/2 PVs was similar in INOVATe (n = 25; 7.7%) and somatic-only BRCA2 PVs were again found in older patients compared with BRCA1 (median age: at testing, 70 vs 63 years; at diagnosis, 68 vs 60 years). CONCLUSIONS: The overall frequency of somatic-only PVs in HR-related genes was similar in older and younger patients with HGSC, highlighting the importance of somatic testing irrespective of age. Limiting somatic testing by age may exclude patients who could benefit from maintenance poly(ADP-ribose) polymerase (PARP) inhibitors.
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    Body mass index and molecular subtypes of colorectal cancer.
    Murphy, N ; Newton, CC ; Song, M ; Papadimitriou, N ; Hoffmeister, M ; Phipps, AI ; Harrison, TA ; Newcomb, PA ; Aglago, EK ; Berndt, SI ; Brenner, H ; Buchanan, DD ; Cao, Y ; Chan, AT ; Chen, X ; Cheng, I ; Chang-Claude, J ; Dimou, N ; Drew, D ; Farris, AB ; French, AJ ; Gallinger, S ; Georgeson, P ; Giannakis, M ; Giles, GG ; Gruber, SB ; Harlid, S ; Hsu, L ; Huang, W-Y ; Jenkins, MA ; Laskar, RS ; Le Marchand, L ; Limburg, P ; Lin, Y ; Mandic, M ; Nowak, JA ; Obón-Santacana, M ; Ogino, S ; Qu, C ; Sakoda, LC ; Schoen, RE ; Southey, MC ; Stadler, ZK ; Steinfelder, RS ; Sun, W ; Thibodeau, SN ; Toland, AE ; Trinh, QM ; Tsilidis, KK ; Ugai, T ; Van Guelpen, B ; Wang, X ; Woods, MO ; Zaidi, SH ; Gunter, MJ ; Peters, U ; Campbell, PT (Oxford University Press (OUP), 2023-02-08)
    BACKGROUND: Obesity is an established risk factor for colorectal cancer (CRC), but the evidence for the association is inconsistent across molecular subtypes of the disease. METHODS: We pooled data on body mass index (BMI), tumor microsatellite instability status, CpG island methylator phenotype status, BRAF and KRAS mutations, and Jass classification types for 11 872 CRC cases and 11 013 controls from 11 observational studies. We used multinomial logistic regression to estimate odds ratios (OR) and 95% confidence intervals (CI) adjusted for covariables. RESULTS: Higher BMI was associated with increased CRC risk (OR per 5 kg/m2 = 1.18, 95% CI = 1.15 to 1.22). The positive association was stronger for men than women but similar across tumor subtypes defined by individual molecular markers. In analyses by Jass type, higher BMI was associated with elevated CRC risk for types 1-4 cases but not for type 5 CRC cases (considered familial-like/Lynch syndrome microsatellite instability-H, CpG island methylator phenotype-low or negative, BRAF-wild type, KRAS-wild type, OR = 1.04, 95% CI = 0.90 to 1.20). This pattern of associations for BMI and Jass types was consistent by sex and design of contributing studies (cohort or case-control). CONCLUSIONS: In contrast to previous reports with fewer study participants, we found limited evidence of heterogeneity for the association between BMI and CRC risk according to molecular subtype, suggesting that obesity influences nearly all major pathways involved in colorectal carcinogenesis. The null association observed for the Jass type 5 suggests that BMI is not a risk factor for the development of CRC for individuals with Lynch syndrome.
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    Risk of cancer in individuals with Lynch-like syndrome and their families: a systematic review
    Nugroho, PP ; Ghozali, SAS ; Buchanan, DD ; Pisano, M ; Reece, JC (SPRINGER, 2022-10-17)
    BACKGROUND: Lynch-like syndrome (LLS) tumors have similar clinicopathological features to Lynch syndrome (LS) tumors but have no identifiable pathogenic germline mismatch repair gene variant. However, cancer risks in LLS patients and first-degree relatives (FDRs) are not well defined. METHODS: To clarify LLS-associated cancer risks, a systematic review of all studies examining all cancer risks in LLS was performed. Searching of Medline, Embase, Pubmed, Cochrane and CINAHL databases and reference/citation checking identified relevant studies published between January 1, 1980 and February 11, 2021. Joanna Briggs Institute Appraisal Tools assessed the risk of bias. RESULTS: Six studies (five cohort/one cross-sectional) were eligible for study inclusion. One study found no difference in colorectal cancer (CRC) incidence between LLS and LS patients or CRC risks at aged 70 years. Three studies found CRC incidence in LLS FDRs was higher than the general population but lower than LS FDRs. Two studies showed no difference in CRC diagnosis age between LLS patients and LS patients. Endometrial cancer risks in LLS patients were higher than the general population but lower than LS patients. CONCLUSION: Evidence of elevated CRC risks in LLS patients and FDRs supports increased colonoscopy surveillance strategies for LLS patients and FDRs in line with current recommendations for LS. Due to heterogeneity amongst LLS populations, extended intervals between screening may be advised for low-risk families. Studies to resolve the molecular characterization and definition of LLS are needed to clarify cancer risks associated with LLS which in turn may individualize surveillance strategies for LLS patients and families.
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    Increased FOXJ1 protein expression is associated with improved overall survival in high-grade serous ovarian carcinoma: an Ovarian Tumor Tissue Analysis Consortium Study
    Weir, A ; Kang, E-Y ; Meagher, NS ; Nelson, GS ; Ghatage, P ; Lee, C-H ; Riggan, MJ ; Gentry-Maharaj, A ; Ryan, A ; Singh, N ; Widschwendter, M ; Alsop, J ; Anglesio, MS ; Beckmann, MW ; Berger, J ; Bisinotto, C ; Boros, J ; Brand, AH ; Brenton, JD ; Brooks-Wilson, A ; Carney, ME ; Cunningham, JM ; Cushing-Haugen, KL ; Cybulski, C ; Elishaev, E ; Erber, R ; Fereday, S ; Fischer, A ; Paz-Ares, L ; Gayarre, J ; Gilks, BC ; Grube, M ; Harnett, PR ; Harris, HR ; Hartmann, A ; Hein, A ; Hendley, J ; Hernandez, BY ; Heublein, S ; Huang, Y ; Huzarski, T ; Jakubowska, A ; Jimenez-Linan, M ; Kennedy, CJ ; Kommoss, FKF ; Koziak, JM ; Kraemer, B ; Le, ND ; Lesnock, J ; Lester, J ; Lubinski, J ; Menkiszak, J ; Ney, B ; Olawaiye, A ; Orsulic, S ; Osorio, A ; Robles-Diaz, L ; Ruebner, M ; Shah, M ; Sharma, R ; Shvetsov, YB ; Steed, H ; Talhouk, A ; Taylor, SE ; Traficante, N ; Vierkant, RA ; Wang, C ; Wilkens, LR ; Winham, SJ ; Benitez, J ; Berchuck, A ; Bowtell, DD ; Candido dos Reis, FJ ; Cook, LS ; DeFazio, A ; Doherty, JA ; Fasching, PA ; Garcia, MJ ; Goode, EL ; Goodman, MT ; Gronwald, J ; Huntsman, DG ; Karlan, BY ; Kommoss, S ; Modugno, F ; Schildkraut, JM ; Sinn, H-P ; Staebler, A ; Kelemen, LE ; Ford, CE ; Menon, U ; Pharoah, PDP ; Koebel, M ; Ramus, SJ ; Bowtell, D ; DeFazio, A ; Traficante, N ; Fereday, S ; Brand, A ; Harnett, P ; Sharma, R (SPRINGERNATURE, 2023-01-26)
    BACKGROUND: Recently, we showed a >60% difference in 5-year survival for patients with tubo-ovarian high-grade serous carcinoma (HGSC) when stratified by a 101-gene mRNA expression prognostic signature. Given the varied patient outcomes, this study aimed to translate prognostic mRNA markers into protein expression assays by immunohistochemistry and validate their survival association in HGSC. METHODS: Two prognostic genes, FOXJ1 and GMNN, were selected based on high-quality antibodies, correlation with protein expression and variation in immunohistochemical scores in a preliminary cohort (n = 134 and n = 80, respectively). Six thousand four hundred and thirty-four (FOXJ1) and 5470 (GMNN) formalin-fixed, paraffin-embedded ovarian neoplasms (4634 and 4185 HGSC, respectively) represented on tissue microarrays from the Ovarian Tumor Tissue Analysis consortium underwent immunohistochemical staining and scoring, then univariate and multivariate survival analysis. RESULTS: Consistent with mRNA, FOXJ1 protein expression exhibited a linear, increasing association with improved overall survival in HGSC patients. Women with >50% expression had the most favourable outcomes (HR = 0.78, 95% CI 0.67-0.91, p < 0.0001). GMNN protein expression was not significantly associated with overall HSGC patient survival. However, HGSCs with >35% GMNN expression showed a trend for better outcomes, though this was not significant. CONCLUSION: We provide foundational evidence for the prognostic value of FOXJ1 in HGSC, validating the prior mRNA-based prognostic association by immunohistochemistry.
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    Semi-quantitative and quantitative dynamic contrast-enhanced (DCE) MRI parameters as prostate cancer imaging biomarkers for biologically targeted radiation therapy
    Reynolds, HM ; Tadimalla, S ; Wang, Y-F ; Montazerolghaem, M ; Sun, Y ; Williams, S ; Mitchell, C ; Finnegan, ME ; Murphy, DG ; Haworth, A (BMC, 2022-12-19)
    BACKGROUND: Biologically targeted radiation therapy treatment planning requires voxel-wise characterisation of tumours. Dynamic contrast enhanced (DCE) DCE MRI has shown promise in defining voxel-level biological characteristics. In this study we consider the relative value of qualitative, semi-quantitative and quantitative assessment of DCE MRI compared with diffusion weighted imaging (DWI) and T2-weighted (T2w) imaging to detect prostate cancer at the voxel level. METHODS: Seventy prostate cancer patients had multiparametric MRI prior to radical prostatectomy, including T2w, DWI and DCE MRI. Apparent Diffusion Coefficient (ADC) maps were computed from DWI, and semi-quantitative and quantitative parameters computed from DCE MRI. Tumour location and grade were validated with co-registered whole mount histology. Kolmogorov-Smirnov tests were applied to determine whether MRI parameters in tumour and benign voxels were significantly different. Cohen's d was computed to quantify the most promising biomarkers. The Parker and Weinmann Arterial Input Functions (AIF) were compared for their ability to best discriminate between tumour and benign tissue. Classifier models were used to determine whether DCE MRI parameters improved tumour detection versus ADC and T2w alone. RESULTS: All MRI parameters had significantly different data distributions in tumour and benign voxels. For low grade tumours, semi-quantitative DCE MRI parameter time-to-peak (TTP) was the most discriminating and outperformed ADC. For high grade tumours, ADC was the most discriminating followed by DCE MRI parameters Ktrans, the initial rate of enhancement (IRE), then TTP. Quantitative parameters utilising the Parker AIF better distinguished tumour and benign voxel values than the Weinmann AIF. Classifier models including DCE parameters versus T2w and ADC alone, gave detection accuracies of 78% versus 58% for low grade tumours and 85% versus 72% for high grade tumours. CONCLUSIONS: Incorporating DCE MRI parameters with DWI and T2w gives improved accuracy for tumour detection at a voxel level. DCE MRI parameters should be used to spatially characterise tumour biology for biologically targeted radiation therapy treatment planning.
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    The Australian Reproductive Genetic Carrier Screening Project (Mackenzie's Mission): Design and Implementation
    Archibald, AD ; McClaren, BJ ; Caruana, J ; Tutty, E ; King, EA ; Halliday, JL ; Best, S ; Kanga-Parabia, A ; Bennetts, BH ; Cliffe, CC ; Madelli, EO ; Ho, G ; Liebelt, J ; Long, JC ; Braithwaite, J ; Kennedy, J ; Massie, J ; Emery, JD ; McGaughran, J ; Marum, JE ; Boggs, K ; Barlow-Stewart, K ; Burnett, L ; Dive, L ; Freeman, L ; Davis, MR ; Downes, MJ ; Wallis, M ; Ferrie, MM ; Pachter, N ; Scuffham, PA ; Casella, R ; Allcock, RJN ; Ong, R ; Edwards, S ; Righetti, S ; Lunke, S ; Lewis, S ; Walker, SP ; Boughtwood, TF ; Hardy, T ; Newson, AJ ; Kirk, EP ; Laing, NG ; Delatycki, MB (MDPI, 2022-11-01)
    Reproductive genetic carrier screening (RGCS) provides people with information about their chance of having children with autosomal recessive or X-linked genetic conditions, enabling informed reproductive decision-making. RGCS is recommended to be offered to all couples during preconception or in early pregnancy. However, cost and a lack of awareness may prevent access. To address this, the Australian Government funded Mackenzie’s Mission—the Australian Reproductive Genetic Carrier Screening Project. Mackenzie’s Mission aims to assess the acceptability and feasibility of an easily accessible RGCS program, provided free of charge to the participant. In study Phase 1, implementation needs were mapped, and key study elements were developed. In Phase 2, RGCS is being offered by healthcare providers educated by the study team. Reproductive couples who provide consent are screened for over 1200 genes associated with >750 serious, childhood-onset genetic conditions. Those with an increased chance result are provided comprehensive genetic counseling support. Reproductive couples, recruiting healthcare providers, and study team members are also invited to complete surveys and/or interviews. In Phase 3, a mixed-methods analysis will be undertaken to assess the program outcomes, psychosocial implications and implementation considerations alongside an ongoing bioethical analysis and a health economic evaluation. Findings will inform the implementation of an ethically robust RGCS program.
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    Body Mass Index, sex, non-steroidal anti-inflammatory drug medications, smoking and alcohol are differentially associated with World Health Organisation criteria and colorectal cancer risk in people with Serrated Polyposis Syndrome: an Australian case-control study
    Anthony, E ; Reece, JC ; Milanzi, E ; Joo, JE ; Joseland, S ; Clendenning, M ; Whelan, A ; Parry, S ; Arnold, J ; Vijay, V ; Atkinson, N ; Hopper, JL ; Win, AK ; Jenkins, MA ; Macrae, FA ; Winship, IM ; Rosty, C ; Buchanan, DD (BMC, 2022-11-26)
    OBJECTIVE: The unknown aetiology of Serrated Polyposis Syndrome (SPS) impedes risk prediction and prevention. We investigated risk factors for SPS, overall and stratified by World Health Organization (WHO)2010 clinical criteria and by colorectal cancer (CRC). METHOD: A retrospective case-control study involving a cross-sectional analysis from 350 unrelated individuals with SPS from the Genetics of Colonic Polyposis Study and 714 controls from the Australasian Colorectal Cancer Family Registry. Univariate and multivariate logistic regression modelling was used to determine the association between risk factors and SPS and risk factors associated with CRC in SPS. RESULTS: Female biological sex (odds ratio (OR) = 4.54; 95%Confidence interval (CI) = 2.77-7.45), increasing body mass index (BMI) at age 20 years (OR = 1.09; 95%CI = 1.04-1.13), hormone replacement therapy (OR = 0.44; 95%CI = 0.20.98), and increasing weekly folate intake (OR = 0.82; 95%CI = 0.75-0.90) were associated with SPS by multivariate analysis. Increasing weekly calcium intake (OR = 0.79; 95%CI = 0.64-0.97) and smoking > 10 cigarettes daily (OR = 0.45; 95%CI = 0.23-0.86) were associated with WHO criterion I only. The consumption of 1-100 g of alcohol per week (OR = 0.39; 95%CI = 0.18-0.83) was associated with WHO criterion III only. Smoking 1-5 cigarettes daily (OR = 2.35; 95%CI = 1.09-5.05), weekly non-steroidal anti-inflammatory drug (NSAIDs) intake (OR = 0.88; 95%CI = 0.78-0.99), and increased height (OR = 1.09; 95% = 1.05-1.13), were associated with SPS fulfilling both WHO criteria I and III. Moreover, weekly NSAIDs intake (OR = 0.81; 95%CI = 0.67-0.98) was associated with a reduced likelihood of CRC in SPS. CONCLUSION: We identified novel risk and potential protective factors associated with SPS, some specific for certain WHO2010 criteria. Weekly use of NSAIDs may reduce the risk of CRC in people with SPS.
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    Interactions between folate intake and genetic predictors of gene expression levels associated with colorectal cancer risk
    Haas, CB ; Su, Y-R ; Petersen, P ; Wang, X ; Bien, SA ; Lin, Y ; Albanes, D ; Weinstein, SJ ; Jenkins, MA ; Figueiredo, JC ; Newcomb, PA ; Casey, G ; Le Marchand, L ; Campbell, PT ; Moreno, V ; Potter, JD ; Sakoda, LC ; Slattery, ML ; Chan, AT ; Li, L ; Giles, GG ; Milne, RL ; Gruber, SB ; Rennert, G ; Woods, MO ; Gallinger, SJ ; Berndt, S ; Hayes, RB ; Huang, W-Y ; Wolk, A ; White, E ; Nan, H ; Nassir, R ; Lindor, NM ; Lewinger, JP ; Kim, AE ; Conti, D ; Gauderman, WJ ; Buchanan, DD ; Peters, U ; Hsu, L (NATURE PORTFOLIO, 2022-11-07)
    Observational studies have shown higher folate consumption to be associated with lower risk of colorectal cancer (CRC). Understanding whether and how genetic risk factors interact with folate could further elucidate the underlying mechanism. Aggregating functionally relevant genetic variants in set-based variant testing has higher power to detect gene-environment (G × E) interactions and may provide information on the underlying biological pathway. We investigated interactions between folate consumption and predicted gene expression on colorectal cancer risk across the genome. We used variant weights from the PrediXcan models of colon tissue-specific gene expression as a priori variant information for a set-based G × E approach. We harmonized total folate intake (mcg/day) based on dietary intake and supplemental use across cohort and case-control studies and calculated sex and study specific quantiles. Analyses were performed using a mixed effects score tests for interactions between folate and genetically predicted expression of 4839 genes with available genetically predicted expression. We pooled results across 23 studies for a total of 13,498 cases with colorectal tumors and 13,918 controls of European ancestry. We used a false discovery rate of 0.2 to identify genes with suggestive evidence of an interaction. We found suggestive evidence of interaction with folate intake on CRC risk for genes including glutathione S-Transferase Alpha 1 (GSTA1; p = 4.3E-4), Tonsuko Like, DNA Repair Protein (TONSL; p = 4.3E-4), and Aspartylglucosaminidase (AGA: p = 4.5E-4). We identified three genes involved in preventing or repairing DNA damage that may interact with folate consumption to alter CRC risk. Glutathione is an antioxidant, preventing cellular damage and is a downstream metabolite of homocysteine and metabolized by GSTA1. TONSL is part of a complex that functions in the recovery of double strand breaks and AGA plays a role in lysosomal breakdown of glycoprotein.
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    Immunization with inactivated whole virus particle influenza virus vaccines improves the humoral response landscape in cynomolgus macaques
    Chua, BY ; Sekiya, T ; Koutsakos, M ; Nomura, N ; Rowntree, LC ; Nguyen, THO ; McQuilten, HA ; Ohno, M ; Ohara, Y ; Nishimura, T ; Endo, M ; Itoh, Y ; Habel, JR ; Selva, KJ ; Wheatley, AK ; Wines, BD ; Hogarth, PM ; Kent, SJ ; Chung, AW ; Jackson, DC ; Brown, LE ; Shingai, M ; Kedzierska, K ; Kida, H ; Klein, SL (PUBLIC LIBRARY SCIENCE, 2022-10-01)
    Although antibody-inducing split virus vaccines (SV) are currently the most effective way to combat seasonal influenza, their efficacy can be modest, especially in immunologically-naïve individuals. We investigated immune responses towards inactivated whole influenza virus particle vaccine (WPV) formulations, predicated to be more immunogenic, in a non-human primate model, as an important step towards clinical testing in humans. Comprehensive analyses were used to capture 46 immune parameters to profile how WPV-induced responses differed to those elicited by antigenically-similar SV formulations. Naïve cynomolgus macaques vaccinated with either monovalent or quadrivalent WPV consistently induced stronger antibody responses and hemagglutination inhibition (HI) antibody titres against vaccine-matched viruses compared to SV formulations, while acute reactogenic effects were similar. Responses in WPV-primed animals were further increased by boosting with the same formulation, conversely to modest responses after priming and boosting with SV. 28-parameter multiplex bead array defined key antibody features and showed that while both WPV and SV induced elevated IgG responses against A/H1N1 nucleoprotein, only WPV increased IgG responses against A/H1N1 hemagglutinin (HA) and HA-Stem, and higher IgA responses to A/H1N1-HA after each vaccine dose. Antibodies to A/H1N1-HA and HA-Stem that could engage FcγR2a and FcγR3a were also present at higher levels after one dose of WPV compared to SV and remained elevated after the second dose. Furthermore, WPV-enhanced antibody responses were associated with higher frequencies of HA-specific B-cells and IFN-γ-producing CD4+ T-cell responses. Our data additionally demonstrate stronger boosting of HI titres by WPV following prior infection and support WPV administered as a priming dose irrespective of the follow up vaccine for the second dose. Our findings thus show that compared to SV vaccination, WPV-induced humoral responses are significantly increased in scope and magnitude, advocating WPV vaccination regimens for priming immunologically-naïve individuals and also in the event of a pandemic outbreak.
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    Independent evaluation of melanoma polygenic risk scores in UK and Australian prospective cohorts
    Steinberg, J ; Lee, JY ; Wang, H ; Law, M ; Smit, A ; Nguyen-Dumont, T ; Giles, G ; Southey, M ; Milne, R ; Mann, G ; MacInnis, R ; Cust, A (OXFORD UNIV PRESS, 2021-09-01)
    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.