48 results on '"Mann, Graham"'
Search Results
2. Acceptability and appropriateness of a risk-tailored organised melanoma screening program: Qualitative interviews with key informants.
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Dunlop, Kate L. A., Keogh, Louise A., Smith, Andrea L., Aranda, Sanchia, Aitken, Joanne, Watts, Caroline G., Smit, Amelia K., Janda, Monika, Mann, Graham J., Cust, Anne E., and Rankin, Nicole M.
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MEDICAL screening ,MEDICAL personnel ,MELANOMA ,EARLY detection of cancer ,HEALTH equity ,ECOLOGICAL risk assessment - Abstract
Introduction: In Australia, opportunistic screening (occurring as skin checks) for the early detection of melanoma is common, and overdiagnosis is a recognised concern. Risk-tailored cancer screening is an approach to cancer control that aims to provide personalised screening tailored to individual risk. This study aimed to explore the views of key informants in Australia on the acceptability and appropriateness of risk-tailored organised screening for melanoma, and to identify barriers, facilitators and strategies to inform potential future implementation. Acceptability and appropriateness are crucial, as successful implementation will require a change of practice for clinicians and consumers. Methods: This was a qualitative study using semi-structured interviews. Key informants were purposively selected to ensure expertise in melanoma early detection and screening, prioritising senior or executive perspectives. Consumers were expert representatives. Data were analysed deductively using the Tailored Implementation for Chronic Diseases (TICD) checklist. Results: Thirty-six participants were interviewed (10 policy makers; 9 consumers; 10 health professionals; 7 researchers). Key informants perceived risk-tailored screening for melanoma to be acceptable and appropriate in principle. Barriers to implementation included lack of trial data, reluctance for low-risk groups to not screen, variable skill level in general practice, differing views on who to conduct screening tests, confusing public health messaging, and competing health costs. Key facilitators included the perceived opportunity to improve health equity and the potential cost-effectiveness of a risk-tailored screening approach. A range of implementation strategies were identified including strengthening the evidence for cost-effectiveness, engaging stakeholders, developing pathways for people at low risk, evaluating different risk assessment criteria and screening delivery models and targeted public messaging. Conclusion: Key informants were supportive in principle of risk-tailored melanoma screening, highlighting important next steps. Considerations around risk assessment, policy and modelling the costs of current verses future approaches will help inform possible future implementation of risk-tailored population screening for melanoma. [ABSTRACT FROM AUTHOR]
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- 2023
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3. Development of melanoma clinical quality indicators for the Australian melanoma clinical outcomes registry (MelCOR): A modified Delphi study.
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Jobson, Dale, Roffey, Benjamin, Arnold, Christopher, Azzi, Anthony, Button‐Sloan, Alison, Dawson, Tamara, Fernandez‐Penas, Pablo, Fishburn, Paul, Gyorki, David E., Hiscutt, Emma L., Jakrot, Valerie, Lilleyman, Alister, Lochhead, Alistair, Long, Georgina V., Mailer, Sonia, Mann, Graham, McCormack, Christopher J., Muir, Jim, Pratt, George F., and Scolyer, Richard A.
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SENTINEL lymph node biopsy ,MEDICAL personnel ,TREATMENT effectiveness ,DELPHI method ,TREND setters - Abstract
Background: Clinical quality registries aim to identify significant variations in care and provide anonymised feedback to institutions to improve patient outcomes. Thirty‐six Australian organisations with an interest in melanoma, raised funds through three consecutive Melanoma Marches, organised by Melanoma Institute Australia, to create a national Melanoma Clinical Outcomes Registry (MelCOR). This study aimed to formally develop valid clinical quality indicators for the diagnosis and early management of cutaneous melanoma as an important step in creating the registry. Methods: Potential clinical quality indicators were identified by examining the literature, including Australian and international melanoma guidelines, and by consulting with key melanoma and registry opinion leaders. A modified two‐round Delphi survey method was used, with participants invited from relevant health professions routinely managing melanoma as well as relevant consumer organisations. Results: Nineteen participants completed at least one round of the Delphi process. 12 of 13 proposed clinical quality indictors met the validity criteria. The clinical quality indicators included acceptable biopsy method, appropriate excision margins, standardised pathology reporting, indications for sentinel lymph node biopsy, and involvement of multidisciplinary care and referrals. Conclusion: This study provides a multi‐stakeholder consensus for important clinical quality indicators that define optimal practice that will now be used in the Australian Melanoma Clinical Outcomes Registry (MelCOR). [ABSTRACT FROM AUTHOR]
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- 2022
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4. A Dual-Antigen Enzyme-Linked Immunosorbent Assay Allows the Assessment of Severe Acute Respiratory Syndrome Coronavirus 2 Antibody Seroprevalence in a Low-Transmission Setting.
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Hicks, Sarah M, Pohl, Kai, Neeman, Teresa, McNamara, Hayley A, Parsons, Kate M, He, Jin-shu, Ali, Sidra A, Nazir, Samina, Rowntree, Louise C, Nguyen, Thi H O, Kedzierska, Katherine, Doolan, Denise L, Vinuesa, Carola G, Cook, Matthew C, Coatsworth, Nicholas, Myles, Paul S, Kurth, Florian, Sander, Leif E, Mann, Graham J, and Gruen, Russell L
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ENZYME-linked immunosorbent assay ,COVID-19 ,SERODIAGNOSIS ,SEROPREVALENCE ,IMMUNOGLOBULIN G ,SARS-CoV-2 - Abstract
Estimates of seroprevalence of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) antibodies have been hampered by inadequate assay sensitivity and specificity. Using an enzyme-linked immunosorbent assay-based approach that combines data about immunoglobulin G responses to both the nucleocapsid and spike receptor binding domain antigens, we show that excellent sensitivity and specificity can be achieved. We used this assay to assess the frequency of virus-specific antibodies in a cohort of elective surgery patients in Australia and estimated seroprevalence in Australia to be 0.28% (95% Confidence Interval, 0-1.15%). These data confirm the low level of transmission of SARS-CoV-2 in Australia before July 2020 and validate the specificity of our assay. [ABSTRACT FROM AUTHOR]
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- 2021
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5. The Melanoma Genomics Managing Your Risk Study randomised controlled trial: statistical analysis plan.
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Lo, Serigne N., Smit, Amelia K., Espinoza, David, Cust, Anne E., on behalf of the Managing Your Risk Study Group, Newson, Ainsley J., Morton, Rachael L., Kimlin, Michael, Keogh, Louise, Law, Matthew H., Kirk, Judy, Dobbinson, Suzanne J., Kanetsky, Peter A., Mann, Graham J., Dawkins, Hugh, Savard, Jacqueline, Dunlop, Kate, Trevena, Lyndal, Jenkins, Mark, and Allen, Martin
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ULTRAVIOLET radiation ,STATISTICS ,CLINICAL trial registries ,GENOMICS ,MELANOMA ,PHARMACOGENOMICS ,BRAF genes ,ENVIRONMENTAL exposure prevention ,CLINICAL trials ,GENETIC testing ,SKIN tumors ,RISK assessment ,DISEASE susceptibility ,HEALTH behavior ,COST effectiveness ,RESEARCH funding ,DATA analysis - Abstract
Background: The Melanoma Genomics Managing Your Risk Study is a randomised controlled trial that aims to evaluate the efficacy of providing information on personal genomic risk of melanoma in reducing ultraviolet radiation (UV) exposure, stratified by traditional risk group (low or high phenotypic risk) in the general population. The primary outcome is objectively measured total daily Standard Erythemal Doses at 12 months. Secondary outcomes include UV exposure at specific time periods, self-reported sun protection and skin-examination behaviours, psychosocial outcomes, and ethical considerations surrounding offering genomic testing at a population level. A within-trial and modelled economic evaluation will be undertaken from an Australian health system perspective to assess the cost-effectiveness of the intervention.Objective: To publish the pre-determined statistical analysis plan (SAP) before database lock and the start of analysis.Methods: This SAP describes the data synthesis, analysis principles and statistical procedures for analysing the outcomes from this trial. The SAP was approved after closure of recruitment and before completion of patient follow-up. It outlines the planned primary analyses and a range of subgroup and sensitivity analyses. Health economic outcomes are not included in this plan but will be analysed separately. The SAP will be adhered to for the final data analysis of this trial to avoid potential analysis bias that may arise from knowledge of the outcome data.Results: This SAP is consistent with best practice and should enable transparent reporting.Conclusion: This SAP has been developed for the Melanoma Genomics Managing Your Risk Study and will be followed to ensure high-quality standards of internal validity and to minimise analysis bias.Trial Registration: Prospectively registered with the Australian New Zealand Clinical Trials Registry, ID: ACTR N12617000691347 . Registered on 15 May 2017. [ABSTRACT FROM AUTHOR]- Published
- 2020
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6. The steadily growing problem of lentigo maligna and lentigo maligna melanoma in Australia: Population‐based data on diagnosis and management.
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Guitera, Pascale, Collgros, Helena, Madronio, Christine M, Goumas, Christopher, Mann, Graham J, Watts, Caroline G, Pereira, Amanda R, Armstrong, Bruce K, Drummond, Martin, Morton, Rachael L, Scolyer, Richard A, Menzies, Scott W, Thompson, John F, and Cust, Anne E
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MELANOMA ,DIAGNOSIS ,PRIMARY care ,RECORDS management ,PHYSICIANS - Abstract
Background/Objectives: There are limited population‐based data documenting the incidence and management of lentigo maligna (LM) and invasive lentigo maligna melanoma (LMM). We report the data on occurrence and management of LM and LMM in an Australian population. Methods: Prospective collection of incidence and clinician‐reported management of melanoma in situ (MIS; n = 450, capped) and localised invasive melanoma (n = 3251) notified to the New South Wales Cancer Registry over 12‐months in 2006–2007. Results: The estimated annual incidence of all MIS was 27.0 per 100 000 (LM 12.2, non‐LM MIS 5.9 and unclassified MIS 9.0). Patients with LM or LMM were on average approximately 10 years older than those with other melanoma subtypes (P < 0.001). The head and neck was the location of 59% of LM, 44% of LMM and <20% of other melanoma subtypes (P < 0.001). The majority of LM and LMM were treated only by specialists. Diagnostic partial biopsies were more frequent for LM and LMM than for other melanoma subtypes, and primary care physicians were more likely than specialists to do a punch partial biopsy than a shave biopsy. The reported median definitive excision margin for LM was 5.0 mm compared with 7.2 mm for non‐LM MIS (P = 0.001). Conclusions: In this Australian population, LM was twice as frequent as other types of MIS. Improved strategies for diagnosis and management are required. [ABSTRACT FROM AUTHOR]
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- 2019
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7. Geographical variation in the penetrance of CDKN2A mutations for melanoma.
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Bishop, D. Timothy, Demenais, Florence, Goldstein, Alisa M., Bergman, Wilma, Bishop, Julia Newton, Bressac-de Paillerets, Brigitte, Chompret, Agnès, Ghiorzo, Paola, Gruis, Nelleke, Hansson, Johan, Harland, Mark, Hayward, Nicholas, Holland, Elizabeth A., Mann, Graham J., Mantelli, Michela, Nancarrow, Derek, Platz, Anton, Tucker, Margaret A., Chompret, Agnès, and Melanoma Genetics Consortium
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MELANOMA ,GENETIC mutation ,CHROMOSOMES ,COMPARATIVE studies ,DISEASE susceptibility ,FAMILIES ,GENETICS ,RESEARCH methodology ,MEDICAL cooperation ,ONCOGENES ,POPULATION geography ,PROTEINS ,RESEARCH ,EVALUATION research - Abstract
Background: Germline mutations in the CDKN2A gene, which encodes two proteins (p16INK4A and p14ARF), are the most common cause of inherited susceptibility to melanoma. We examined the penetrance of such mutations using data from eight groups from Europe, Australia and the United States that are part of The Melanoma Genetics Consortium.Methods: We analyzed 80 families with documented CDKN2A mutations and multiple cases of cutaneous melanoma. We modeled penetrance for melanoma using a logistic regression model incorporating survival analysis. Hypothesis testing was based on likelihood ratio tests. Covariates included gender, alterations in p14ARF protein, and population melanoma incidence rates. All statistical tests were two-sided.Results: The 80 analyzed families contained 402 melanoma patients, 320 of whom were tested for mutations and 291 were mutation carriers. We also tested 713 unaffected family members for mutations and 194 were carriers. Overall, CDKN2A mutation penetrance was estimated to be 0.30 (95% confidence interval (CI) = 0.12 to 0.62) by age 50 years and 0.67 (95% CI = 0.31 to 0.96) by age 80 years. Penetrance was not statistically significantly modified by gender or by whether the CDKN2A mutation altered p14ARF protein. However, there was a statistically significant effect of residing in a location with a high population incidence rate of melanoma (P =.003). By age 50 years CDKN2A mutation penetrance reached 0.13 in Europe, 0.50 in the United States, and 0.32 in Australia; by age 80 years it was 0.58 in Europe, 0.76 in the United States, and 0.91 in Australia.Conclusions: This study, which gives the most informed estimates of CDKN2A mutation penetrance available, indicates that the penetrance varies with melanoma population incidence rates. Thus, the same factors that affect population incidence of melanoma may also mediate CDKN2A penetrance. [ABSTRACT FROM AUTHOR]- Published
- 2002
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8. 1036Independent evaluation of melanoma polygenic risk scores in UK and Australian prospective cohorts.
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Steinberg, Julia, Lee, Jin Yee, Wang, Harry, Law, Matthew, Smit, Amelia, Nguyen-Dumont, Tu, Giles, Graham, Southey, Melissa, Milne, Roger, Mann, Graham, MacInnis, Robert, and Cust, Anne
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MELANOMA ,GENETIC variation ,AGE groups ,META-analysis ,CONFIDENCE intervals - Abstract
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]
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- 2021
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9. Testing technologies and strategies for exploration in Australian Mars analogues: A review
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West, Michael D., D.A. Clarke, Jonathan, Laing, Jennifer H., Willson, David, Waldie, James M.A., Murphy, Guy M., Thomas, Matilda, and Mann, Graham A.
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TESTING , *LITERATURE reviews , *HUMAN-robot interaction , *LUNAR surface vehicles , *SPACE colonies , *EARTH analogs to Martian geology , *MARTIAN exploration , *MARS (Planet) - Abstract
Abstract: Australia is an ideal testing ground in preparation for the robotic and human exploration of Mars. Numerous sites with landforms or processes analogous to those on Mars are present and the deserts of central Australia provide a range of locations for free-ranging Mars analogue mission simulations. The latest developments in testing technologies and strategies for exploration in Australian Mars analogues are reviewed. These include trials of analogue space suits based on mechanical counter pressure technology and the development of an analogue, crewed, pressurized rover for long-range exploration. Field science activities and instrumentation testing relevant to robotic and future crewed missions are discussed. Australian-led human factors research undertaken during expeditions to Mars analogue research stations and expeditions to Antarctica are also reviewed. Education and public outreach activities related to Mars analogue research in Australia are also detailed. [Copyright &y& Elsevier]
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- 2010
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10. The landscape of genomic structural variation in Indigenous Australians.
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Reis ALM, Rapadas M, Hammond JM, Gamaarachchi H, Stevanovski I, Ayuputeri Kumaheri M, Chintalaphani SR, Dissanayake DSB, Siggs OM, Hewitt AW, Llamas B, Brown A, Baynam G, Mann GJ, McMorran BJ, Easteal S, Hermes A, Jenkins MR, Patel HR, and Deveson IW
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- Humans, Alleles, Australia ethnology, Datasets as Topic, DNA Copy Number Variations genetics, Genetic Loci genetics, Genetics, Medical, Genomics, INDEL Mutation genetics, Interspersed Repetitive Sequences genetics, Microsatellite Repeats genetics, Australian Aboriginal and Torres Strait Islander Peoples genetics, Genomic Structural Variation genetics, Genome, Human genetics
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Indigenous Australians harbour rich and unique genomic diversity. However, Aboriginal and Torres Strait Islander ancestries are historically under-represented in genomics research and almost completely missing from reference datasets
1-3 . Addressing this representation gap is critical, both to advance our understanding of global human genomic diversity and as a prerequisite for ensuring equitable outcomes in genomic medicine. Here we apply population-scale whole-genome long-read sequencing4 to profile genomic structural variation across four remote Indigenous communities. We uncover an abundance of large insertion-deletion variants (20-49 bp; n = 136,797), structural variants (50 b-50 kb; n = 159,912) and regions of variable copy number (>50 kb; n = 156). The majority of variants are composed of tandem repeat or interspersed mobile element sequences (up to 90%) and have not been previously annotated (up to 62%). A large fraction of structural variants appear to be exclusive to Indigenous Australians (12% lower-bound estimate) and most of these are found in only a single community, underscoring the need for broad and deep sampling to achieve a comprehensive catalogue of genomic structural variation across the Australian continent. Finally, we explore short tandem repeats throughout the genome to characterize allelic diversity at 50 known disease loci5 , uncover hundreds of novel repeat expansion sites within protein-coding genes, and identify unique patterns of diversity and constraint among short tandem repeat sequences. Our study sheds new light on the dimensions and dynamics of genomic structural variation within and beyond Australia., (© 2023. The Author(s).)- Published
- 2023
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11. ACEMID cohort study: protocol of a prospective cohort study using 3D total body photography for melanoma imaging and diagnosis.
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Koh U, Cust AE, Fernández-Peñas P, Mann G, Morton R, Wolfe R, Payne E, Horsham C, Kwaan G, Mahumud RA, Sashindranath M, Soyer HP, Mar V, and Janda M
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- Humans, Cohort Studies, Australia epidemiology, Prospective Studies, Photography, Quality of Life, Melanoma diagnostic imaging
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Introduction: Three-dimensional (3D) total body photography may improve early detection of melanoma and facilitate surveillance, leading to better prognosis and lower healthcare costs. The Australian Centre of Excellence in Melanoma Imaging and Diagnosis (ACEMID) cohort study will assess long-term outcomes from delivery of a precision strategy of monitoring skin lesions using skin surface imaging technology embedded into health services across Australia., Methods and Analysis: A prospective cohort study will enrol 15 000 participants aged 18 years and above, across 15 Australian sites. Participants will attend study visits according to their melanoma risk category: very high risk, high risk or low/average risk, every 6, 12 and 24 months, respectively, over 3 years. Participants will undergo 3D total body photography and dermoscopy imaging at study visits. A baseline questionnaire will be administered to collect sociodemographic, phenotypic, quality of life and sun behaviour data. A follow-up questionnaire will be administered every 12 months to obtain changes in sun behaviour and quality of life. A saliva sample will be collected at the baseline visit from a subsample., Ethics and Dissemination: The ACEMID cohort study was approved by the Metro South Health Human Research Ethics Committee (approval number: HREC/2019/QMS/57206) and the University of Queensland Human Research Ethics Committee (approval number: 2019003077). The findings will be reported through peer-reviewed and lay publications and presentations at conferences., Trial Registration Number: ACTRN12619001706167., Competing Interests: Competing interests: HPS is a shareholder of MoleMap NZ and E-derm-Consult and undertakes regular teledermatological reporting for both companies. HPS is a Medical Consultant for Canfield Scientific, Blaze Bioscience and a Medical Advisor for First Derm. VM has received speakers fees from Novartis, Bristol Myers Squibb, Merck, Janssen and conference sponsorship from L’Oreal. PF-P has consulted for Leo, Amgen, Abbvie, UCB, Sanofi, Janssen, Novartis, BMS, MSD, Pfizer and Lilly. PF-P has received speakers fees from Janssen, Leo, Amgen, Sanofi, Lilly, Abbvie, UCB, Novartis, Merck and Pfizer., (© Author(s) (or their employer(s)) 2023. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)
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- 2023
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12. The association of dermatologist demographic density with melanoma survival in New South Wales, Australia.
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Blake SC, Guitera P, Cust AE, Galea C, Lo SN, Scolyer RA, Armstrong BK, Thompson JF, Menzies SW, Madronio C, Morton RL, Mann GJ, and Watts CG
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- Humans, New South Wales epidemiology, Dermatologists, Australia epidemiology, Demography, Melanoma epidemiology, Skin Neoplasms epidemiology
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- 2023
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13. The MC1R r allele does not increase melanoma risk in MITF E318K carriers.
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Wallingford CK, Demeshko A, Krishnakripa AK, Smit DJ, Duffy DL, Betz-Stablein B, Pflugfelder A, Jagirdar K, Holland E, Mann GJ, Primiero CA, Yanes T, Malvehy J, Badenas C, Carrera C, Aguilera P, Olsen CM, Ward SV, Haass NK, Sturm RA, Puig S, Whiteman DC, Law MH, Cust AE, Potrony M, Soyer HP, and McInerney-Leo AM
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- Humans, Alleles, Receptor, Melanocortin, Type 1 genetics, Microphthalmia-Associated Transcription Factor genetics, Australia epidemiology, Genotype, Genetic Predisposition to Disease genetics, Melanoma genetics, Skin Neoplasms genetics
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Background: Population-wide screening for melanoma is not cost-effective, but genetic characterization could facilitate risk stratification and targeted screening. Common Melanocortin-1 receptor (MC1R) red hair colour (RHC) variants and Microphthalmia-associated transcription factor (MITF) E318K separately confer moderate melanoma susceptibility, but their interactive effects are relatively unexplored., Objectives: To evaluate whether MC1R genotypes differentially affect melanoma risk in MITF E318K+ vs. E318K- individuals., Materials and Methods: Melanoma status (affected or unaffected) and genotype data (MC1R and MITF E318K) were collated from research cohorts (five Australian and two European). In addition, RHC genotypes from E318K+ individuals with and without melanoma were extracted from databases (The Cancer Genome Atlas and Medical Genome Research Bank, respectively). χ2 and logistic regression were used to evaluate RHC allele and genotype frequencies within E318K+/- cohorts depending on melanoma status. Replication analysis was conducted on 200 000 general-population exomes (UK Biobank)., Results: The cohort comprised 1165 MITF E318K- and 322 E318K+ individuals. In E318K- cases MC1R R and r alleles increased melanoma risk relative to wild type (wt), P < 0.001 for both. Similarly, each MC1R RHC genotype (R/R, R/r, R/wt, r/r and r/wt) increased melanoma risk relative to wt/wt (P < 0.001 for all). In E318K+ cases, R alleles increased melanoma risk relative to the wt allele [odds ratio (OR) 2.04 (95% confidence interval 1.67-2.49); P = 0.01], while the r allele risk was comparable with the wt allele [OR 0.78 (0.54-1.14) vs. 1.00, respectively]. E318K+ cases with the r/r genotype had a lower but not significant melanoma risk relative to wt/wt [OR 0.52 (0.20-1.38)]. Within the E318K+ cohort, R genotypes (R/R, R/r and R/wt) conferred a significantly higher risk compared with non-R genotypes (r/r, r/wt and wt/wt) (P < 0.001). UK Biobank data supported our findings that r did not increase melanoma risk in E318K+ individuals., Conclusions: RHC alleles/genotypes modify melanoma risk differently in MITF E318K- and E318K+ individuals. Specifically, although all RHC alleles increase risk relative to wt in E318K- individuals, only MC1R R increases melanoma risk in E318K+ individuals. Importantly, in the E318K+ cohort the MC1R r allele risk is comparable with wt. These findings could inform counselling and management for MITF E318K+ individuals., Competing Interests: Conflicts of interest H.P.S. is a shareholder of MoleMap NZ Limited and e-derm consult GmbH, and undertakes regular teledermatological reporting for both companies; he is also a Medical Consultant for Canfield Scientific Inc., Blaze Bioscience Inc., MoleMap Australia Pty Limited, and a Medical Advisor for First Derm and Revenio Research Oy. The other authors state no conflicts of interest., (© The Author(s) 2023. Published by Oxford University Press on behalf of British Association of Dermatologists.)
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- 2023
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14. Risk of developing a second primary melanoma after a first primary melanoma in a population-based Australian cohort.
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Ni Y, Watts CG, Scolyer RA, Madronio C, Armstrong BK, Morton RL, Menzies SW, Mann GJ, Thompson JF, Lo SN, and Cust AE
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- Humans, Australia epidemiology, Melanoma epidemiology, Melanoma etiology, Melanoma diagnosis, Skin Neoplasms epidemiology, Skin Neoplasms etiology, Skin Neoplasms diagnosis
- Abstract
Competing Interests: Conflicts of interest R.A.S. has received fees for professional services from MetaOptima Technology Inc., F. Hoffmann-La Roche Ltd, Evaxion, Provectus Biopharmaceuticals Australia, Qbiotics, Novartis, Merck Sharp & Dohme, NeraCare, AMGEN Inc., Bristol Myers Squibb, Myriad Genetics and GlaxoSmithKline. J.F.T. has received honoraria for advisory board participation from BMS Australia, MSD Australia, GSK and Provectus Inc, and travel and conference support from GSK, Provectus Inc and Novartis. S.N.L. and A.E.C. contributed equally to this article.
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- 2023
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15. Independent evaluation of melanoma polygenic risk scores in UK and Australian prospective cohorts.
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Steinberg J, Iles MM, Lee JY, Wang X, Law MH, Smit AK, Nguyen-Dumont T, Giles GG, Southey MC, Milne RL, Mann GJ, Bishop DT, MacInnis RJ, and Cust AE
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- Australia epidemiology, Genetic Predisposition to Disease, Genome-Wide Association Study, Humans, Polymorphism, Single Nucleotide, Prospective Studies, Risk Assessment, Risk Factors, United Kingdom epidemiology, Melanoma epidemiology, Melanoma genetics, Multifactorial Inheritance
- 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., (© 2022 The Authors. British Journal of Dermatology published by John Wiley & Sons Ltd on behalf of British Association of Dermatologists.)
- Published
- 2022
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16. Impact of personal genomic risk information on melanoma prevention behaviors and psychological outcomes: a randomized controlled trial.
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Smit AK, Allen M, Beswick B, Butow P, Dawkins H, Dobbinson SJ, Dunlop KL, Espinoza D, Fenton G, Kanetsky PA, Keogh L, Kimlin MG, Kirk J, Law MH, Lo S, Low C, Mann GJ, Reyes-Marcelino G, Morton RL, Newson AJ, Savard J, Trevena L, Wordsworth S, and Cust AE
- Subjects
- Adolescent, Adult, Aged, Australia, Female, Genomics, Humans, Middle Aged, National Health Programs, Young Adult, Melanoma diagnosis, Melanoma genetics, Melanoma prevention & control, Skin Neoplasms genetics, Skin Neoplasms prevention & control
- Abstract
Purpose: We evaluated the impact of personal melanoma genomic risk information on sun-related behaviors and psychological outcomes., Methods: In this parallel group, open, randomized controlled trial, 1,025 Australians of European ancestry without melanoma and aged 18-69 years were recruited via the Medicare database (3% consent). Participants were randomized to the intervention (n = 513; saliva sample for genetic testing, personalized melanoma risk booklet based on a 40-variant polygenic risk score, telephone-based genetic counseling, educational booklet) or control (n = 512; educational booklet). Wrist-worn ultraviolet (UV) radiation dosimeters (10-day wear) and questionnaires were administered at baseline, 1 month postintervention, and 12 months postbaseline., Results: At 12 months, 948 (92%) participants completed dosimetry and 973 (95%) the questionnaire. For the primary outcome, there was no effect of the genomic risk intervention on objectively measured UV exposure at 12 months, irrespective of traditional risk factors. For secondary outcomes at 12 months, the intervention reduced sunburns (risk ratio: 0.72, 95% confidence interval: 0.54-0.96), and increased skin examinations among women. Melanoma-related worry was reduced. There was no overall impact on general psychological distress., Conclusion: Personalized genomic risk information did not influence sun exposure patterns but did improve some skin cancer prevention and early detection behaviors, suggesting it may be useful for precision prevention. There was no evidence of psychological harm., (© 2021. The Author(s).)
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- 2021
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17. FRAMe: Familial Risk Assessment of Melanoma-a risk prediction tool to guide CDKN2A germline mutation testing in Australian familial melanoma.
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Holland EA, Lo S, Kelly B, Schmid H, Cust AE, Palmer JM, Drummond M, Hayward NK, Pritchard AL, and Mann GJ
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- Adult, Age Factors, Australia, Genetic Carrier Screening, Genetic Counseling, Humans, Logistic Models, Melanoma diagnosis, Neoplasms, Multiple Primary diagnosis, Neoplasms, Multiple Primary genetics, Pancreatic Neoplasms diagnosis, Predictive Value of Tests, Queensland, ROC Curve, Risk Assessment, Skin Neoplasms diagnosis, Family Health, Genes, p16, Germ-Line Mutation, Melanoma genetics, Skin Neoplasms genetics
- Abstract
Germline mutations in CDKN2A greatly increase risk of developing cutaneous melanoma. We have constructed a risk prediction model, Familial Risk Assessment of Melanoma (FRAMe), for estimating the likelihood of carrying a heritable CDKN2A mutation among Australian families, where the prevalence of these mutations is low. Using logistic regression, we analysed characteristics of 299 Australian families recruited through the Sydney site of GenoMEL (international melanoma genetics consortium) with at least three cases of cutaneous melanoma (in situ and invasive) among first-degree blood relatives, for predictors of the presence of a pathogenic CDKN2A mutation. The final multivariable prediction model was externally validated in an independent cohort of 61 melanoma kindreds recruited through GenoMEL Queensland. Family variables independently associated with the presence of a CDKN2A mutation in a multivariable model were number of individuals diagnosed with melanoma under 40 years of age, number of individuals diagnosed with more than one primary melanoma, and number of individuals blood related to a melanoma case in the first degree diagnosed with any cancer excluding melanoma and non-melanoma skin cancer. The number of individuals diagnosed with pancreatic cancer was not independently associated with mutation status. The risk prediction model had an area under the receiver operating characteristic curve (AUC) of 0.851 (95% CI 0.793, 0.909) in the training dataset, and 0.745 (95%CI 0.612, 0.877) in the validation dataset. This model is the first to be developed and validated using only Australian data, which is important given the higher rate of melanoma in the population. This model will help to effectively identify families suitable for genetic counselling and testing in areas of high ambient ultraviolet radiation. A user-friendly electronic nomogram is available at www.melanomarisk.org.au .
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- 2021
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18. Implementation of patient-reported outcome measures and patient-reported experience measures in melanoma clinical quality registries: a systematic review.
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Blood Z, Tran A, Caleo L, Saw R, Dieng M, Shackleton M, Soyer HP, Arnold C, Mann GJ, and Morton RL
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- Australia, Humans, Patient Reported Outcome Measures, Quality of Life, Registries, Melanoma therapy, Skin Neoplasms therapy
- Abstract
Objectives: To identify patient-reported outcome measures (PROMs) and patient-reported experience measures (PREMs) in clinical quality registries, for people with cutaneous melanoma, to inform a new Australian Melanoma Clinical Outcomes Registry; and describe opportunities and challenges of routine PROM/PREM collection, especially in primary care., Design: Systematic review., Primary and Secondary Outcome Measures: Which PROMs and PREMs are used in clinical quality registries for people with cutaneous melanoma, how they are collected, frequency of collection, participant recruitment methods and funding models for each registry., Results: 1134 studies were identified from MEDLINE, PreMEDLINE, Embase, PsychInfo, Cochrane Database of Abstracts of Reviews of Effects databases and TUFTS Cost-Effectiveness Analysis Registry, alongside grey literature, from database inception to 5th February 2020. Following screening, 14 studies were included, identifying four relevant registries: Dutch Melanoma Registry, Adelphi Real-World Disease-Specific Programme (Melanoma), Patient-Reported Outcomes Following Initial treatment and Long-term Evaluation of Survivorship Registry, and Cancer Experience Registry. These used seven PROMs: EuroQol-5 Dimensions, Functional Assessment of Cancer-General (FACT-G) and FACT-Melanoma (FACT-M), European Organisation for Research and Treatment of Cancer Quality of Life Questionnaire-Cancer 30 (EORTC QLQ-C30), Fatigue Assessment Scale Hospital Anxiety and Depression Scale, Patient-Reported Outcome Measures Information System-29 and one PREM; EORTC QLQ-Information Module 26. PROMs/PREMs in registries were reported to improve transparency of care; facilitate clinical auditing for quality assessment; enable cost-effectiveness analyses and create large-scale research platforms. Challenges included resource burden for data entry and potential collection bias toward younger, more affluent respondents. Feedback from patients with melanoma highlighted the relevance of PROMs/PREMs in assessing patient outcomes and patient experiences., Conclusions: Clinical registries indicate PROMs/PREMs for melanoma care can be incorporated and address important gaps, however cost and collection bias may limit generalisability., Prospero Registration Number: CRD42018086737., Competing Interests: Competing interests: RS has received honoraria for advisory board participation from MSD, Novartis and Qbiotics, and speaking honoraria from BMS. HPS is a shareholder of MoleMap NZ and e-derm consult GmbH, and undertakes regular teledermatological reporting for both companies. HPS is a Medical Consultant for Canfield Scientific, Revenio Research Oy and also a Medical Advisor for First Derm. CA is a Director of BioGrid Australia., (© Author(s) (or their employer(s)) 2021. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)
- Published
- 2021
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19. Prevalence of asymptomatic SARS-CoV-2 infection in elective surgical patients in Australia: a prospective surveillance study.
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Coatsworth N, Myles PS, Mann GJ, Cockburn IA, Forbes AB, Gardiner EE, Lum G, Cheng AC, and Gruen RL
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- Adult, Aged, Aged, 80 and over, Australia, COVID-19 diagnosis, COVID-19 Nucleic Acid Testing, COVID-19 Serological Testing, Carrier State diagnosis, Female, Humans, Male, Middle Aged, Prevalence, Prospective Studies, Reverse Transcriptase Polymerase Chain Reaction, COVID-19 epidemiology, Carrier State epidemiology, Elective Surgical Procedures, Hospitalization
- Abstract
Background: The study aimed to estimate the prevalence of active or previous SARS-CoV-2 infection in asymptomatic adults admitted for elective surgery in Australian hospitals. This surveillance activity was established as part of the National Pandemic Health Intelligence Plan., Methods: Participants (n = 3037) were recruited from 11 public and private hospitals in four states (NSW, Vic, SA and WA) between 2 June and 17 July 2020, with an overall 66% participation rate. Presence of SARS-CoV-2 viral RNA was assessed by Reverse Transcriptase - Polymerase Chain Reaction (RT-PCR) analysis of nasopharyngeal swabs taken after induction of anaesthesia. Presence of anti-SARS-CoV-2 antibodies was assessed by analysis of serum collected at the same time using a novel dual-antigen ELISA assay., Results: No patient (0/3010) returned a positive RT-PCR result. The Bayesian estimated prevalence of active infection of 0.02% (95% probability interval 0.00-0.11%), with the upper endpoint being 1 in 918. Positive serology (IgG) was observed in 15 of 2991 patients, with a strong positive in five of those individuals (Bayesian estimated seroprevalence 0.16%; 95% probability interval 0.00-0.47%)., Conclusion: These results confirm that during periods of low community prevalence of SARS-CoV-2 elective surgery patients without fever or respiratory symptoms had a very low prevalence of active SARS-CoV-2 infection., (© 2021 Royal Australasian College of Surgeons.)
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- 2021
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20. Improved Risk Prediction Calculator for Sentinel Node Positivity in Patients With Melanoma: The Melanoma Institute Australia Nomogram.
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Lo SN, Ma J, Scolyer RA, Haydu LE, Stretch JR, Saw RPM, Nieweg OE, Shannon KF, Spillane AJ, Ch'ng S, Mann GJ, Gershenwald JE, Thompson JF, and Varey AHR
- Subjects
- Adolescent, Adult, Aged, Aged, 80 and over, Australia, Female, Humans, Middle Aged, Prognosis, Risk Factors, Young Adult, Lymph Nodes pathology, Melanoma pathology, Nomograms, Sentinel Lymph Node Biopsy methods
- Abstract
Purpose: For patients with primary cutaneous melanoma, the risk of sentinel node (SN) metastasis varies according to several clinicopathologic parameters. Patient selection for SN biopsy can be assisted by National Comprehensive Cancer Network (NCCN) and ASCO/Society of Surgical Oncology (SSO) guidelines and the Memorial Sloan Kettering Cancer Center (MSKCC) online nomogram. We sought to develop an improved online risk calculator using alternative clinicopathologic parameters to more accurately predict SN positivity., Patients and Methods: Data from 3,477 patients with melanoma who underwent SN biopsy at Melanoma Institute Australia (MIA) were analyzed. A new nomogram was developed by replacing body site and Clark level from the MSKCC model with mitotic rate, melanoma subtype, and lymphovascular invasion. The predictive performance of the new nomogram was externally validated using data from The University of Texas MD Anderson Cancer Center (n = 3,496)., Results: The MSKCC model receiver operating characteristic curve had a predictive accuracy of 67.7% (95% CI, 65.3% to 70.0%). The MIA model had a predictive accuracy of 73.9% (95% CI, 71.9% to 75.9%), a 9.2% increase in accuracy over the MSKCC model ( P < .001). Among the 2,748 SN-negative patients, SN biopsy would not have been offered to 22.1%, 13.4%, and 12.4% based on the MIA model, the MSKCC model, and NCCN or ASCO/SSO criteria, respectively. External validation generated a C-statistic of 75.0% (95% CI, 73.2% to 76.7%)., Conclusion: A robust nomogram was developed that more accurately estimates the risk of SN positivity in patients with melanoma than currently available methods. The model only requires the input of 6 widely available clinicopathologic parameters. Importantly, the number of patients undergoing unnecessary SN biopsy would be significantly reduced compared with use of the MSKCC nomogram or the NCCN or ASCO/SSO guidelines, without losing sensitivity. An online calculator is available at www.melanomarisk.org.au.
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- 2020
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21. Equitable Expanded Carrier Screening Needs Indigenous Clinical and Population Genomic Data.
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Easteal S, Arkell RM, Balboa RF, Bellingham SA, Brown AD, Calma T, Cook MC, Davis M, Dawkins HJS, Dinger ME, Dobbie MS, Farlow A, Gwynne KG, Hermes A, Hoy WE, Jenkins MR, Jiang SH, Kaplan W, Leslie S, Llamas B, Mann GJ, McMorran BJ, McWhirter RE, Meldrum CJ, Nagaraj SH, Newman SJ, Nunn JS, Ormond-Parker L, Orr NJ, Paliwal D, Patel HR, Pearson G, Pratt GR, Rambaldini B, Russell LW, Savarirayan R, Silcocks M, Skinner JC, Souilmi Y, Vinuesa CG, and Baynam G
- Subjects
- Australia, Genetic Variation genetics, Humans, Metagenomics methods, Population Groups genetics
- Abstract
Expanded carrier screening (ECS) for recessive monogenic diseases requires prior knowledge of genomic variation, including DNA variants that cause disease. The composition of pathogenic variants differs greatly among human populations, but historically, research about monogenic diseases has focused mainly on people with European ancestry. By comparison, less is known about pathogenic DNA variants in people from other parts of the world. Consequently, inclusion of currently underrepresented Indigenous and other minority population groups in genomic research is essential to enable equitable outcomes in ECS and other areas of genomic medicine. Here, we discuss this issue in relation to the implementation of ECS in Australia, which is currently being evaluated as part of the national Government's Genomics Health Futures Mission. We argue that significant effort is required to build an evidence base and genomic reference data so that ECS can bring significant clinical benefit for many Aboriginal and/or Torres Strait Islander Australians. These efforts are essential steps to achieving the Australian Government's objectives and its commitment "to leveraging the benefits of genomics in the health system for all Australians." They require culturally safe, community-led research and community involvement embedded within national health and medical genomics programs to ensure that new knowledge is integrated into medicine and health services in ways that address the specific and articulated cultural and health needs of Indigenous people. Until this occurs, people who do not have European ancestry are at risk of being, in relative terms, further disadvantaged., (Copyright © 2020 American Society of Human Genetics. All rights reserved.)
- Published
- 2020
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22. Identifying challenges to implementation of clinical practice guidelines for sentinel lymph node biopsy in patients with melanoma in Australia: protocol paper for a mixed methods study.
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Rapport F, Smith AL, Cust AE, Mann GJ, Watts CG, Gyorki DE, Henderson M, Hong AM, Kelly JW, Long GV, Mar VJ, Morton RL, Saw RP, Scolyer RA, Spillane AJ, Thompson JF, and Braithwaite J
- Subjects
- Australia, Cross-Sectional Studies, Humans, Interviews as Topic, Neoplasm Staging, Surveys and Questionnaires, Melanoma, Cutaneous Malignant, Clinical Protocols, Melanoma pathology, Practice Guidelines as Topic, Sentinel Lymph Node Biopsy methods, Skin Neoplasms pathology
- Abstract
Introduction: Sentinel lymph node biopsy (SLNB) is a diagnostic procedure developed in the 1990s. It is currently used to stage patients with primary cutaneous melanoma, provide prognostic information and guide management. The Australian Clinical Practice Guidelines state that SLNB should be considered for patients with cutaneous melanoma >1 mm in thickness (or >0.8 mm with high-risk pathology features). Until recently, sentinel lymph node (SLN) status was used to identify patients who might benefit from a completion lymph node dissection, a procedure that is no longer routinely recommended. SLN status is now also being used to identify patients who might benefit from systemic adjuvant therapies such as anti-programmed cell death 1 (PD1) checkpoint inhibitor immunotherapy or BRAF-directed molecular targeted therapy, treatments that have significantly improved relapse-free survival for patients with resected stage III melanoma and improved overall survival of patients with unresectable stage III and stage IV melanoma. Australian and international data indicate that approximately half of eligible patients receive an SLNB., Methods and Analysis: This mixed-methods study seeks to understand the structural, contextual and cultural factors affecting implementation of the SLNB guidelines. Data collection will include: (1) cross-sectional questionnaires and semistructured interviews with general practitioners and dermatologists; (2) semistructured interviews with other healthcare professionals involved in the diagnosis and early definitive care of melanoma patients and key stakeholders including researchers, representatives of professional colleges, training organisations and consumer melanoma groups; and (3) documentary analysis of documents from government, health services and non-government organisations. Descriptive analyses and multivariable regression models will be used to examine factors related to SLNB practices and attitudes. Qualitative data will be analysed using thematic analysis., Ethics and Dissemination: Ethics approval has been granted by the University of Sydney. Results will be disseminated through publications and presentations to clinicians, patients, policymakers and researchers and will inform the development of strategies for implementing SLNB guidelines in Australia., Competing Interests: Competing interests: JFT has received honoraria for advisory board participation from BMS Australia, MSD Australia, GSK and Provectus Inc, and travel support from GSK and Provectus Inc., (© Author(s) (or their employer(s)) 2020. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)
- Published
- 2020
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23. Evaluation of the contribution of germline variants in BRCA1 and BRCA2 to uveal and cutaneous melanoma.
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Johansson PA, Nathan V, Bourke LM, Palmer JM, Zhang T, Symmons J, Howlie M, Patch AM, Read J, Holland EA, Schmid H, Warrier S, Glasson W, Höiom V, Wadt K, Jönsson G, Olsson H, Ingvar C, Mann G, Brown KM, Hayward NK, and Pritchard AL
- Subjects
- Alleles, Australia, Computational Biology, Denmark, Exome, Female, Frameshift Mutation, Gene Deletion, Gene Frequency, Genetic Predisposition to Disease, Humans, Male, Netherlands, Sweden, Whole Genome Sequencing, Melanoma, Cutaneous Malignant, BRCA1 Protein genetics, BRCA2 Protein genetics, Germ-Line Mutation, Melanoma genetics, Skin Neoplasms genetics, Uveal Neoplasms genetics
- Abstract
Germline mutations of BRCA1 and BRCA2 predispose individuals to a high risk of breast and ovarian cancer, and elevated risk of other cancers, including those of the pancreas and prostate. BRCA2 mutation carriers may have increased risk of uveal melanoma (UM) and cutaneous melanoma (CM), but associations with these cancers in BRCA1 mutation carriers have been mixed. Here, we further assessed whether UM and CM are associated with BRCA1 or BRCA2 by assessing the presence, segregation and reported/predicted pathogenicity of rare germline mutations (variant allele frequency < 0.01) in families with multiple members affected by these cancers. Whole-genome or exome sequencing was performed on 160 CM and/or UM families from Australia, the Netherlands, Denmark and Sweden. Between one and five cases were sequenced from each family, totalling 307 individuals. Sanger sequencing was performed to validate BRCA1 and BRCA2 germline variants and to assess carrier status in other available family members. A nonsense and a frameshift mutation were identified in BRCA1, both resulting in premature truncation of the protein (the first at p.Q516 and the second at codon 91, after the introduction of seven amino acids due to a frameshift deletion). These variants co-segregated with CM in individuals who consented for testing and were present in individuals with pancreatic, prostate and breast cancer in the respective families. In addition, 33 rare missense mutations (variant allele frequency ranging from 0.00782 to 0.000001 in the aggregated ExAC data) were identified in 34 families. Examining the previously reported evidence of functional consequence of these variants revealed all had been classified as either benign or of unknown consequence. Seeking further evidence of an association between BRCA1 variants and melanoma, we examined two whole-genome/exome sequenced collections of sporadic CM patients (total N = 763). We identified one individual with a deleterious BRCA1 variant, however, this allele was lost (with the wild-type allele remaining) in the corresponding CM, indicating that defective BRCA1 was not a driver of tumorigenesis in this instance. Although this is the first time that deleterious BRCA1 mutations have been described in high-density CM families, we conclude that there is an insufficient burden of evidence to state that the increased familial CM or UM susceptibility is because of these variants. In addition, in conjunction with other studies, we conclude that the previously described association between BRCA2 mutations and UM susceptibility represents a rare source of increased risk.
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- 2019
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24. Assessing the Incremental Contribution of Common Genomic Variants to Melanoma Risk Prediction in Two Population-Based Studies.
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Cust AE, Drummond M, Kanetsky PA, Goldstein AM, Barrett JH, MacGregor S, Law MH, Iles MM, Bui M, Hopper JL, Brossard M, Demenais F, Taylor JC, Hoggart C, Brown KM, Landi MT, Newton-Bishop JA, Mann GJ, and Bishop DT
- Subjects
- Adolescent, Adult, Aged, Alleles, Australia epidemiology, Ethnicity, Female, Genetic Predisposition to Disease, Humans, Male, Melanoma epidemiology, Melanoma genetics, Middle Aged, Polymorphism, Genetic, Prognosis, Risk Assessment, Skin Neoplasms epidemiology, Skin Neoplasms genetics, United Kingdom epidemiology, Young Adult, Melanoma diagnosis, Pathology, Molecular statistics & numerical data, Population Groups, Skin Neoplasms diagnosis
- Abstract
It is unclear to what degree genomic and traditional (phenotypic and environmental) risk factors overlap in their prediction of melanoma risk. We evaluated the incremental contribution of common genomic variants (in pigmentation, nevus, and other pathways) and their overlap with traditional risk factors, using data from two population-based case-control studies from Australia (n = 1,035) and the United Kingdom (n = 1,460) that used the same questionnaires. Polygenic risk scores were derived from 21 gene regions associated with melanoma and odds ratios from published meta-analyses. Logistic regression models were adjusted for age, sex, center, and ancestry. Adding the polygenic risk score to a model with traditional risk factors increased the area under the receiver operating characteristic curve (AUC) by 2.3% (P = 0.003) for Australia and by 2.8% (P = 0.002) for Leeds. Gene variants in the pigmentation pathway, particularly MC1R, were responsible for most of the incremental improvement. In a cross-tabulation of polygenic by traditional tertile risk scores, 59% (Australia) and 49% (Leeds) of participants were categorized in the same (concordant) tertile. Of participants with low traditional risk, 9% (Australia) and 21% (Leeds) had high polygenic risk. Testing of genomic variants can identify people who are susceptible to melanoma despite not having a traditional phenotypic risk profile., (Copyright © 2018 The Authors. Published by Elsevier Inc. All rights reserved.)
- Published
- 2018
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25. Sunscreen Use and Melanoma Risk Among Young Australian Adults.
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Watts CG, Drummond M, Goumas C, Schmid H, Armstrong BK, Aitken JF, Jenkins MA, Giles GG, Hopper JL, Mann GJ, and Cust AE
- Subjects
- Adolescent, Adult, Age of Onset, Australia epidemiology, Case-Control Studies, Educational Status, Female, Humans, Male, Melanoma diagnosis, Nevus epidemiology, Nevus pathology, Risk Factors, Skin Neoplasms diagnosis, Skin Pigmentation, Sunburn epidemiology, Young Adult, Health Behavior, Melanoma epidemiology, Skin Neoplasms epidemiology, Sunscreening Agents therapeutic use
- Abstract
Importance: There are limited data among young adults on sunscreen use during childhood and adulthood and on the association of sunscreen use with melanoma risk., Objective: To assess correlates of early-life sunscreen use and the association between sunscreen use and risk of cutaneous melanoma before age 40 years., Design, Setting, and Participants: This population-based, case-control family study analyzed Australian Melanoma Family Study data for persons with questionnaire data on sunscreen use collected by interview from 2001 to 2005 across 3 states in Australia, representing two-thirds of the country's population. Case participants (aged 18-39 years) had confirmed first primary melanoma. Siblings of case participants were included, and case participants without a sibling control were excluded. Unrelated controls (aged 18-44 years) were recruited from the electoral roll or were a spouse, partner, or friend nominated by case participants. Data analyses were conducted from October 2017 to February 2018., Exposures: Self- and parent-reported sunscreen use, sun exposure, and other candidate risk factors during childhood and adulthood., Main Outcomes and Measures: Logistic regression analyses adjusted for potential confounders were used to estimate odds ratios (ORs) for melanoma and for correlates of sunscreen use., Results: Participation was 629 of 830 contactable cases (76%) (629 of 1197 overall [53%]), 240 of 570 contactable controls (42%) from the electoral roll (240 of 1068 overall [23%]), and 295 of 371 nominated spouse or friend controls (80%); analysis incuded 603 cases and 1088 controls. The median (interquartile range) age was 32 (28-36) years for 603 cases, 35 (30-38) years for 478 unrelated controls, and 34 (29-38) years for 610 sibling controls. There were more women than men (range, 57%-62%) in all groups, approximately 40% (range, 39%-43%) of participants had a university education, and most participants (range, 58%-73%) had British/northern European ethnicity. Risk of melanoma was less with higher use of sunscreen in childhood (OR for highest vs lowest tertiles, 0.60; 95% CI, 0.42-0.87; P = .02 for trend) and across the lifetime (OR, 0.65; 95% CI, 0.45-0.93; P = .07 for trend). Subgroup analyses suggested that the protective association of sunscreen with melanoma was stronger for people reporting blistering sunburn, receiving a diagnosis of melanoma at a younger age, or having some or many nevi. Total lifetime sun exposure was unrelated to melanoma risk (OR for highest vs lowest tertile, 0.97; 95% CI, 0.66-1.43; P = .94 for trend). By contrast, total sun exposure inversely weighted by sunscreen use (as a measure of sun exposure unprotected by sunscreen) was significantly associated with melanoma risk (OR, 1.80; 95% CI, 1.22-2.65; P = .007 for trend) and appeared stronger for people having lighter pigmentation or some or many nevi or using sunscreen to stay longer in the sun. Regular users of sunscreen were more likely to be female, younger, and of British or northern European ancestry and to have higher educational levels, lighter skin pigmentation, and a stronger history of blistering sunburn., Conclusions and Relevance: Our findings provided evidence that regular sunscreen use is significantly associated with reduced risk of cutaneous melanoma among young adults and identified several characteristics associated with less sunscreen use.
- Published
- 2018
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26. The melanoma genomics managing your risk study: A protocol for a randomized controlled trial evaluating the impact of personal genomic risk information on skin cancer prevention behaviors.
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Smit AK, Newson AJ, Morton RL, Kimlin M, Keogh L, Law MH, Kirk J, Dobbinson S, Kanetsky PA, Fenton G, Allen M, Butow P, Dunlop K, Trevena L, Lo S, Savard J, Dawkins H, Wordsworth S, Jenkins M, Mann GJ, and Cust AE
- Subjects
- Adolescent, Adult, Aged, Australia, Clinical Protocols, Cost-Benefit Analysis, Environmental Exposure prevention & control, Female, Follow-Up Studies, Health Behavior, Humans, Male, Melanoma economics, Melanoma genetics, Melanoma psychology, Middle Aged, Prospective Studies, Risk Assessment, Skin Neoplasms economics, Skin Neoplasms genetics, Skin Neoplasms psychology, Ultraviolet Rays adverse effects, Young Adult, Genetic Predisposition to Disease, Genetic Testing economics, Genomics economics, Melanoma prevention & control, Skin Neoplasms prevention & control
- Abstract
Background: Reducing ultraviolet radiation (UV) exposure and improving early detection may reduce melanoma incidence, mortality and health system costs. This study aims to evaluate the efficacy and cost-effectiveness of providing information on personal genomic risk of melanoma in reducing UV exposure at 12 months, according to low and high traditional risk., Methods: In this randomized controlled trial, participants (target sample = 892) will be recruited from the general population, and randomized (1:1 ratio, intervention versus control). Intervention arm participants provide a saliva sample, receive personalized melanoma genomic risk information, a genetic counselor phone call, and an educational booklet on melanoma prevention. Control arm participants receive only the educational booklet. Eligible participants are aged 18-69 years, have European ancestry and no personal history of melanoma. All participants will complete a questionnaire and wear a UV dosimeter to objectively measure their sun exposure at baseline, 1- and 12-month time-points, except 1-month UV dosimetry will be limited to ~250 participants. The primary outcome is total daily Standard Erythemal Doses at 12 months. Secondary outcomes include objectively measured UV exposure for specific time periods (e.g. midday hours), self-reported sun protection and skin-examination behaviors, psycho-social outcomes, and ethical considerations surrounding offering genomic testing at a population level. A within-trial and modelled economic evaluation will be undertaken from an Australian health system perspective to assess the intervention costs and outcomes., Discussion: This trial will inform the clinical and personal utility of introducing genomic testing into the health system for melanoma prevention and early detection at a population-level., Trial Registration: Australian New Zealand Clinical Trials Registry ACTRN12617000691347., (Copyright © 2018 Elsevier Inc. All rights reserved.)
- Published
- 2018
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27. A National Budget Impact Analysis of a Specialised Surveillance Programme for Individuals at Very High Risk of Melanoma in Australia.
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Watts CG, Wortley S, Norris S, Menzies SW, Guitera P, Askie L, Mann GJ, Morton RL, and Cust AE
- Subjects
- Australia epidemiology, Cost Savings methods, Cost-Benefit Analysis, Early Detection of Cancer methods, Early Detection of Cancer statistics & numerical data, Humans, Melanoma diagnosis, Melanoma economics, Melanoma etiology, Risk Factors, Early Detection of Cancer economics, Health Care Costs statistics & numerical data, Melanoma epidemiology
- Abstract
Background: Specialised surveillance using total body photography and digital dermoscopy to monitor people at very high risk of developing a second or subsequent melanoma has been reported as cost effective., Objectives: We aimed to estimate the 5-year healthcare budget impact of providing specialised surveillance for people at very high risk of subsequent melanoma from the perspective of the Australian healthcare system., Methods: A budget impact model was constructed to assess the costs of monitoring and potential savings compared with current routine care based on identification of patients at the time of a melanoma diagnosis. We used data from a published cost-effectiveness analysis of specialised surveillance, and Cancer Registry data, to estimate the patient population and healthcare costs for 2017-2021., Results: When all eligible patients, estimated at 18% of patients with melanoma diagnosed annually in Australia, received specialised surveillance rather than routine care, the cumulative 5-year cost was estimated at $93.5 million Australian dollars ($AU) ($US 64 million) for specialised surveillance compared with $AU 120.7 million ($US 82.7 million) for routine care, delivering savings of $AU 27.2 million ($US 18.6 million). With a staggered introduction of 60% of eligible patients accessing surveillance in year 1, increasing to 90% in years 4 and 5, the cumulative cost over 5 years was estimated at $AU 98.1 million ($US 67.2 million), amounting to savings of $AU 22.6 million ($US 15.5 million) compared with routine care., Conclusions: Specialised melanoma surveillance is likely to provide substantial cost savings for the Australian healthcare system.
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- 2018
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28. Follow-Up Recommendations after Diagnosis of Primary Cutaneous Melanoma: A Population-Based Study in New South Wales, Australia.
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Read RL, Madronio CM, Cust AE, Goumas C, Watts CG, Menzies S, Curtin AM, Mann G, Thompson JF, and Morton RL
- Subjects
- Aged, Australia epidemiology, Combined Modality Therapy, Disease Management, Female, Follow-Up Studies, Humans, Male, Melanoma diagnosis, Melanoma epidemiology, Middle Aged, Prognosis, Prospective Studies, Registries, Skin Neoplasms diagnosis, Skin Neoplasms epidemiology, Melanoma, Cutaneous Malignant, Aftercare standards, Melanoma prevention & control, Practice Guidelines as Topic standards, Skin Neoplasms prevention & control
- Abstract
Background: Follow-up practices after diagnosis and treatment of primary cutaneous melanoma vary considerably. We aimed to determine factors associated with recommendations for follow-up setting, frequency, skin surveillance, and concordance with clinical guidelines., Methods: The population-based Melanoma Patterns of Care study documented clinicians' recommendations for follow-up for 2148 patients diagnosed with primary cutaneous melanoma over a 12-month period (2006/2007) in New South Wales, Australia. Multivariate log binomial regression models adjusted for patient and lesion characteristics were used to examine factors associated with follow-up practices., Results: Of 2158 melanomas, Breslow thickness was < 1 mm for 57% and ≥ 1 mm for 30%, while in situ melanomas accounted for 13%. Follow-up was recommended for 2063 patients (96%). On multivariate analysis, factors associated with a recommendation for follow-up at a specialist center were Breslow thickness ≥ 1 mm [prevalence ratio (PR) 1.05, 95% confidence interval (CI) 1.01-1.09] and initial treatment at a specialist center (PR 1.12, 95% CI 1.08-1.16). Longer follow-up intervals of > 3 months were more likely to be recommended for females, less likely for people living in rural compared with urban areas, and less likely for thicker (≥ 1 mm) melanomas compared with in situ melanomas. Skin self-examination was encouraged in 84% of consultations and was less likely to be recommended for patients ≥ 70 years (PR 0.88, 95% CI 0.84-0.93) and for those with thicker (≥ 1 mm) melanomas (PR 0.92, 95% CI 0.86-0.99). Only 1% of patients were referred for psychological care., Conclusions: Follow-up recommendations were generally consistent with Australian national guidelines for management of melanoma, however some variations could be targeted to improve patient outcomes.
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- 2018
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29. Sensitivity of Preference-Based Quality-of-Life Measures for Economic Evaluations in Early-Stage Melanoma.
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Dieng M, Kasparian NA, Cust AE, Costa DSJ, Tran A, Butow PN, Menzies SW, Mann GJ, and Morton RL
- Subjects
- Adult, Age Factors, Aged, Australia, Fear psychology, Female, Humans, Male, Melanoma pathology, Middle Aged, Neoplasm Invasiveness pathology, Neoplasm Recurrence, Local epidemiology, Neoplasm Staging, New Zealand, Risk Assessment, Sensitivity and Specificity, Sex Factors, Skin Neoplasms pathology, Surveys and Questionnaires, Melanoma economics, Melanoma psychology, Neoplasm Recurrence, Local psychology, Quality of Life, Skin Neoplasms economics, Skin Neoplasms psychology
- Abstract
Importance: The diagnosis of a life-threatening disease like melanoma can affect all aspects of a person's life, including health-related quality of life (HRQOL) and psychological aspects of melanoma such as fear of cancer recurrence (FCR). Economic evaluations of psychological interventions require preference-based (utility) instruments that are sensitive to changes in well-being and HRQOL; however, very few studies have evaluated the sensitivity of these instruments when used for people with melanoma., Objective: To compare utility scores from the multiple-attribute instrument Assessment of Quality of Life-8-Dimension Scale (AQoL-8D) with the mapped utility scores of the Functional Assessment of Cancer Therapy-Melanoma (FACT-M) and to investigate the sensitivity of both instruments in identifying the influence of FCR on HRQOL., Design, Setting, and Participants: This assessment of data from a randomized clinical trial of a psychoeducational intervention to reduce FCR, conducted at 3 high-risk melanoma clinics in Australia, evaluated 164 patients with early-stage melanoma and a high risk of developing a second primary melanoma., Main Outcomes and Measures: The FACT-M and AQoL-8D were used to assess HRQOL and FCR among the study participants. Concurrent validity was assessed by comparing the total and subdomain scores of the 2 instruments, and the strength of associations was assessed using Pearson correlation coefficient. Convergent validity was assessed by comparing participants' HRQOL, demographic, and clinical characteristics using the χ2 test and F statistic. Both the FACT-M and AQoL-8D utilities were regressed on FCR Inventory (FCRI) severity scores to estimate the effect of elevated FCR on HRQOL., Results: A total of 164 participants completed the baseline questionnaires, but only 163 met all inclusion criteria and underwent the full analysis: 72 were women; 91 were men; and mean (SD) age was 58.2 (12.1) years. Both the AQoL-8D and FACT-M instruments showed good concurrent validity and could differentiate between relevant subgroups including level of FCRI severity. The AQoL-8D and FACT-M utilities were strongly correlated (r2 = 0.57). Respondents had a mean (SD) AQoL-8D utility of 0.77 (0.2), and a mean (SD) FACT-M utility score of 0.76 (0.07). High levels of FCRI severity were associated with a decrease in utility of 0.12 (95% CI, -0.19 to -0.05) as measured by AQoL-8D, and a decrease of 0.03 (95% CI, -0.05 to -0.01) as measured by the FACT-M., Conclusions and Relevance: For economic evaluations of psychological interventions in melanoma, the AQoL-8D and FACT-M are valid measures of utility; however, the AQoL-8D demonstrates greater sensitivity to FCRI severity. Our results suggest a significant association between FCR and HRQOL.
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- 2018
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30. Development and External Validation of a Melanoma Risk Prediction Model Based on Self-assessed Risk Factors.
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Vuong K, Armstrong BK, Weiderpass E, Lund E, Adami HO, Veierod MB, Barrett JH, Davies JR, Bishop DT, Whiteman DC, Olsen CM, Hopper JL, Mann GJ, Cust AE, and McGeechan K
- Subjects
- Adolescent, Adult, Aged, Aged, 80 and over, Area Under Curve, Australia epidemiology, Case-Control Studies, Child, Diagnostic Self Evaluation, Female, Hair Color, Humans, Logistic Models, Male, Melanoma epidemiology, Melanoma genetics, Middle Aged, Multivariate Analysis, ROC Curve, Risk Factors, Skin Neoplasms epidemiology, Skin Neoplasms genetics, Sweden epidemiology, Ultraviolet Rays adverse effects, United Kingdom epidemiology, Young Adult, Carcinoma, Basal Cell diagnosis, Carcinoma, Squamous Cell diagnosis, Melanoma prevention & control, Nevus pathology, Risk Assessment methods, Skin Neoplasms pathology, Skin Neoplasms prevention & control
- Abstract
Importance: Identifying individuals at high risk of melanoma can optimize primary and secondary prevention strategies., Objective: To develop and externally validate a risk prediction model for incident first-primary cutaneous melanoma using self-assessed risk factors., Design, Setting, and Participants: We used unconditional logistic regression to develop a multivariable risk prediction model. Relative risk estimates from the model were combined with Australian melanoma incidence and competing mortality rates to obtain absolute risk estimates. A risk prediction model was developed using the Australian Melanoma Family Study (629 cases and 535 controls) and externally validated using 4 independent population-based studies: the Western Australia Melanoma Study (511 case-control pairs), Leeds Melanoma Case-Control Study (960 cases and 513 controls), Epigene-QSkin Study (44 544, of which 766 with melanoma), and Swedish Women's Lifestyle and Health Cohort Study (49 259 women, of which 273 had melanoma)., Main Outcomes and Measures: We validated model performance internally and externally by assessing discrimination using the area under the receiver operating curve (AUC). Additionally, using the Swedish Women's Lifestyle and Health Cohort Study, we assessed model calibration and clinical usefulness., Results: The risk prediction model included hair color, nevus density, first-degree family history of melanoma, previous nonmelanoma skin cancer, and lifetime sunbed use. On internal validation, the AUC was 0.70 (95% CI, 0.67-0.73). On external validation, the AUC was 0.66 (95% CI, 0.63-0.69) in the Western Australia Melanoma Study, 0.67 (95% CI, 0.65-0.70) in the Leeds Melanoma Case-Control Study, 0.64 (95% CI, 0.62-0.66) in the Epigene-QSkin Study, and 0.63 (95% CI, 0.60-0.67) in the Swedish Women's Lifestyle and Health Cohort Study. Model calibration showed close agreement between predicted and observed numbers of incident melanomas across all deciles of predicted risk. In the external validation setting, there was higher net benefit when using the risk prediction model to classify individuals as high risk compared with classifying all individuals as high risk., Conclusions and Relevance: The melanoma risk prediction model performs well and may be useful in prevention interventions reliant on a risk assessment using self-assessed risk factors.
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- 2016
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31. Accuracy of self-reported nevus and pigmentation phenotype compared with clinical assessment in a population-based study of young Australian adults.
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Cust AE, Pickles KM, Goumas C, Vu T, Schmid H, Nagore E, Kelly J, Aitken JF, Giles GG, Hopper JL, Jenkins MA, and Mann GJ
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- Adolescent, Adult, Australia, Case-Control Studies, Eye Color physiology, Female, Hair Color physiology, Humans, Male, Phenotype, Reproducibility of Results, Self Report, Surveys and Questionnaires, Young Adult, Nevus, Pigmented diagnosis, Skin Neoplasms diagnosis, Skin Pigmentation
- Abstract
Background: Awareness of individual risk may encourage improved prevention and early detection of melanoma., Methods: We evaluated the accuracy of self-reported pigmentation and nevus phenotype compared with clinical assessment, and examined agreement between nevus counts from selected anatomical regions. The sample included 456 cases with invasive cutaneous melanoma diagnosed between ages 18 to 39 years and 538 controls from the population-based Australian Melanoma Family Study. Participants completed a questionnaire about their pigmentation and nevus phenotype, and attended a dermatologic skin examination., Results: There was strong agreement between self-reported and clinical assessment of eye color [κ, = 0.78; 95% confidence interval (CI), 0.74-0.81]; and moderate agreement for hair color (κ = 0.46; 95% CI, 0.42-0.50). Agreement between self-reported skin color and spectrophotometer-derived measurements was poor (κ = 0.12; 95% CI, 0.08-0.16) to moderate (Spearman correlation rs = -0.37; 95% CI, -0.32 to -0.42). Participants tended to underestimate their nevus counts and pigmentation; men were more likely to underreport their skin color. The rs was 0.43 (95% CI, 0.38-0.49) comparing clinical total body nevus counts with self-reported nevus categories. There was good agreement between total body nevus counts and site-specific nevus counts, particularly on both arms., Conclusions: Young adults have suboptimal accuracy when assessing important risk characteristics including nevus numbers and pigmentation. Measuring nevus count on the arms is a good predictor of full body nevus count., Impact: These results have implications for the likely success of targeted public health programs that rely on self-assessment of these factors., (©2015 American Association for Cancer Research.)
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- 2015
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32. The effect on melanoma risk of genes previously associated with telomere length.
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Iles MM, Bishop DT, Taylor JC, Hayward NK, Brossard M, Cust AE, Dunning AM, Lee JE, Moses EK, Akslen LA, Andresen PA, Avril MF, Azizi E, Scarrà GB, Brown KM, Dębniak T, Elder DE, Friedman E, Ghiorzo P, Gillanders EM, Goldstein AM, Gruis NA, Hansson J, Harland M, Helsing P, Hočevar M, Höiom V, Ingvar C, Kanetsky PA, Landi MT, Lang J, Lathrop GM, Lubiński J, Mackie RM, Martin NG, Molven A, Montgomery GW, Novaković S, Olsson H, Puig S, Puig-Butille JA, Radford-Smith GL, Randerson-Moor J, van der Stoep N, van Doorn R, Whiteman DC, MacGregor S, Pooley KA, Ward SV, Mann GJ, Amos CI, Pharoah PD, Demenais F, Law MH, Newton Bishop JA, and Barrett JH
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- Australia, Confounding Factors, Epidemiologic, DNA Helicases genetics, Europe, Humans, Israel, Predictive Value of Tests, RNA genetics, Research Design, Ribonucleoproteins genetics, Telomerase genetics, United States, Zinc Fingers genetics, Germ-Line Mutation, Melanoma genetics, Polymorphism, Single Nucleotide, Skin Neoplasms genetics, Telomere genetics, Telomere-Binding Proteins genetics
- Abstract
Telomere length has been associated with risk of many cancers, but results are inconsistent. Seven single nucleotide polymorphisms (SNPs) previously associated with mean leukocyte telomere length were either genotyped or well-imputed in 11108 case patients and 13933 control patients from Europe, Israel, the United States and Australia, four of the seven SNPs reached a P value under .05 (two-sided). A genetic score that predicts telomere length, derived from these seven SNPs, is strongly associated (P = 8.92x10(-9), two-sided) with melanoma risk. This demonstrates that the previously observed association between longer telomere length and increased melanoma risk is not attributable to confounding via shared environmental effects (such as ultraviolet exposure) or reverse causality. We provide the first proof that multiple germline genetic determinants of telomere length influence cancer risk., (© The Author 2014. Published by Oxford University Press.)
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- 2014
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33. Online prostate cancer screening decision aid for at-risk men: a randomized trial.
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Watts KJ, Meiser B, Wakefield CE, Barratt AL, Howard K, Cheah BC, Mann GJ, Lobb EA, Gaff CL, and Patel MI
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- Adult, Aged, Australia, Conflict, Psychological, Decision Making, Early Detection of Cancer methods, Early Detection of Cancer statistics & numerical data, Humans, Internet, Logistic Models, Male, Middle Aged, Prostate-Specific Antigen blood, Prostatic Neoplasms diagnosis, Prostatic Neoplasms genetics, Risk Assessment methods, Surveys and Questionnaires, Decision Support Techniques, Early Detection of Cancer psychology, Prostatic Neoplasms psychology
- Abstract
Objective: This study examines the efficacy of an online screening decision aid (DA) for men with a family history of prostate cancer., Methods: Unaffected Australian men (40-79 years) with at least one affected relative completed the first online questionnaire, were randomized to read either the tailored DA (intervention) or nontailored information about prostate cancer screening (control), then completed a questionnaire postreading and 12 months later. The primary outcome was decisional conflict regarding prostate specific antigen (PSA) testing. The impact of the DA on longitudinal outcomes was analyzed by using random intercept mixed effects models. Logistic and linear regressions were used to analyze the impact of the DA on screening behavior and decision regret. Stage of decision-making was tested as a moderator for decisional conflict and decision regret. The frequency of online material access was recorded., Results: The DA had no effect on decisional conflict, knowledge, inclination toward PSA testing, accuracy of perceived risk, or screening behavior. However, among men considering PSA testing, those who read the DA had lower decision regret compared with men who read the control materials, β = 0.34, p < .001, 95% confidence interval (CI) = [.22, .53]., Conclusions: This is the first study to our knowledge to evaluate the uptake and efficacy of an online screening DA among men with a family history of prostate cancer. Men who were undecided about screening at baseline benefitted from the DA, experiencing less regret 12 months later. In relation to decisional conflict, the control materials may have operated as a less complex and equally informative DA., ((PsycINFO Database Record (c) 2014 APA, all rights reserved).)
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- 2014
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34. MC1R genotype as a predictor of early-onset melanoma, compared with self-reported and physician-measured traditional risk factors: an Australian case-control-family study.
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Cust AE, Goumas C, Vuong K, Davies JR, Barrett JH, Holland EA, Schmid H, Agha-Hamilton C, Armstrong BK, Kefford RF, Aitken JF, Giles GG, Bishop D, Newton-Bishop JA, Hopper JL, Mann GJ, and Jenkins MA
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- Adolescent, Adult, Age of Onset, Australia epidemiology, Case-Control Studies, Family, Female, Follow-Up Studies, Genotype, Humans, Male, Melanoma epidemiology, Melanoma genetics, Models, Statistical, Neoplasm Staging, Phenotype, Prognosis, ROC Curve, Risk Factors, Skin Neoplasms epidemiology, Skin Neoplasms genetics, Young Adult, Melanoma diagnosis, Physicians, Polymorphism, Genetic genetics, Receptor, Melanocortin, Type 1 genetics, Self Report, Skin Neoplasms diagnosis
- Abstract
Background: Melanocortin-1 receptor (MC1R) gene variants are very common and are associated with melanoma risk, but their contribution to melanoma risk prediction compared with traditional risk factors is unknown. We aimed to 1) evaluate the separate and incremental contribution of MC1R genotype to prediction of early-onset melanoma, and compare this with the contributions of physician-measured and self-reported traditional risk factors, and 2) develop risk prediction models that include MC1R, and externally validate these models using an independent dataset from a genetically similar melanoma population., Methods: Using data from an Australian population-based, case-control-family study, we included 413 case and 263 control participants with sequenced MC1R genotype, clinical skin examination and detailed questionnaire. We used unconditional logistic regression to estimate predicted probabilities of melanoma. Results were externally validated using data from a similar study in England., Results: When added to a base multivariate model containing only demographic factors, MC1R genotype improved the area under the receiver operating characteristic curve (AUC) by 6% (from 0.67 to 0.73; P < 0.001) and improved the quartile classification by a net 26% of participants. In a more extensive multivariate model, the factors that contributed significantly to the AUC were MC1R genotype, number of nevi and previous non-melanoma skin cancer; the AUC was 0.78 (95% CI 0.75-0.82) for the model with self-reported nevi and 0.83 (95% CI 0.80-0.86) for the model with physician-counted nevi. Factors that did not further contribute were sun and sunbed exposure and pigmentation characteristics. Adding MC1R to a model containing pigmentation characteristics and other self-reported risk factors increased the AUC by 2.1% (P = 0.01) and improved the quartile classification by a net 10% (95% CI 1-18%, P = 0.03)., Conclusions: Although MC1R genotype is strongly associated with skin and hair phenotype, it was a better predictor of early-onset melanoma than was pigmentation characteristics. Physician-measured nevi and previous non-melanoma skin cancer were also strong predictors. There might be modest benefit to measuring MC1R genotype for risk prediction even if information about traditional self-reported or clinically measured pigmentation characteristics and nevi is already available.
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- 2013
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35. Association between putative functional variants in the PSMB9 gene and risk of melanoma--re-analysis of published melanoma genome-wide association studies.
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Qian J, Liu H, Wei S, Liu Z, Li Y, Wang LE, Chen WV, Amos CI, Lee JE, Iles MM, Law MH, Cust AE, Barrett JH, Montgomery GW, Taylor J, Bishop JA, Macgregor S, Bishop DT, Mann GJ, Hayward NK, and Wei Q
- Subjects
- Australia, Base Sequence, Case-Control Studies, Cell Cycle genetics, Cysteine Endopeptidases metabolism, Gene Expression Regulation, Neoplastic, Humans, Molecular Sequence Data, Promoter Regions, Genetic genetics, RNA, Messenger genetics, RNA, Messenger metabolism, Reproducibility of Results, Risk Factors, Cysteine Endopeptidases genetics, Genetic Predisposition to Disease, Genome-Wide Association Study, Melanoma enzymology, Melanoma genetics, Polymorphism, Single Nucleotide genetics, Publications
- Abstract
To mine possibly hidden causal single-nucleotide polymorphisms (SNPs) of melanoma, we investigated the association of SNPs in 76 M/G1 transition genes with melanoma risk using our published genome-wide association study (GWAS) data set with 1804 melanoma cases and 1026 cancer-free controls. We found multiple SNPs with P < 0.01 and performed validation studies for 18 putative functional SNPs in PSMB9 in two other GWAS data sets. Two SNPs (rs1351383 and rs2127675) were associated with melanoma risk in the GenoMEL data set (P = 0.013 and 0.004, respectively), but failed in validation using the Australian data set. Genotype-phenotype analysis revealed these two SNPs were significantly correlated with mRNA expression level of PSMB9. Further experiments revealed that SNP rs2071480, which is in high LD with rs1351383 and rs2127675, may have a weak effect on the promoter activity of PSMB9. Taken together, our data suggested that functional variants in PSMB9 may contribute to melanoma susceptibility., (© 2013 John Wiley & Sons A/S.)
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- 2013
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36. MC1R genotypes and risk of melanoma before age 40 years: a population-based case-control-family study.
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Cust AE, Goumas C, Holland EA, Agha-Hamilton C, Aitken JF, Armstrong BK, Giles GG, Kefford RF, Schmid H, Hopper JL, Mann GJ, and Jenkins MA
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- Adolescent, Adult, Alleles, Australia, Base Sequence, Case-Control Studies, Family, Female, Genes, Regulator, Genetic Variation, Genotype, Humans, Male, Melanins biosynthesis, Melanoma epidemiology, Risk, Sequence Analysis, DNA, Skin Neoplasms epidemiology, Surveys and Questionnaires, Young Adult, Genetic Predisposition to Disease, Melanoma genetics, Receptor, Melanocortin, Type 1 genetics, Skin Neoplasms genetics
- Abstract
The contribution of melanocortin-1 receptor (MC1R) gene variants to the development of early-onset melanoma is unknown. Using an Australian population-based, case-control-family study, we sequenced MC1R for 565 cases with invasive cutaneous melanoma diagnosed between ages 18 and 39 years, 409 unrelated controls and 518 sibling controls. Variants were classified a priori into "R" variants (D84E, R142H, R151C, I155T, R160W, D294H) and "r" variants (all other nonsynonymous variants). We estimated odds ratios (OR) for melanoma using unconditional (unrelated controls) and conditional (sibling controls) logistic regression. The prevalence of having at least one R or r variant was 86% for cases, 73% for unrelated controls and 81% for sibling controls. R151C conferred the highest risk (per allele OR 2.57, 95% confidence interval 1.86-3.56 for the case-unrelated-control analysis and 1.70 (1.12-2.60) for the case-sibling-control analysis). When mutually adjusted, the ORs per R allele were 2.23 (1.77-2.80) and 2.06 (1.47-2.88), respectively, from the two types of analysis, and the ORs per r allele were 1.69 (1.33-2.13) and 1.25 (0.88-1.79), respectively. The associations were stronger for men and those with none or few nevi or with high childhood sun exposure. Adjustment for phenotype, nevi and sun exposure attenuated the overall log OR for R variants by approximately 18% but had lesser influence on r variant risk estimates. MC1R variants explained about 21% of the familial aggregation of melanoma. Some MC1R variants are important determinants of early-onset melanoma. The strength of association with melanoma differs according to the type and number of variants., (Copyright © 2011 UICC.)
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- 2012
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37. Sunbed use during adolescence and early adulthood is associated with increased risk of early-onset melanoma.
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Cust AE, Armstrong BK, Goumas C, Jenkins MA, Schmid H, Hopper JL, Kefford RF, Giles GG, Aitken JF, and Mann GJ
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- Adolescent, Adult, Age of Onset, Australia epidemiology, Case-Control Studies, Female, Humans, Male, Odds Ratio, Risk Factors, Melanoma epidemiology, Skin Neoplasms epidemiology, Sunbathing
- Abstract
Sunbed use is associated with increased risk of melanoma. Younger people might be more susceptible to the carcinogenic effects of ultraviolet radiation. We investigated the association between sunbed use and risk of early-onset cutaneous malignant melanoma. From the Australian Melanoma Family Study, a multicentre, population-based, case-control-family study, we analysed data for 604 cases diagnosed between ages 18 and 39 years and 479 controls. Data were collected by interview. Associations were estimated as odds ratios (ORs) using unconditional logistic regression, adjusting for age, sex, city, education, family history, skin color, usual skin response to sunlight and sun exposure. Compared with having never used a sunbed, the OR for melanoma associated with ever-use was 1.41 (95% confidence interval (CI) 1.01-1.96), and 2.01 (95% CI 1.22-3.31) for more than 10 lifetime sessions (P(trend) 0.01 with cumulative use). The association was stronger for earlier age at first use (P(trend) 0.02). The association was also stronger for melanoma diagnosed when aged 18-29 years (OR for more than 10 lifetime sessions = 6.57, 95% CI 1.41-30.49) than for melanoma diagnosed when 30-39 years (OR 1.60, 95% CI 0.92-2.77; P(interaction) 0.01). Among those who had ever used a sunbed and were diagnosed between 18 and 29 years of age, three quarters (76%) of melanomas were attributable to sunbed use. Sunbed use is associated with increased risk of early-onset melanoma, with risk increasing with greater use, an earlier age at first use and for earlier onset disease., (Copyright © 2010 UICC.)
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- 2011
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38. Population-based, case-control-family design to investigate genetic and environmental influences on melanoma risk: Australian Melanoma Family Study.
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Cust AE, Schmid H, Maskiell JA, Jetann J, Ferguson M, Holland EA, Agha-Hamilton C, Jenkins MA, Kelly J, Kefford RF, Giles GG, Armstrong BK, Aitken JF, Hopper JL, and Mann GJ
- Subjects
- Adolescent, Adult, Age Factors, Australia epidemiology, Case-Control Studies, Female, Genetic Predisposition to Disease, Humans, Male, Melanoma genetics, Middle Aged, Phenotype, Residence Characteristics, Risk Factors, Skin Neoplasms genetics, Socioeconomic Factors, Sunlight adverse effects, Young Adult, Environment, Melanoma epidemiology, Melanoma etiology, Skin Neoplasms epidemiology, Skin Neoplasms etiology
- Abstract
Discovering and understanding genetic risk factors for melanoma and their interactions with phenotype, sun exposure, and other risk factors could lead to new strategies for melanoma control. This paper describes the Australian Melanoma Family Study, which uses a multicenter, population-based, case-control-family design. From 2001 to 2005, the authors recruited 1,164 probands including 629 cases with histopathologically confirmed, first-primary cutaneous melanoma diagnosed before age 40 years, 240 population-based controls frequency matched for age, and 295 spouse/friend controls. Information on lifetime sun exposure, phenotype, and residence history was collected for probands and nearly 4,000 living relatives. More than 3,000 subjects donated a blood sample. Proxy-reported information was collected for childhood sun exposure and deceased relatives. Important features of this study include the population-based, family-based design; a focus on early onset disease; probands from 3 major cities differing substantially in solar ultraviolet exposure and melanoma incidence; a population at high risk because of high ultraviolet exposure and susceptible pigmentation phenotypes; population-based, spouse/friend, and sibling controls; systematic recruitment of relatives of case and control probands; self and parent reports of childhood sun exposure; and objective clinical skin examinations. The authors discuss methodological and analytical issues related to the study design and conduct, as well as the potentially novel insights the study can deliver.
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- 2009
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39. Genetic testing for melanoma risk: a prospective cohort study of uptake and outcomes among Australian families.
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Kasparian NA, Meiser B, Butow PN, Simpson JM, and Mann GJ
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- Adolescent, Adult, Australia epidemiology, Cohort Studies, Cyclin-Dependent Kinase Inhibitor p16 genetics, Family Health, Female, Genetic Testing, Heterozygote, Humans, Logistic Models, Male, Melanoma epidemiology, Melanoma psychology, Middle Aged, Mutation, Prospective Studies, Risk Factors, Social Class, Young Adult, Genetic Counseling methods, Melanoma genetics, Surveys and Questionnaires
- Abstract
Purpose: The aim of this prospective cohort study was to examine uptake and psychological, behavioral, and cognitive outcomes of genetic testing for melanoma risk among individuals with a known family-specific CDKN2A mutation., Methods: A total of 119 individuals were ascertained via a genetic epidemiological study and completed a series of mailed, self-administered questionnaires at multiple time points, including notification of genetic test availability, and 2 weeks and 12 months after receipt of genetic test results (for "test participants"), or 12 months after notification (for "decliners")., Results: Since January 2005, 21% of participants (n = 25) have undergone genetic testing, with 75% of those who have received results identified as mutation carriers (n = 15). Factors associated with uptake of genetic counseling included perceived susceptibility to melanoma (odds ratio = 3.60, P = 0.0008), and fatalistic beliefs about melanoma (odds ratio = 0.57, P = 0.005). Compared with baseline, carriers reported significantly reduced anxiety scores at 2 weeks, and reduced depression scores at 2 weeks and 12 months, after receipt of genetic test results. Carriers also reported a significantly greater frequency of clinical skin examination at 12-month follow-up compared with decliners (chi2 = 5.70, P = 0.02). No hypothesis testing was carried out for noncarriers because of their limited number., Conclusion: These data provide preliminary evidence for healthy psychological, behavioral, and cognitive adjustment after participation in genetic testing for melanoma risk.
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- 2009
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40. High- and average-risk individuals' beliefs about, and perceptions of, malignant melanoma: an Australian perspective.
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Kasparian NA, Butow PN, Meiser B, and Mann GJ
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- Adaptation, Psychological, Adult, Affect, Australia epidemiology, Female, Genetic Predisposition to Disease epidemiology, Heliotherapy statistics & numerical data, Humans, Interviews as Topic, Male, Melanoma psychology, Middle Aged, Psychology, Risk Factors, Skin Neoplasms genetics, Attitude to Health, Culture, Health Behavior, Melanoma epidemiology, Melanoma genetics, Skin Neoplasms epidemiology, Skin Neoplasms etiology
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Despite expanding knowledge regarding the genetics of melanoma, there have been few attempts to define the psychosocial experiences of individuals with a family history of this disease. This study explored the ways in which individuals at varying levels of risk perceive, and respond to, melanoma. Forty semi-structured interviews were undertaken with affected (n = 20) and unaffected (n = 20) individuals with or without a family history of melanoma. Data were analysed for potential thematic differences between risk groups, genders, and intentions to pursue genetic testing for melanoma risk. Overall, participants with a family history were in acceptance of their increased risk status and had developed ways of coping without major disruption to their daily lives. However, some participants expressed ambiguity regarding the causes of melanoma and the effectiveness of health behaviours such as sun protection. Major thematic patterns identified for those intending to pursue genetic testing were: negative emotional associations with melanoma; an emphasis on screening and sun avoidance, but not sun protection; and heightened perceptions of personal susceptibility to melanoma. In contrast, thematic patterns identified for those likely to decline testing were: ready access to stories of melanoma survival; and an emphasis on the causal role of sun exposure, whilst still believing that genetic factors may contribute to melanoma susceptibility. Compared to males, females reported a greater tendency to completely avoid the sun in order to reduce their melanoma risk. The data provide preliminary evidence for the importance of identifying misconceptions that may impede informed decision-making about genetic testing for melanoma risk., ((c) 2007 John Wiley & Sons, Ltd)
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- 2008
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41. Is MSH2 a breast cancer susceptibility gene?
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Wong EM, Tesoriero AA, Pupo GM, McCredie MR, Giles GG, Hopper JL, Mann GJ, Goldgar DE, and Southey MC
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- Australia epidemiology, Breast Neoplasms epidemiology, Case-Control Studies, DNA Mismatch Repair, Female, Genetic Predisposition to Disease, Humans, Middle Aged, Mutation, Registries, Risk Assessment, Risk Factors, Breast Neoplasms genetics, MutS Homolog 2 Protein genetics
- Abstract
Mutations in the DNA mismatch repair gene MSH2 lead to increased replication error and microsatellite instability and account for a substantial proportion of hereditary non-polyposis colorectal cancer (Lynch syndrome). A recent international collaborative genome-wide linkage scan (GWS) for breast cancer susceptibility loci found some evidence for there being a breast cancer susceptibility gene in a genomic region on chromosome 2p close to MSH2. We sought to investigate the possibility that mutations in MSH2 might explain the multiple cases of breast cancer in some families that were included in the international GWS. DNA samples from the affected probands of 59 multiple-case breast cancer families, many of whom gave LOD scores >0.5 in the MSH2 region, were screened for large genomic alterations in MSH2 via the Multiplex Ligation-dependent Probe Amplification (MLPA) assay and for coding region mutations via exonic sequencing. Several of the families also contained cases of colorectal cancer in addition to breast cancer and had been included in the GWS that had identified a positive LOD score on chromosome 2p. Using MLPA, c.1236C > T was identified in one proband but this variant was not predicted to create an alternate acceptor/donor site within exon 7 MSH2 using in silico analyses. A c.1734T > C was identified in a second proband via exonic sequencing but testing of the variant in other family members did not support segregation of this variant with disease. Extensive screening of 59 multiple-case breast cancer families did not identify any coding region mutations or larger genomic alterations in MSH2 that might implicate MSH2 as a breast cancer susceptibility gene.
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- 2008
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42. Low prevalence of RAS-RAF-activating mutations in Spitz melanocytic nevi compared with other melanocytic lesions.
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Indsto JO, Kumar S, Wang L, Crotty KA, Arbuckle SM, and Mann GJ
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- Adolescent, Australia epidemiology, Cell Line, Tumor, Child, Preschool, DNA Mutational Analysis, DNA, Neoplasm analysis, Female, Gene Expression Regulation, Neoplastic, Humans, Male, Melanoma epidemiology, Melanoma secondary, Nevus, Epithelioid and Spindle Cell epidemiology, Nevus, Epithelioid and Spindle Cell pathology, Prevalence, Proto-Oncogene Proteins B-raf metabolism, Skin Neoplasms epidemiology, Skin Neoplasms pathology, Genes, ras, Melanoma genetics, Mutation, Nevus, Epithelioid and Spindle Cell genetics, Proto-Oncogene Proteins B-raf genetics, Skin Neoplasms genetics
- Abstract
Melanocytic lesions, including Spitz nevi (SN), common benign nevi (CBN) and cutaneous metastatic melanoma (CMM), were analyzed for activating mutations in NRAS, HRAS and BRAF oncogenes, which induce cellular proliferation via the MAP kinase pathway. One of 22 (4.5%) SN tested showed an HRAS G61L mutation. Another lesion, a 'halo' SN, showed a BRAF V600E (T1796A) mutation. BRAF V600E mutations were found in two thirds (20/31) of CBN, while a further 19% (6/31) showed NRAS codon 61 mutations. One third of CMM (10/30) had various BRAF mutations of codon 600, and a further 6% (2/31) showed NRAS codon 61 mutations. Seventeen SN tested for loss of heterozygosity (LOH) at 9p and 10q regions, known to be frequently deleted in melanoma, showed LOH at the 9p loci D9S942 and IFNA. A further lesion was found with low-level microsatellite instability at one locus, D10S214. The low rate of RAS-RAF mutations (2/22, 9.1%) observed in SN suggests that these lesions harbor as yet undetected activating mutations in other components of the RAS-RAF-MEK-ERK-MAPK pathway. Germline DNA from members of 111 multiple-case melanoma families, representing a range of known (CDKN2A) and unknown predisposing gene defects, was analyzed for germline BRAF mutations, but none was found.
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- 2007
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43. Features associated with germline CDKN2A mutations: a GenoMEL study of melanoma-prone families from three continents.
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Goldstein AM, Chan M, Harland M, Hayward NK, Demenais F, Bishop DT, Azizi E, Bergman W, Bianchi-Scarra G, Bruno W, Calista D, Albright LA, Chaudru V, Chompret A, Cuellar F, Elder DE, Ghiorzo P, Gillanders EM, Gruis NA, Hansson J, Hogg D, Holland EA, Kanetsky PA, Kefford RF, Landi MT, Lang J, Leachman SA, MacKie RM, Magnusson V, Mann GJ, Bishop JN, Palmer JM, Puig S, Puig-Butille JA, Stark M, Tsao H, Tucker MA, Whitaker L, and Yakobson E
- Subjects
- Australia epidemiology, Europe epidemiology, Female, Genetic Variation, Humans, Incidence, Male, Melanoma epidemiology, North America epidemiology, Skin Neoplasms epidemiology, Cyclin-Dependent Kinase Inhibitor p16 genetics, Germ-Line Mutation, Melanoma genetics, Skin Neoplasms genetics
- Abstract
Background: The major factors individually reported to be associated with an increased frequency of CDKN2A mutations are increased number of patients with melanoma in a family, early age at melanoma diagnosis, and family members with multiple primary melanomas (MPM) or pancreatic cancer., Methods: These four features were examined in 385 families with > or =3 patients with melanoma pooled by 17 GenoMEL groups, and these attributes were compared across continents., Results: Overall, 39% of families had CDKN2A mutations ranging from 20% (32/162) in Australia to 45% (29/65) in North America to 57% (89/157) in Europe. All four features in each group, except pancreatic cancer in Australia (p = 0.38), individually showed significant associations with CDKN2A mutations, but the effects varied widely across continents. Multivariate examination also showed different predictors of mutation risk across continents. In Australian families, > or =2 patients with MPM, median age at melanoma diagnosis < or =40 years and > or =6 patients with melanoma in a family jointly predicted the mutation risk. In European families, all four factors concurrently predicted the risk, but with less stringent criteria than in Australia. In North American families, only > or =1 patient with MPM and age at diagnosis < or =40 years simultaneously predicted the mutation risk., Conclusions: The variation in CDKN2A mutations for the four features across continents is consistent with the lower melanoma incidence rates in Europe and higher rates of sporadic melanoma in Australia. The lack of a pancreatic cancer-CDKN2A mutation relationship in Australia probably reflects the divergent spectrum of mutations in families from Australia versus those from North America and Europe. GenoMEL is exploring candidate host, genetic and/or environmental risk factors to better understand the variation observed.
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- 2007
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44. Anticipated uptake of genetic testing for familial melanoma in an Australian sample: An exploratory study.
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Kasparian NA, Meiser B, Butow PN, Soames Job RF, and Mann GJ
- Subjects
- Adult, Aged, Attitude to Health, Australia, Female, Genetic Predisposition to Disease psychology, Humans, Male, Melanoma epidemiology, Melanoma psychology, Middle Aged, Patient Acceptance of Health Care statistics & numerical data, Risk Assessment statistics & numerical data, Skin Neoplasms epidemiology, Skin Neoplasms psychology, Genetic Predisposition to Disease genetics, Genetic Testing psychology, Melanoma genetics, Patient Acceptance of Health Care psychology, Skin Neoplasms genetics
- Abstract
Introduction: The potential role of genetic testing in families with an inherited pattern of melanoma is a complex issue, and yet limited data exist on perceptions of predictive genetic testing for mutations among individuals at high risk of melanoma., Methodology: Forty semi-structured interviews were undertaken with affected and unaffected individuals at either high or average risk of developing melanoma due to family history. Interviews addressed key issues such as: the role of genetics in causal attributions for melanoma; genetic testing intentions and motivations; perceived accuracy of genetic testing in predicting melanoma onset, and the impact of varied accuracy on testing intentions; views on the testing of children; perceived benefits and limitations of testing; and information needs and communication preferences., Results: In-depth thematic analysis revealed a number of important qualitative differences between groups at varying risk of melanoma, and genders. Specifically, participants with a family history of melanoma believed genetic factors play an important role in melanoma causation; conveyed strong intentions to pursue genetic testing; and viewed the benefits of genetic testing as outweighing the limitations. Females appeared to endorse the testing of children more firmly than males, and males' intentions to pursue testing appeared more contingent on penetrance than females'. Across groups, the most preferred communication option was an informational video., Conclusion: Those at high risk of melanoma due to family history express a strong interest in predictive genetic testing., (Copyright 2006 John Wiley & Sons, Ltd.)
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- 2007
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45. Analysis of cancer risk and BRCA1 and BRCA2 mutation prevalence in the kConFab familial breast cancer resource.
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Mann GJ, Thorne H, Balleine RL, Butow PN, Clarke CL, Edkins E, Evans GM, Fereday S, Haan E, Gattas M, Giles GG, Goldblatt J, Hopper JL, Kirk J, Leary JA, Lindeman G, Niedermayr E, Phillips KA, Picken S, Pupo GM, Saunders C, Scott CL, Spurdle AB, Suthers G, Tucker K, and Chenevix-Trench G
- Subjects
- Adult, Age of Onset, Aged, Aged, 80 and over, Algorithms, Australia, Cohort Studies, DNA Mutational Analysis, Data Collection, Epidemiologic Studies, Female, Germ-Line Mutation, Humans, Life Style, Middle Aged, New Zealand, Pedigree, Research organization & administration, Risk Factors, Specimen Handling, Breast Neoplasms genetics, Genes, BRCA1, Genes, BRCA2, Ovarian Neoplasms genetics, Tissue Banks
- Abstract
Introduction: The Kathleen Cuningham Foundation Consortium for Research into Familial Breast Cancer (kConFab) is a multidisciplinary, collaborative framework for the investigation of familial breast cancer. Based in Australia, the primary aim of kConFab is to facilitate high-quality research by amassing a large and comprehensive resource of epidemiological and clinical data with biospecimens from individuals at high risk of breast and/or ovarian cancer, and from their close relatives., Methods: Epidemiological, family history and lifestyle data, as well as biospecimens, are collected from multiple-case breast cancer families ascertained through family cancer clinics in Australia and New Zealand. We used the Tyrer-Cuzick algorithms to assess the prospective risk of breast cancer in women in the kConFab cohort who were unaffected with breast cancer at the time of enrolment in the study., Results: Of kConFab's first 822 families, 518 families had multiple cases of female breast cancer alone, 239 had cases of female breast and ovarian cancer, 37 had cases of female and male breast cancer, and 14 had both ovarian cancer as well as male and female breast cancer. Data are currently held for 11,422 people and germline DNAs for 7,389. Among the 812 families with at least one germline sample collected, the mean number of germline DNA samples collected per family is nine. Of the 747 families that have undergone some form of mutation screening, 229 (31%) carry a pathogenic or splice-site mutation in BRCA1 or BRCA2. Germline DNAs and data are stored from 773 proven carriers of BRCA1 or BRCA1 mutations. kConFab's fresh tissue bank includes 253 specimens of breast or ovarian tissue--both normal and malignant--including 126 from carriers of BRCA1 or BRCA2 mutations., Conclusion: These kConFab resources are available to researchers anywhere in the world, who may apply to kConFab for biospecimens and data for use in ethically approved, peer-reviewed projects. A high calculated risk from the Tyrer-Cuzick algorithms correlated closely with the subsequent occurrence of breast cancer in BRCA1 and BRCA2 mutation positive families, but this was less evident in families in which no pathogenic BRCA1 or BRCA2 mutation has been detected.
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- 2006
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46. Localization of a novel melanoma susceptibility locus to 1p22.
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Gillanders E, Juo SH, Holland EA, Jones M, Nancarrow D, Freas-Lutz D, Sood R, Park N, Faruque M, Markey C, Kefford RF, Palmer J, Bergman W, Bishop DT, Tucker MA, Bressac-de Paillerets B, Hansson J, Stark M, Gruis N, Bishop JN, Goldstein AM, Bailey-Wilson JE, Mann GJ, Hayward N, and Trent J
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- Adolescent, Adult, Age of Onset, Aged, Australia, Child, Chromosome Mapping, Humans, Lod Score, Middle Aged, Pedigree, Chromosomes, Human, Pair 1 genetics, Melanoma genetics, Skin Neoplasms genetics
- Abstract
Over the past 20 years, the incidence of cutaneous malignant melanoma (CMM) has increased dramatically worldwide. A positive family history of the disease is among the most established risk factors for CMM; it is estimated that 10% of CMM cases result from an inherited predisposition. Although mutations in two genes, CDKN2A and CDK4, have been shown to confer an increased risk of CMM, they account for only 20%-25% of families with multiple cases of CMM. Therefore, to localize additional loci involved in melanoma susceptibility, we have performed a genomewide scan for linkage in 49 Australian pedigrees containing at least three CMM cases, in which CDKN2A and CDK4 involvement has been excluded. The highest two-point parametric LOD score (1.82; recombination fraction [theta] 0.2) was obtained at D1S2726, which maps to the short arm of chromosome 1 (1p22). A parametric LOD score of 4.65 (theta=0) and a nonparametric LOD score of 4.19 were found at D1S2779 in nine families selected for early age at onset. Additional typing yielded seven adjacent markers with LOD scores >3 in this subset, with the highest parametric LOD score, 4.95 (theta=0) (nonparametric LOD score 5.37), at D1S2776. Analysis of 33 additional multiplex families with CMM from several continents provided further evidence for linkage to the 1p22 region, again strongest in families with the earliest mean age at diagnosis. A nonparametric ordered sequential analysis was used, based on the average age at diagnosis in each family. The highest LOD score, 6.43, was obtained at D1S2779 and occurred when the 15 families with the earliest ages at onset were included. These data provide significant evidence of a novel susceptibility gene for CMM located within chromosome band 1p22.
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- 2003
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47. Geographical variation in the penetrance of CDKN2A mutations for melanoma.
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Bishop DT, Demenais F, Goldstein AM, Bergman W, Bishop JN, Bressac-de Paillerets B, Chompret A, Ghiorzo P, Gruis N, Hansson J, Harland M, Hayward N, Holland EA, Mann GJ, Mantelli M, Nancarrow D, Platz A, and Tucker MA
- Subjects
- Australia, Europe, Family, Genes, p16, Genetic Variation, Geography, Humans, Melanoma epidemiology, Risk Factors, United States, Cyclin-Dependent Kinase Inhibitor p16 genetics, Genetic Predisposition to Disease, Melanoma genetics, Mutation
- Abstract
Background: Germline mutations in the CDKN2A gene, which encodes two proteins (p16INK4A and p14ARF), are the most common cause of inherited susceptibility to melanoma. We examined the penetrance of such mutations using data from eight groups from Europe, Australia and the United States that are part of The Melanoma Genetics Consortium., Methods: We analyzed 80 families with documented CDKN2A mutations and multiple cases of cutaneous melanoma. We modeled penetrance for melanoma using a logistic regression model incorporating survival analysis. Hypothesis testing was based on likelihood ratio tests. Covariates included gender, alterations in p14ARF protein, and population melanoma incidence rates. All statistical tests were two-sided., Results: The 80 analyzed families contained 402 melanoma patients, 320 of whom were tested for mutations and 291 were mutation carriers. We also tested 713 unaffected family members for mutations and 194 were carriers. Overall, CDKN2A mutation penetrance was estimated to be 0.30 (95% confidence interval (CI) = 0.12 to 0.62) by age 50 years and 0.67 (95% CI = 0.31 to 0.96) by age 80 years. Penetrance was not statistically significantly modified by gender or by whether the CDKN2A mutation altered p14ARF protein. However, there was a statistically significant effect of residing in a location with a high population incidence rate of melanoma (P =.003). By age 50 years CDKN2A mutation penetrance reached 0.13 in Europe, 0.50 in the United States, and 0.32 in Australia; by age 80 years it was 0.58 in Europe, 0.76 in the United States, and 0.91 in Australia., Conclusions: This study, which gives the most informed estimates of CDKN2A mutation penetrance available, indicates that the penetrance varies with melanoma population incidence rates. Thus, the same factors that affect population incidence of melanoma may also mediate CDKN2A penetrance.
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- 2002
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48. Evaluation of linkage of breast cancer to the putative BRCA3 locus on chromosome 13q21 in 128 multiple case families from the Breast Cancer Linkage Consortium.
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Thompson D, Szabo CI, Mangion J, Oldenburg RA, Odefrey F, Seal S, Barfoot R, Kroeze-Jansema K, Teare D, Rahman N, Renard H, Mann G, Hopper JL, Buys SS, Andrulis IL, Senie R, Daly MB, West D, Ostrander EA, Offit K, Peretz T, Osorio A, Benitez J, Nathanson KL, Sinilnikova OM, Olàh E, Bignon YJ, Ruiz P, Badzioch MD, Vasen HF, Futreal AP, Phelan CM, Narod SA, Lynch HT, Ponder BA, Eeles RA, Meijers-Heijboer H, Stoppa-Lyonnet D, Couch FJ, Eccles DM, Evans DG, Chang-Claude J, Lenoir G, Weber BL, Devilee P, Easton DF, Goldgar DE, and Stratton MR
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- Australia, Europe, Female, Humans, Lod Score, North America, Breast Neoplasms genetics, Chromosomes, Human, Pair 13 genetics, Genes, Tumor Suppressor, Genetic Linkage
- Abstract
The known susceptibility genes for breast cancer, including BRCA1 and BRCA2, only account for a minority of the familial aggregation of the disease. A recent study of 77 multiple case breast cancer families from Scandinavia found evidence of linkage between the disease and polymorphic markers on chromosome 13q21. We have evaluated the contribution of this candidate "BRCA3" locus to breast cancer susceptibility in 128 high-risk breast cancer families of Western European ancestry with no identified BRCA1 or BRCA2 mutations. No evidence of linkage was found. The estimated proportion (alpha) of families linked to a susceptibility locus at D13S1308, the location estimated by Kainu et al. [(2000) Proc. Natl. Acad. Sci. USA 97, 9603-9608], was 0 (upper 95% confidence limit 0.13). Adjustment for possible bias due to selection of families on the basis of linkage evidence at BRCA2 did not materially alter this result (alpha = 0, upper 95% confidence limit 0.18). The proportion of linked families reported by Kainu et al. (0.65) is excluded with a high degree of confidence in our dataset [heterogeneity logarithm of odds (HLOD) at alpha = 0.65 was -11.0]. We conclude that, if a susceptibility gene does exist at this locus, it can only account for a small proportion of non-BRCA1/2 families with multiple cases of early-onset breast cancer.
- Published
- 2002
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