Publications by authors named "Peter A Kanetsky"

142 Publications

Impact of personal genomic risk information on melanoma prevention behaviors and psychological outcomes: a randomized controlled trial.

Genet Med 2021 Aug 12. Epub 2021 Aug 12.

The Daffodil Centre, The University of Sydney, a joint venture with Cancer Council NSW, NSW, Sydney, Australia.

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.
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http://dx.doi.org/10.1038/s41436-021-01292-wDOI Listing
August 2021

Identification of 22 susceptibility loci associated with testicular germ cell tumors.

Nat Commun 2021 07 23;12(1):4487. Epub 2021 Jul 23.

Institute of Human Genetics, University Medical Center Hamburg-Eppendorf, Hamburg, Germany.

Testicular germ cell tumors (TGCT) are the most common tumor in young white men and have a high heritability. In this study, the international Testicular Cancer Consortium assemble 10,156 and 179,683 men with and without TGCT, respectively, for a genome-wide association study. This meta-analysis identifies 22 TGCT susceptibility loci, bringing the total to 78, which account for 44% of disease heritability. Men with a polygenic risk score (PRS) in the 95 percentile have a 6.8-fold increased risk of TGCT compared to men with median scores. Among men with independent TGCT risk factors such as cryptorchidism, the PRS may guide screening decisions with the goal of reducing treatment-related complications causing long-term morbidity in survivors. These findings emphasize the interconnected nature of two known pathways that promote TGCT susceptibility: male germ cell development within its somatic niche and regulation of chromosomal division and structure, and implicate an additional biological pathway, mRNA translation.
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http://dx.doi.org/10.1038/s41467-021-24334-yDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8302763PMC
July 2021

A Randomized Trial of Precision Prevention Materials to Improve Primary and Secondary Melanoma Prevention Activities among Individuals with Limited Melanoma Risk Phenotypes.

Cancers (Basel) 2021 Jun 23;13(13). Epub 2021 Jun 23.

Department of Cancer Epidemiology, H. Lee Moffitt Cancer Center & Research Institute, Tampa, FL 33612, USA.

Inherited variation at is associated with elevated melanoma risk among non-Hispanic whites (NHWs). genetic testing may unmask previously unrecognized disease risk, especially among individuals with few melanoma phenotypic risk factors. We recruited NHW individuals with limited phenotypic risk factors from two primary care clinics in west-central Florida. Participants ( = 1134) were randomized within genotype risk group (average/higher) to receive mailed precision prevention (i.e., intervention) or generic prevention materials. Participants reported hours of weekday and weekend sun exposure, frequency of intentional outdoor tanning and sun protection behaviors, number of sunburns, indoor tanning episodes, and skin examinations at baseline, and after 6 and 12 months. Among higher-risk participants, the intervention increased the likelihood of often or always wearing a shirt with sleeves (OR = 1.49, = 0.03) and seeking shade or using an umbrella (OR = 1.42, = 0.046), and it decreased the number of sunburns among their young children (β = -0.13, = 0.03). Intervention effects were not noted among average-risk participants. Moderation analyses identified intervention effects within subgroups in average-risk and higher-risk participants. Precision prevention information conveying testing results can increase the practice of some sun protection behaviors among at-risk individuals with limited melanoma risk phenotypes and may provide a cross-generational tool to counteract increasing incidence of melanoma.
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http://dx.doi.org/10.3390/cancers13133143DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8267659PMC
June 2021

Sun Exposure, Tanning Behaviors, and Sunburn: Examining Activities Associated With Harmful Ultraviolet Radiation Exposures in College Students.

J Prim Prev 2021 Oct 21;42(5):425-440. Epub 2021 Jun 21.

Department of Psychiatry & Behavioral Sciences, Memorial Sloan Kettering Cancer Center, New York, NY, 10022, USA.

Understanding the behaviors that lead to sunburn is an important objective toward developing intervention strategies to reduce risk for skin cancers. Our cross-sectional study surveyed 400 college students aged 18 and older at a public state university in the northeastern US in 2018 to assess tanning behaviors, outdoor activities, sun protection, and sunburn over the past year. Sunburn was exceedingly common; over half reported one or more sunburns in the past 12 months. Outdoor intentional and unintentional tanning were also common. Male sex, White race, sun sensitive skin type, and outdoor intentional and unintentional tanning were independently associated with increased odds of sunburn. Water and non-water sports, sunbathing, and vacations were also associated with sunburn. These results indicate that tanning and outdoor activities such as sports are important behaviors on which to focus for sunburn prevention among college students. Understanding the behaviors that are associated with sunburn provides useful opportunities to prevent skin cancer among young people.
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http://dx.doi.org/10.1007/s10935-021-00638-zDOI Listing
October 2021

Morphologic and molecular correlates of EZH2 as a predictor of platinum resistance in high-grade ovarian serous carcinoma.

BMC Cancer 2021 Jun 17;21(1):714. Epub 2021 Jun 17.

Department of Pathology, Moffitt Cancer Center, 12902 USF Magnolia Dr, Tampa, FL, 33612, USA.

Background: Enhancer of zesta homologue 2 (EZH2) is an essential component of polycomb repressive complex 2 (PRC2) that contributes to tumor progression and chemo-resistance. The aim of this study was to comprehensively assess the prognostic value of EZH2 across the morphologic and molecular spectra of high-grade serous ovarian carcinoma (HGSOC) by utilizing both immunohistochemistry (IHC) and proteogenomic technologies.

Methods: IHC of EZH2 was performed using a tissue microarray of 79 HGSOC scored (+/-) for lymphovascular invasion (LVI), tumor-infiltrating lymphocytic aggregates ≥1 mm (TIL) and architectural growth patterns. The association of EZH2 H-score with response to therapy and overall survival was evaluated by tumor features. We also evaluated EZH2 transcriptional (RNA sequencing) and protein (mass spectrometry) expression from bulk tumor samples from 336 HGSOC from The Cancer Genome Atlas (TCGA). EZH2 expression and co-expression networks were compared by clinical outcomes.

Results: For HGSOC without TIL (58%), EZH2 expression was almost 2-fold higher in platinum resistant tumors (P = 0.01). Conversely, EZH2 was not associated with platinum resistance among TIL+ HGSOC (P = 0.41). EZH2 expression was associated with reduced survival for tumors with LVI (P = 0.04). Analysis of TCGA found higher EZH2 expression in immunoreactive and proliferative tumors (P = 6.7 × 10) although protein levels were similar across molecular subtypes (P = 0.52). Both mRNA and protein levels of EZH2 were lower in platinum resistant tumors although they were not associated with survival. Co-expression analysis revealed EZH2 networks totaling 1049 mRNA and 448 proteins that were exclusive to platinum sensitive or resistant tumors. The EZH2 network in resistant HGSOC included CARM1 which was positively correlated with EZH2 at both mRNA (r = 0.33, p = 0.003) and protein (r = 0.14, P = 0.01) levels. Further, EZH2 co-expression with CARM1 corresponded to a decreased prognostic significance of EZH2 expression in resistant tumors.

Conclusions: Our findings demonstrate that EZH2 expression varies based on its interactions with immunologic pathways and tumor microenvironment, impacting the prognostic interpretation. The association between high EZH2 expression and platinum resistance in TIL- HGSOC warrants further study of the implications for therapeutic strategies.
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http://dx.doi.org/10.1186/s12885-021-08413-3DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8212453PMC
June 2021

Birth cohort-specific trends of sun-related behaviors among individuals from an international consortium of melanoma-prone families.

BMC Public Health 2021 04 23;21(1):692. Epub 2021 Apr 23.

Department of Dermatology, Leiden University Medical Centre, Leiden, The Netherlands.

Background: Individuals from melanoma-prone families have similar or reduced sun-protective behaviors compared to the general population. Studies on trends in sun-related behaviors have been temporally and geographically limited.

Methods: Individuals from an international consortium of melanoma-prone families (GenoMEL) were retrospectively asked about sunscreen use, sun exposure (time spent outside), sunburns, and sunbed use at several timepoints over their lifetime. Generalized linear mixed models were used to examine the association between these outcomes and birth cohort defined by decade spans, after adjusting for covariates.

Results: A total of 2407 participants from 547 families across 17 centers were analyzed. Sunscreen use increased across subsequent birth cohorts, and although the likelihood of sunburns increased until the 1950s birth cohort, it decreased thereafter. Average sun exposure did not change across the birth cohorts, and the likelihood of sunbed use increased in more recent birth cohorts. We generally did not find any differences in sun-related behavior when comparing melanoma cases to non-cases. Melanoma cases had increased sunscreen use, decreased sun exposure, and decreased odds of sunburn and sunbed use after melanoma diagnosis compared to before diagnosis.

Conclusions: Although sunscreen use has increased and the likelihood of sunburns has decreased in more recent birth cohorts, individuals in melanoma-prone families have not reduced their overall sun exposure and had an increased likelihood of sunbed use in more recent birth cohorts. These observations demonstrate partial improvements in melanoma prevention and suggest that additional intervention strategies may be needed to achieve optimal sun-protective behavior in melanoma-prone families.
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http://dx.doi.org/10.1186/s12889-021-10424-5DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8063451PMC
April 2021

Genetically Inferred Telomere Length and Testicular Germ Cell Tumor Risk.

Cancer Epidemiol Biomarkers Prev 2021 06 18;30(6):1275-1278. Epub 2021 Mar 18.

Division of Cancer Epidemiology and Genetics, NCI, Rockville, Maryland.

Background: Studies evaluating the association between peripheral blood leukocyte telomere length (LTL) and testicular germ cell tumor (TGCT) risk have produced conflicting results.

Methods: Using available genotype data from the Testicular Cancer Consortium (TECAC), polygenic risk score and Mendelian randomization analyses of genetic variants previously associated with LTL were used to assess potential etiologic associations between telomere length and TGCT risk.

Results: Genetically inferred telomere length was not associated with TGCT risk among 2,049 cases and 6,921 controls with individual-level genotype data (OR, 1.02; 95% confidence interval, 0.97-1.07). Mendelian randomization analyses using summary statistic data further indicated no evidence for an association between telomere length and TGCT risk among all available TECAC participants (3,558 cases and 13,971 controls).

Conclusions: Our analyses in the largest molecular genetic testicular cancer study to date provide no evidence for an association between genetically inferred peripheral blood LTL and TGCT risk.

Impact: The lack of evidence for an overall association indicates that peripheral blood LTL is likely not a strong biomarker for TGCT risk.
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http://dx.doi.org/10.1158/1055-9965.EPI-20-1775DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8172526PMC
June 2021

Lower abdominal and pelvic radiation and testicular germ cell tumor risk.

PLoS One 2020 11;15(11):e0239321. Epub 2020 Nov 11.

Department of Cancer Epidemiology, H. Lee Moffitt Cancer Center and Research Institute, Tampa, Florida, United States of America.

Background: Testicular germ cell tumor (TGCT) incidence has increased in recent decades along with the use and dose of diagnostic radiation. Here we examine the association between reported exposure to diagnostic radiation and TGCT risk.

Methods: We conducted a case-control study of men with and without TGCT recruited from hospital- and population-based settings. Participants reported on exposures to 1) x-ray or CT below the waist and 2) lower GI series or barium enema, which consists of a series of x-rays of the colon. We also derived a combined measure of exposure. We used logistic regression to determine the risk of developing TGCT according to categories of exposures (0, 1-2, or ≥3 exposures) and age at first exposure, adjusting for age, year of birth, race, county, body mass index at diagnosis, family history of TGCT, and personal history of cryptorchidism.

Results: There were 315 men with TGCT and 931 men without TGCT in our study. Compared to no exposures, risk of TGCT was significantly elevated among those reporting at least three exposures to x-ray or CT (OR≥3 exposures, 1.78; 95% CI, 1.15-2.76; p = 0.010), lower GI series or barium enema (OR≥3 exposures, 4.58; 95% CI, 2.39-8.76; p<0.001), and the combined exposure variable (OR≥3 exposures, 1.59; 95% CI, 1.05-2.42; p = 0.029). The risk of TGCT was elevated for those exposed to diagnostic radiation at age 0-10 years, compared to those first exposed at age 18 years or later, although this association did not reach statistical significance (OR, 2.00; 95% CI, 0.91-4.42; p = 0.086).

Conclusions: Exposure to diagnostic radiation below the waist may increase TGCT risk. If these results are validated, efforts to reduce diagnostic radiation doses to the testes should be prioritized.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0239321PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7657535PMC
December 2020

Lack of pathogenic germline DICER1 variants in males with testicular germ-cell tumors.

Cancer Genet 2020 10 24;248-249:49-56. Epub 2020 Oct 24.

Clinical Genetics Branch, Division of Cancer Epidemiology and Genetics, National Cancer Institute, NIH, Rockville, MD, USA. Electronic address:

Background: Several studies have reported conflicting evidence on the inclusion of testicular germ cell tumors (TGCT) in the DICER1 tumor-predisposition phenotype. We evaluated the relationship between DICER1 and TGCT by reviewing scrotal ultrasounds of males with pathogenic germline variants in DICER1 and queried exome data from TGCT-affected men for DICER1 variants.

Methodology: Fifty-four male DICER1-carriers and family controls (n=41) enrolled in the National Cancer Institute (NCI) DICER1 Natural History Study were offered scrotal ultrasounds. These studies were examined by a single radiologist for abnormalities. In parallel, DICER1 variants from two large exome-sequenced TGCT cohorts were extracted. We used previously published AMG-AMP criteria to characterize rare DICER1 variants.

Results: There was no observed difference in frequency of testicular cystic structures in DICER1-carriers versus controls. DICER1 variation was not associated with TGCT in the NCI DICER1-carriers. In 1,264 exome-sequenced men with TGCT, none harbored ClinVar- or InterVar-determined pathogenic or likely pathogenic variants in DICER1. Three DICER1 variants of uncertain significance (one case and two controls) were predicted "damaging" based on a priori criteria.

Conclusion: Using two complementary approaches, we found no evidence of an association between pathogenic DICER1 variants and TGCT.
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http://dx.doi.org/10.1016/j.cancergen.2020.10.002DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7704203PMC
October 2020

Metabolomics of primary cutaneous melanoma and matched adjacent extratumoral microenvironment.

PLoS One 2020 27;15(10):e0240849. Epub 2020 Oct 27.

Department of Cancer Epidemiology, H. Lee Moffitt Cancer Center & Research Institute, Tampa, Florida, United States of America.

Background: Melanoma causes the vast majority of deaths attributable to skin cancer, largely due to its propensity for metastasis. To date, few studies have examined molecular changes between primary cutaneous melanoma and adjacent putatively normal skin. To broaden temporal inferences related to initiation of disease, we performed a metabolomics investigation of primary melanoma and matched extratumoral microenvironment (EM) tissues; and, to make inferences about progressive disease, we also compared unmatched metastatic melanoma tissues to EM tissues.

Methods: Ultra-high performance liquid chromatography-mass spectrometry-based metabolic profiling was performed on frozen human tissues.

Results: We observed 824 metabolites as differentially abundant among 33 matched tissue samples, and 1,118 metabolites as differentially abundant between metastatic melanoma (n = 46) and EM (n = 34) after false discovery rate (FDR) adjustment (p<0.01). No significant differences in metabolite abundances were noted comparing primary and metastatic melanoma tissues.

Conclusions: Overall, pathway-based results significantly distinguished melanoma tissues from EM in the metabolism of: ascorbate and aldarate, propanoate, tryptophan, histidine, and pyrimidine. Within pathways, the majority of individual metabolite abundances observed in comparisons of primary melanoma vs. EM and metastatic melanoma vs. EM were directionally consistent. This observed concordance suggests most identified compounds are implicated in the initiation or maintenance of melanoma.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0240849PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7591037PMC
December 2020

MC1R variants and cutaneous melanoma risk according to histological type, body site, and Breslow thickness: a pooled analysis from the M-SKIP project.

Melanoma Res 2020 10;30(5):500-510

Departments of Dermatology.

Little is known on whether melanocortin 1 receptor (MC1R) associated cutaneous melanoma (CM) risk varies depending on histological subtype and body site, and whether tumour thickness at diagnosis (the most important prognostic factor for CM patients) differs between MC1R variant carriers and wild-type individuals. We studied the association between MC1R variants and CM risk by histological subtype, body site, and Breslow thickness, using the database of the M-SKIP project. We pooled individual data from 15 case-control studies conducted during 2005-2015 in Europe and the USA. Study-specific, multi-adjusted odds ratios were pooled into summary odds ratios (SOR) and 95% confidence intervals (CI) using random-effects models. Six thousand eight hundred ninety-one CM cases and 5555 controls were included. CM risk was increased among MC1R variant carriers vs. wild-type individuals. The increase in risk was comparable across histological subtypes (SOR for any variant vs. wild-type ranged between 1.57 and 1.70, always statistical significant) except acral lentiginous melanoma (ALM), for which no association emerged; and slightly greater on chronically (1.74, 95% CI 1.47-2.07) than intermittently (1.55, 95% CI 1.34-1.78) sun-exposed skin. CM risk was greater for those carrying 'R' vs. 'r' variants; correlated with the number of variants; and was more evident among individuals not showing the red hair colour phenotype. Breslow thickness was not associated with MC1R status. MC1R variants were associated with an increased risk of CM of any histological subtype (except ALM) and occurring on both chronically and intermittently sun-exposed skin.
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http://dx.doi.org/10.1097/CMR.0000000000000668DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7479262PMC
October 2020

Association of Known Melanoma Risk Factors with Primary Melanoma of the Scalp and Neck.

Cancer Epidemiol Biomarkers Prev 2020 11 20;29(11):2203-2210. Epub 2020 Aug 20.

School of Population and Global Health, The University of Western Australia, Perth, Western Australia, Australia.

Background: Scalp and neck (SN) melanoma confers a worse prognosis than melanoma of other sites but little is known about its determinants. We aimed to identify associations between SN melanoma and known risk genes, phenotypic traits, and sun exposure patterns.

Methods: Participants were cases from the Western Australian Melanoma Health Study ( = 1,200) and the Genes, Environment, and Melanoma Study ( = 3,280). Associations between risk factors and SN melanoma, compared with truncal and arm/leg melanoma, were investigated using binomial logistic regression. Facial melanoma was also compared with the trunk and extremities, to evaluate whether associations were subregion specific, or reflective of the whole head/neck region.

Results: Compared with other sites, increased odds of SN and facial melanoma were observed in older individuals [SN: OR = 1.28, 95% confidence interval (CI) = 0.92-1.80, = 0.016; Face: OR = 4.57, 95% CI = 3.34-6.35, < 0.001] and those carrying -rs12203592*T (SN: OR = 1.35, 95% CI = 1.12-1.63, = 0.002; Face: OR = 1.29, 95% CI = 1.10-1.50, = 0.001). Decreased odds were observed for females (SN: OR = 0.49, 95% CI = 0.37-0.64, < 0.001; Face: OR = 0.66, 95% CI = 0.53-0.82, < 0.001) and the presence of nevi (SN: OR = 0.66, 95% CI = 0.49-0.89, = 0.006; Face: OR = 0.65, 95% CI = 0.52-0.83, < 0.001).

Conclusions: Differences observed between SN melanoma and other sites were also observed for facial melanoma. Factors previously associated with the broader head and neck region, notably older age, may be driven by the facial subregion. A novel finding was the association of -rs12203592 with both SN and facial melanoma.

Impact: Understanding the epidemiology of site-specific melanoma will enable tailored strategies for risk factor reduction and site-specific screening campaigns.
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http://dx.doi.org/10.1158/1055-9965.EPI-20-0595DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7641988PMC
November 2020

Assessment of polygenic architecture and risk prediction based on common variants across fourteen cancers.

Nat Commun 2020 07 3;11(1):3353. Epub 2020 Jul 3.

Section of Epidemiology and Biostatistics, Leeds Institute of Cancer and Pathology, University of Leeds, Leeds, UK.

Genome-wide association studies (GWAS) have led to the identification of hundreds of susceptibility loci across cancers, but the impact of further studies remains uncertain. Here we analyse summary-level data from GWAS of European ancestry across fourteen cancer sites to estimate the number of common susceptibility variants (polygenicity) and underlying effect-size distribution. All cancers show a high degree of polygenicity, involving at a minimum of thousands of loci. We project that sample sizes required to explain 80% of GWAS heritability vary from 60,000 cases for testicular to over 1,000,000 cases for lung cancer. The maximum relative risk achievable for subjects at the 99th risk percentile of underlying polygenic risk scores (PRS), compared to average risk, ranges from 12 for testicular to 2.5 for ovarian cancer. We show that PRS have potential for risk stratification for cancers of breast, colon and prostate, but less so for others because of modest heritability and lower incidence.
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http://dx.doi.org/10.1038/s41467-020-16483-3DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7335068PMC
July 2020

The Association of Mutation with Tumor Mutation Burden and Its Prognostic Implications in Cutaneous Melanoma.

Cancer Epidemiol Biomarkers Prev 2020 09 1;29(9):1792-1799. Epub 2020 Jul 1.

Department of Immunology, H. Lee Moffitt Cancer Center and Research Institute, Tampa, Florida.

Background: is a mucin marker that is frequently mutated in melanoma, but whether mutations could be useful as a surrogate biomarker for tumor mutation burden (TMB) remains unclear.

Methods: This study rigorously evaluates the mutation as a clinical biomarker in cutaneous melanoma by utilizing genomic and clinical data from patient samples from The Cancer Genome Atlas (TCGA) and two independent validation cohorts. We further extended the analysis to studies with patients treated with immunotherapies.

Results: Analysis results showed that samples with mutations had a higher TMB than the samples of wild-type, with strong statistical significance ( < 0.001) in all melanoma cohorts tested. Associations between mutations and TMB remained statistically significant after adjusting for potential confounding factors in the TCGA cohort [OR, 9.28 (95% confidence interval (CI), 5.18-17.39); < 0.001], Moffitt cohort [OR, 31.95 (95% CI, 8.71-163.90); < 0.001], and Yale cohort [OR, 8.09 (95% CI, 3.12-23.79); < 0.01]. mutations were also found to be associated with overall survival in the TCGA [HR, 0.62; (95% CI, 0.45-0.85); < 0.01] and Moffitt cohorts [HR, 0.49 (95% CI, 0.28-0.87); = 0.014]. Strikingly, is the only top frequently mutated gene for which prognostic significance was observed. mutations were also found valuable in predicting anti-CTLA-4 and anti-PD-1 therapy responses.

Conclusions: mutation appears to be a useful predictive marker of global TMB and patient survival in melanoma.

Impact: This is, to the best of our knowledge, the first systematic evaluation of mutation as a clinical biomarker and a predictive biomarker for immunotherapy in melanoma.
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http://dx.doi.org/10.1158/1055-9965.EPI-20-0307DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7483810PMC
September 2020

MC1R variants and associations with pigmentation characteristics and genetic ancestry in a Hispanic, predominately Puerto Rican, population.

Sci Rep 2020 04 29;10(1):7303. Epub 2020 Apr 29.

Department of Cancer Epidemiology, Moffitt Cancer Center and Research Institute, Tampa, FL, USA.

Skin cancer risk information based on melanocortin-1 receptor (MC1R) variants could inform prevention and screening recommendations for Hispanics, but limited evidence exists on the impact of MC1R variants in Hispanic populations. We studied Hispanic subjects, predominately of Puerto Rican heritage, from Tampa, Florida, US, and Ponce, PR. Blood or saliva samples were collected by prospective recruitment or retrieved from biobanks for genotyping of MC1R variants and ancestry informative markers. Participant demographic and self-reported phenotypic information was collected via biobank records or questionnaires. We determined associations of MC1R genetic risk categories and phenotypic variables and genetic ancestry. Over half of participants carried MC1R variants known to increase risk of skin cancer, and there was diversity in the observed variants across sample populations. Associations between MC1R genetic risk groups and some pigmentation characteristics were identified. Among Puerto Ricans, the proportion of participants carrying MC1R variants imparting elevated skin cancer risk was consistent across quartiles of European, African, and Native American genetic ancestry. These findings demonstrate that MC1R variants are important for pigmentation characteristics in Hispanics and that carriage of high risk MC1R alleles occurs even among Hispanics with stronger African or Native American genetic ancestry.
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http://dx.doi.org/10.1038/s41598-020-64019-yDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7190662PMC
April 2020

Genome-wide association meta-analyses combining multiple risk phenotypes provide insights into the genetic architecture of cutaneous melanoma susceptibility.

Nat Genet 2020 05 27;52(5):494-504. Epub 2020 Apr 27.

Department of Dermatology, Instituto Valenciano de Oncología, Valencia, Spain.

Most genetic susceptibility to cutaneous melanoma remains to be discovered. Meta-analysis genome-wide association study (GWAS) of 36,760 cases of melanoma (67% newly genotyped) and 375,188 controls identified 54 significant (P < 5 × 10) loci with 68 independent single nucleotide polymorphisms. Analysis of risk estimates across geographical regions and host factors suggests the acral melanoma subtype is uniquely unrelated to pigmentation. Combining this meta-analysis with GWAS of nevus count and hair color, and transcriptome association approaches, uncovered 31 potential secondary loci for a total of 85 cutaneous melanoma susceptibility loci. These findings provide insights into cutaneous melanoma genetic architecture, reinforcing the importance of nevogenesis, pigmentation and telomere maintenance, together with identifying potential new pathways for cutaneous melanoma pathogenesis.
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http://dx.doi.org/10.1038/s41588-020-0611-8DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7255059PMC
May 2020

Exploring the prognostic value of the neutrophil-to-lymphocyte ratio in cancer.

Sci Rep 2019 12 23;9(1):19673. Epub 2019 Dec 23.

Department of Cancer Epidemiology H. Lee Moffitt Cancer Center and Research Institute, Tampa, FL, USA.

In cancer patients, a high pre-treatment neutrophil-to-lymphocyte ratio (NLR) is associated with poorer survival outcomes. Significant variation in the magnitude of this association has been observed between studies, but sources of this variation are poorly understood. Here, we explore differences in the prognostic potential of NLR between patient subgroups stratified by demographic and clinical characteristics using a retrospective cohort of 5,363 patients treated at Moffitt Cancer Center (Tampa, FL). We identify patients for whom NLR has maximum prognostic potential via adjusted hazard ratios (HRs) calculated using multivariable Cox proportional hazards models and area under the curve analysis. NLR demonstrates stronger associations (HRs > 2) with survival among African-American patients, patients receiving radiation therapy, stage IV patients, and melanoma patients when compared with the overall study population (HR = 1.58). Sensitivity and specificity of NLR as a prognostic marker are also higher in these patient subgroups, and increase further with combinations of multiple "high-risk" demographic or clinical characteristics. In summary, NLR may have greater prognostic value in patients with certain demographic and clinical features. Future prospective studies could validate this hypothesis, after further characterization of populations in which NLR has maximum prognostic potential and the identification of meaningful thresholds for risk stratification.
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http://dx.doi.org/10.1038/s41598-019-56218-zDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6928022PMC
December 2019

Non-del(5q) myelodysplastic syndromes-associated loci detected by SNP-array genome-wide association meta-analysis.

Blood Adv 2019 11;3(22):3579-3589

Department of Malignant Hematology and.

Myelodysplastic syndromes (MDS) are hematopoietic stem cell malignancies. Known predisposing factors to adult MDS include rare germline mutations, cytotoxic therapy, age-related clonal hematopoiesis, and autoimmune or chronic inflammatory disorders. To date, no published studies characterizing MDS-associated germline susceptibility polymorphisms exist. We performed a genome-wide association study of 2 sample sets (555 MDS cases vs 2964 control subjects; 352 MDS cases vs 2640 control subjects) in non-del(5q) MDS cases of European genomic ancestry. Meta-analysis identified 8 MDS-associated loci at 1q31.1 (PLA2G4A), 3p14.1 (FAM19A4), 5q21.3 (EFNA5), 6p21.33, 10q23.1 (GRID1), 12q24.32, 15q26.1, and 20q13.12 (EYA2) that approached genome-wide significance. Gene expression for 5 loci that mapped within or near genes was significantly upregulated in MDS bone marrow cells compared with those of control subjects (P < .01). Higher PLA2G4A expression and lower EYA2 expression were associated with poorer overall survival (P = .039 and P = .037, respectively). Higher PLA2G4A expression is associated with mutations in NRAS (P < .001), RUNX1 (P = .012), ASXL1 (P = .007), and EZH2 (P = .038), all of which are known to contribute to MDS development. EYA2 expression was an independently favorable risk factor irrespective of age, sex, and Revised International Scoring System score (relative risk, 0.67; P = .048). Notably, these genes have regulatory roles in innate immunity, a critical driver of MDS pathogenesis. EYA2 overexpression induced innate immune activation, whereas EYA2 inhibition restored colony-forming potential in primary MDS cells indicative of hematopoietic restoration and possible clinical relevance. In conclusion, among 8 suggestive MDS-associated loci, 5 map to genes upregulated in MDS with functional roles in innate immunity and potential biological relevance to MDS.
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http://dx.doi.org/10.1182/bloodadvances.2019000922DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6880887PMC
November 2019

Inherited Melanoma Risk Variants Associated with Histopathologically Amelanotic Melanoma.

J Invest Dermatol 2020 04 27;140(4):918-922.e7. Epub 2019 Sep 27.

Department of Dermatology, University of North Carolina, Chapel Hill, North Carolina; Lineberger Comprehensive Cancer Center, University of North Carolina, Chapel Hill, North Carolina. Electronic address:

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http://dx.doi.org/10.1016/j.jid.2019.09.006DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7093215PMC
April 2020

Sociodemographic and lifestyle factors associated with the neutrophil-to-lymphocyte ratio.

Ann Epidemiol 2019 10 1;38:11-21.e6. Epub 2019 Aug 1.

Department of Cancer Epidemiology, H. Lee Moffitt Cancer Center and Research Institute, Tampa, FL.

Purpose: The neutrophil-to-lymphocyte ratio (NLR) is a marker of systemic inflammation with established prognostic value in patients with cancer. Although high NLR is associated with poorer clinical outcomes, factors that influence the magnitude of NLR independently of disease are poorly understood.

Methods: We identified 48,023 adults who participated in the National Health and Nutrition Examination Survey (1999-2016). Demographic, socioeconomic, and lifestyle factors associated with the magnitude of NLR after adjusting for comorbidities including heart disease, cancer, diabetes, and hypertension, and medications including aspirin, were identified. Effect modification by comorbidity status and demographics was explored.

Results: Female gender, age less than 60 years, and non-Hispanic black race/ethnicity were associated with lower NLR. Marital statuses of widowed, separated, or never married demonstrated increased NLR as compared with those who were currently married. Never-smoking and moderate alcohol consumption were associated with lower NLR. Participation in physical activity was associated with decreased NLR after adjustment for potential confounders, primarily among non-Hispanic whites.

Conclusions: Multiple demographic and lifestyle factors are independently associated with NLR. Sex, age, race, marital status, body mass index, physical activity, smoking history, and alcohol consumption should all be routinely collected and adjusted for to improve the accuracy of assessment of the prognostic power of NLR.
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http://dx.doi.org/10.1016/j.annepidem.2019.07.015DOI Listing
October 2019

Big Returns on Investment.

Authors:
Peter A Kanetsky

Cancer Epidemiol Biomarkers Prev 2019 07;28(7):1271-1272

Department of Cancer Epidemiology, H. Lee Moffitt Cancer Center and Research Institute, Tampa, Florida.

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http://dx.doi.org/10.1158/1055-9965.EPI-19-0525DOI Listing
July 2019

MC1R variants in childhood and adolescent melanoma: a retrospective pooled analysis of a multicentre cohort.

Lancet Child Adolesc Health 2019 05 12;3(5):332-342. Epub 2019 Mar 12.

Department of Pathophysiology and Transplantation, University of Milan, Foundation IRCCS Ca' Granda Ospedale Maggiore Policlinico, Milan, Italy.

Background: Germline variants in the melanocortin 1 receptor gene (MC1R) might increase the risk of childhood and adolescent melanoma, but a clear conclusion is challenging because of the low number of studies and cases. We assessed the association of MC1R variants with childhood and adolescent melanoma in a large study comparing the prevalence of MC1R variants in child or adolescent patients with melanoma to that in adult patients with melanoma and in healthy adult controls.

Methods: In this retrospective pooled analysis, we used the M-SKIP Project, the Italian Melanoma Intergroup, and other European groups (with participants from Australia, Canada, France, Greece, Italy, the Netherlands, Serbia, Spain, Sweden, Turkey, and the USA) to assemble an international multicentre cohort. We gathered phenotypic and genetic data from children or adolescents diagnosed with sporadic single-primary cutaneous melanoma at age 20 years or younger, adult patients with sporadic single-primary cutaneous melanoma diagnosed at age 35 years or older, and healthy adult individuals as controls. We calculated odds ratios (ORs) for childhood and adolescent melanoma associated with MC1R variants by multivariable logistic regression. Subgroup analysis was done for children aged 18 or younger and 14 years or younger.

Findings: We analysed data from 233 young patients, 932 adult patients, and 932 healthy adult controls. Children and adolescents had higher odds of carrying MC1R r variants than did adult patients (OR 1·54, 95% CI 1·02-2·33), including when analysis was restricted to patients aged 18 years or younger (1·80, 1·06-3·07). All investigated variants, except Arg160Trp, tended, to varying degrees, to have higher frequencies in young patients than in adult patients, with significantly higher frequencies found for Val60Leu (OR 1·60, 95% CI 1·05-2·44; p=0·04) and Asp294His (2·15, 1·05-4·40; p=0·04). Compared with those of healthy controls, young patients with melanoma had significantly higher frequencies of any MC1R variants.

Interpretation: Our pooled analysis of MC1R genetic data of young patients with melanoma showed that MC1R r variants were more prevalent in childhood and adolescent melanoma than in adult melanoma, especially in patients aged 18 years or younger. Our findings support the role of MC1R in childhood and adolescent melanoma susceptibility, with a potential clinical relevance for developing early melanoma detection and preventive strategies.

Funding: SPD-Pilot/Project-Award-2015; AIRC-MFAG-11831.
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http://dx.doi.org/10.1016/S2352-4642(19)30005-7DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6942319PMC
May 2019

Estimating CDKN2A mutation carrier probability among global familial melanoma cases using GenoMELPREDICT.

J Am Acad Dermatol 2019 Aug 5;81(2):386-394. Epub 2019 Feb 5.

Department of Clinical Sciences, Lund University Hospital Lund, Sweden; Department of Surgery, Lund University Hospital, Lund, Sweden.

Background: Although rare in the general population, highly penetrant germline mutations in CDKN2A are responsible for 5%-40% of melanoma cases reported in melanoma-prone families. We sought to determine whether MELPREDICT was generalizable to a global series of families with melanoma and whether performance improvements can be achieved.

Methods: In total, 2116 familial melanoma cases were ascertained by the international GenoMEL Consortium. We recapitulated the MELPREDICT model within our data (GenoMELPREDICT) to assess performance improvements by adding phenotypic risk factors and history of pancreatic cancer. We report areas under the curve (AUC) with 95% confidence intervals (CIs) along with net reclassification indices (NRIs) as performance metrics.

Results: MELPREDICT performed well (AUC 0.752, 95% CI 0.730-0.775), and GenoMELPREDICT performance was similar (AUC 0.748, 95% CI 0.726-0.771). Adding a reported history of pancreatic cancer yielded discriminatory improvement (P < .0001) in GenoMELPREDICT (AUC 0.772, 95% CI 0.750-0.793, NRI 0.40). Including phenotypic risk factors did not improve performance.

Conclusion: The MELPREDICT model functioned well in a global data set of familial melanoma cases. Adding pancreatic cancer history improved model prediction. GenoMELPREDICT is a simple tool for predicting CDKN2A mutational status among melanoma patients from melanoma-prone families and can aid in directing these patients to receive genetic testing or cancer risk counseling.
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http://dx.doi.org/10.1016/j.jaad.2019.01.079DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6634996PMC
August 2019

Association of Inherited Pathogenic Variants in Checkpoint Kinase 2 (CHEK2) With Susceptibility to Testicular Germ Cell Tumors.

JAMA Oncol 2019 Apr;5(4):514-522

Institute of Human Genetics, University Medical Center Hamburg-Eppendorf, Hamburg, Germany.

Importance: Approximately 50% of the risk for the development of testicular germ cell tumors (TGCTs) is estimated to be heritable, but no mendelian TGCT predisposition genes have yet been identified. It is hypothesized that inherited pathogenic DNA repair gene (DRG) alterations may drive susceptibility to TGCTs.

Objective: To systematically evaluate the enrichment of germline pathogenic variants in the mendelian cancer predisposition DRGs in patients with TGCTs vs healthy controls.

Design, Setting, And Participants: A case-control enrichment analysis was performed from January 2016 to May 2018 to screen for 48 DRGs in 205 unselected men with TGCT and 27 173 ancestry-matched cancer-free individuals from the Exome Aggregation Consortium cohort in the discovery stage. Significant findings were selectively replicated in independent cohorts of 448 unselected men with TGCTs and 442 population-matched controls, as well as 231 high-risk men with TGCTs and 3090 ancestry-matched controls. Statistical analysis took place from January to May 2018.

Main Outcomes And Measures: Gene-level enrichment analysis of germline pathogenic variants in individuals with TGCTs relative to cancer-free controls.

Results: Among 205 unselected men with TGCTs (mean [SD] age, 33.04 [9.67] years), 22 pathogenic germline DRG variants, one-third of which were in CHEK2 (OMIM 604373), were identified in 20 men (9.8%; 95% CI, 6.1%-14.7%). Unselected men with TGCTs were approximately 4 times more likely to carry germline loss-of-function CHEK2 variants compared with cancer-free individuals from the Exome Aggregation Consortium cohort (odds ratio [OR], 3.87; 95% CI, 1.65-8.86; nominal P = .006; q = 0.018). Similar enrichment was also seen in an independent cohort of 448 unselected Croatian men with TGCTs (mean [SD] age, 31.98 [8.11] years) vs 442 unselected Croatian men without TGCTs (at least 50 years of age at time of sample collection) (OR, >1.4; P = .03) and 231 high-risk men with TGCTs (mean [SD] age, 31.54 [9.24] years) vs 3090 men (all older than 50 years) from the Penn Medicine Biobank (OR, 6.30; 95% CI, 2.34-17.31; P = .001). The low-penetrance CHEK2 variant (p.Ile157Thr) was found to be a Croatian founder TGCT risk variant (OR, 3.93; 95% CI, 1.53-9.95; P = .002). Individuals with the pathogenic CHEK2 loss-of-function variants developed TGCTs 6 years earlier than individuals with CHEK2 wild-type alleles (5.95 years; 95% CI, 1.48-10.42; P = .009).

Conclusions And Relevance: This multicenter case-control analysis of men with or without TGCTs provides evidence for CHEK2 as a novel moderate-penetrance TGCT susceptibility gene, with potential clinical utility. In addition to highlighting DNA-repair deficiency as a potential mechanism driving TGCT susceptibility, this analysis also provides new avenues to explore management strategies and biological investigations for high-risk individuals.
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http://dx.doi.org/10.1001/jamaoncol.2018.6477DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6459214PMC
April 2019

National Survey of Oncologists at National Cancer Institute-Designated Comprehensive Cancer Centers: Attitudes, Knowledge, and Practice Behaviors About LGBTQ Patients With Cancer.

J Clin Oncol 2019 03 16;37(7):547-558. Epub 2019 Jan 16.

2 New York University School of Medicine, New York, NY.

Purpose: To identify potential gaps in attitudes, knowledge, and institutional practices toward lesbian, gay, bisexual, transgender, and queer/questioning (LGBTQ) patients, a national survey of oncologists at National Cancer Institute-Designated Comprehensive Cancer Centers was conducted to measure these attributes related to LGBTQ patients and desire for future training and education.

Methods: A random sample of 450 oncologists from 45 cancer centers was selected from the American Medical Association's Physician Masterfile to complete a survey measuring attitudes and knowledge about LGBTQ health and institutional practices. Results were quantified using descriptive and stratified analyses and by a novel attitude summary measure.

Results: Of the 149 respondents, there was high agreement (65.8%) regarding the importance of knowing the gender identity of patients, which was contrasted by low agreement (39.6%) regarding the importance of knowing sexual orientation. There was high interest in receiving education regarding the unique health needs of LGBTQ patients (70.4%), and knowledge questions yielded high percentages of "neutral" and "do not know or prefer not to answer" responses. After completing the survey, there was a significant decrease ( P < .001) in confidence in knowledge of health needs for LGB (53.1% agreed they were confident during survey assessment v 38.9% postsurvey) and transgender patients (36.9% v 19.5% postsurvey). Stratified analyses revealed some but limited influence on attitudes and knowledge by having LGBTQ friends and/or family members, political affiliation, oncology specialty, years since graduation, and respondents' region of the country.

Conclusion: This was the first nationwide study, to our knowledge, of oncologists assessing attitudes, knowledge, and institutional practices of LGBTQ patients with cancer. Overall, there was limited knowledge about LGBTQ health and cancer needs but a high interest in receiving education regarding this community.
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http://dx.doi.org/10.1200/JCO.18.00551DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6553841PMC
March 2019

A practical approach to adjusting for population stratification in genome-wide association studies: principal components and propensity scores (PCAPS).

Stat Appl Genet Mol Biol 2018 12 4;17(6). Epub 2018 Dec 4.

Division of Population Sciences, Dana Farber Cancer Institute and Department of Epidemiology, Harvard T.H. Chan School of Public Health, Boston, MA 02215, USA.

Genome-wide association studies (GWAS) are susceptible to bias due to population stratification (PS). The most widely used method to correct bias due to PS is principal components (PCs) analysis (PCA), but there is no objective method to guide which PCs to include as covariates. Often, the ten PCs with the highest eigenvalues are included to adjust for PS. This selection is arbitrary, and patterns of local linkage disequilibrium may affect PCA corrections. To address these limitations, we estimate genomic propensity scores based on all statistically significant PCs selected by the Tracy-Widom (TW) statistic. We compare a principal components and propensity scores (PCAPS) approach to PCA and EMMAX using simulated GWAS data under no, moderate, and severe PS. PCAPS reduced spurious genetic associations regardless of the degree of PS, resulting in odds ratio (OR) estimates closer to the true OR. We illustrate our PCAPS method using GWAS data from a study of testicular germ cell tumors. PCAPS provided a more conservative adjustment than PCA. Advantages of the PCAPS approach include reduction of bias compared to PCA, consistent selection of propensity scores to adjust for PS, the potential ability to handle outliers, and ease of implementation using existing software packages.
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http://dx.doi.org/10.1515/sagmb-2017-0054DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6475581PMC
December 2018

Assessing the Incremental Contribution of Common Genomic Variants to Melanoma Risk Prediction in Two Population-Based Studies.

J Invest Dermatol 2018 12 8;138(12):2617-2624. Epub 2018 Jun 8.

Section of Epidemiology and Biostatistics, Leeds Institute of Cancer and Pathology, University of Leeds, Leeds, UK.

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.
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http://dx.doi.org/10.1016/j.jid.2018.05.023DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6249137PMC
December 2018

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.

Contemp Clin Trials 2018 07 23;70:106-116. Epub 2018 May 23.

Cancer Epidemiology and Prevention Research, Sydney School of Public Health, The University of Sydney, NSW 2006, Australia; Melanoma Institute Australia, The University of Sydney, NSW 2006, Australia.

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.
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http://dx.doi.org/10.1016/j.cct.2018.05.014DOI Listing
July 2018
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