Functional melanoma‐risk variant
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            rs12203592 associated with Breslow thickness: a pooled international study of primary melanomas

Gibbs, David C.; Ward, Sarah; Orlow, Irene; Cadby, Gemma; Kanetsky, Peter A.; Luo, Li; Busam, Klaus J.; Kricker, Anne; Armstrong, Bruce K.; Cust, Anne E.; Anton‐Culver, Hoda; Gallagher, R. P.; Zanetti, Roberto; Rosso, Stefano; Sacchetto, Lidia; Ollila, David W.; Begg, Colin B.; Berwick, Marianne; Thomas, Nancy E.

doi:10.1111/bjd.15784

Cited by 15 publications

(21 citation statements)

References 10 publications

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“…The IRF4 rs12203592*T SNP is strongly associated with low adult naevus count, fair skin, pale eyes, darker hair colour and hair greying, but studies of its role in AHM are limited. Melanomas in patients carrying the T allele present at older age, arise on chronically UV damaged skin and have an increased Breslow thickness . Consequently, we hypothesized it was a potential driver in the reduction of pigmentation in AHMs.…”

Section: Discussionmentioning

confidence: 99%

“…Melanomas in patients carrying the T allele present at older age, 34 arise on chronically UV damaged skin and have an increased Breslow thickness. 35 Consequently, we hypothesized it was a potential driver in the reduction of pigmentation in AHMs. The frequency of the minor allele was higher in our AHM population than our pigmented melanoma population (34.1% vs. 25.3%; P = 0.06), but there was no significant change in AHM OR.…”

Section: Discussionmentioning

confidence: 99%

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Phenotypic and genotypic analysis of amelanotic and hypomelanotic melanoma patients

Rayner

McMeniman

Duffy

et al. 2019

Acad Dermatol Venereol

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Background Amelanotic/hypomelanotic melanoma is associated with poorer outcomes due to a more advanced disease stage at diagnosis. Objective To determine phenotypic risks and genotypic associations with amelanotic/hypomelanotic melanoma to develop a clinical and genetic profile that could assist in identifying high‐risk individuals. Methods The Brisbane Naevus Morphology Study conducted from 2009 to 2016 has recruited a core of 1254 participants. Participants were drawn from a combination of volunteers from dermatology outpatient clinics, private dermatology clinics, the Brisbane Longitudinal Twin Study and QSkin study. Case participants had a personal history of melanoma and control participants no personal history of melanoma. We specifically examined seven known candidate pigmentation and melanoma genes and pigmentary phenotypic characteristics in participants with amelanotic/hypomelanotic melanoma compared to pigmented melanomas. This assayed single nucleotide polymorphisms in MC1R, TYR, HERC/OCA2, IRF4, MTAP, PLA2G6 and MITF. Results Forty‐seven participants had at least one amelanotic/hypomelanotic melanoma, and 389 had pigmented melanomas, with amelanotic/hypomelanotic melanoma patients significantly older than pigmented melanoma participants (63.3 ± 13.0 vs. 54.6 ± 15.3 years; P < 0.001). Amelanotic/hypomelanotic melanoma patients were more likely than pigmented melanoma patients to have red hair (34% vs. 15%; P = 0.01), severe hand freckling (13% vs. 5%; P = 0.01) and propensity to sunburn (63% vs. 44%; P = 0.01). MC1R R/R genotype was much more frequent in our amelanotic/hypomelanotic melanoma population (31.1% vs. 11%; P < 0.001; OR 26.4 vs. 5.9; control 1.0). Amelanotic/hypomelanotic melanoma was associated with TYR rs1126809*A/A [OR (CI 95%) 2.7 (1.1–6.8) vs. 1.2 (0.8–1.9)] and PLA2G6 rs11570734*A/A [OR (CI 95%) 3.7 (1.0–13.6) vs. 1.3 (0.9–2.0)]. The MTAP melanoma risk SNP genotype, associated with darker pigmentation, (rs4636294*A/A) was less common in amelanotic/hypomelanotic melanoma patients [OR (CI 95%) 0.8 (0.3–2.1) vs. 2.0 (1.3–3.1)]. Conclusions Knowledge of phenotypic and genotypic associations of amelanotic/hypomelanotic melanoma can help predict risks and associations of this difficult to diagnose melanoma, which may ultimately assist clinical management and patient skin self‐examination.

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Phenotypic and genotypic analysis of amelanotic and hypomelanotic melanoma patients

Rayner

McMeniman

Duffy

et al. 2019

Acad Dermatol Venereol

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“…Details concerning the GEM study population, genotyping, and BRAF/NRAS mutational subtyping have been published previously (Begg et al, 2005, Gibbs et al, 2016, Gibbs et al, 2015, Gibbs et al, 2017, Thomas et al, 2015, Thomas et al, 2017, Vernali et al, 2017). Patient characteristics were collected via phone interviews and self-completed questionnaires (Kricker et al, 2007, Thomas et al, 2007, Thomas et al, 2010b).…”

Section: Methodsmentioning

confidence: 99%

Inherited Genetic Variants Associated with Melanoma BRAF/NRAS Subtypes

Thomas

Edmiston

Orlow

et al. 2018

Journal of Investigative Dermatology

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BRAF and NRAS mutations arise early in melanoma development, but their associations with low-penetrance melanoma susceptibility loci remain unknown. In the Genes, Environment and Melanoma Study, 1,223 European-origin participants had their incident invasive primary melanomas screened for BRAF/NRAS mutations and germline DNA genotyped for 47 single-nucleotide polymorphisms identified as low-penetrant melanoma-risk variants. We used multinomial logistic regression to simultaneously examine each single-nucleotide polymorphism's relationship to BRAF V600E, BRAF V600K, BRAF other, and NRAS+ relative to BRAF-/NRAS- melanoma adjusted for study features. IRF4 rs12203592*T was associated with BRAF V600E (odds ratio [OR] = 0.59, 95% confidence interval [CI] = 0.43-0.79) and V600K (OR = 0.65, 95% CI = 0.41-1.03), but not BRAF other or NRAS+ melanoma. A global test of etiologic heterogeneity (P = 0.001) passed false discovery (P = 0.0026). PLA2G6 rs132985*T was associated with BRAF V600E (OR = 1.32, 95% CI = 1.05-1.67) and BRAF other (OR = 1.82, 95% CI = 1.11-2.98), but not BRAF V600K or NRAS+ melanoma. The test for etiologic heterogeneity (P) was 0.005. The IRF4 rs12203592 associations were slightly attenuated after adjustment for melanoma-risk phenotypes. The PLA2G6 rs132985 associations were independent of phenotypes. IRF4 and PLA2G6 inherited genotypes may influence melanoma BRAF/NRAS subtype development.

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“…Our results suggest that IRF4 rs12203592 is associated with poorer melanoma‐specific survival, largely mediated through Breslow thickness, reinforcing our previous findings related to rs12203592*T and tumour thickness . This variant's adverse effect on survival may occur through its functional effect on IRF4 expression.…”

Section: Association Between Irf4 Single‐nucleotide Polymorphism (Snpmentioning

confidence: 99%

Association of IRF 4 single‐nucleotide polymorphism rs12203592 with melanoma‐specific survival

et al. 2020

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or less commonly with radiation (7Á9%) or chemotherapy (2Á3%). Wide local excision was the most common surgical technique used (38Á9%). The 5-and 10-year OS rates were 68Á8% and 54Á3%, respectively, with a median follow-up time of 4Á7 years (range 0-13Á8). On Cox proportional hazards regression, older age [hazard ratio (HR) 1Á08, 95% confidence interval (CI) 1Á06-1Á10]; tumours 20-40 mm (HR 2Á37, 95% CI 1Á15-4Á88), 40-60 mm (HR 4Á43, 95% CI 1Á68-11Á7) and > 60 mm (HR 4Á74, 95% CI 1Á63-13Á8); and stage IV disease (HR 5Á95, 95% CI 1Á84-19Á3) were independently associated with decreased OS. Lesions of the lower extremities and hip were associated with a more favourable prognosis (HR 0Á46, 95% CI 0Á25-0Á84). The tumour size varied greatly in our study cohort, with a mean diameter of 23Á88 mm and a range in size of 1-130 mm. Larger tumour size was strongly and independently associated with decreased OS. This finding is consistent with the AJCC staging guidelines for nonmelanoma and non-Merkel cell skin cancers, including EPC, in which tumour diameter > 2 cm is associated with worse prognosis. 3 Other studies of EPC have shown a similarly wide range in tumour size, but with no definitive relation to prognosis. 4 Our study found that 8Á1% of patients had metastatic disease at diagnosis. Patients with distant metastases (AJCC stage IV) had a poor prognosis, consistent with the literature. 4-7 However, in our study, metastases at diagnosis to lymph nodes and/ or distant organs were less common than previously reported in some reviews and meta-analyses, which reported rates of metastases at presentation as high as 31%. 5,7 These reviews detailed cases that were locally aggressive or had lymph node or distant metastases. Other studies similarly suggest that aggressive behaviour and metastases may be the exception. 4,6,8 There are several limitations in retrospective, registry-based studies. The NCDB is a clinician-reported database that relies on accurate and complete reporting by contributing institutions. Missing or erroneous data can lead to bias and data misinterpretation. Additionally, the NCDB does not report on treatment-specific outcomes or disease-specific survival, which may overestimate the mortality risk from EPC, especially if patients have comorbidities. EPC is a rare cutaneous tumour of unknown aetiology that has the potential for extracutaneous spread and increased mortality. Thus, it is crucial to diagnose and treat EPC appropriately. Our findings add to the growing body of evidence that early diagnosis and surgical treatment are the main good prognostic factors.

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Functional melanoma‐risk variant IRF 4 rs12203592 associated with Breslow thickness: a pooled international study of primary melanomas

Cited by 15 publications

References 10 publications

Phenotypic and genotypic analysis of amelanotic and hypomelanotic melanoma patients

Phenotypic and genotypic analysis of amelanotic and hypomelanotic melanoma patients

Inherited Genetic Variants Associated with Melanoma BRAF/NRAS Subtypes

Association of IRF 4 single‐nucleotide polymorphism rs12203592 with melanoma‐specific survival

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