Per Helsing

Genome-wide association study identifies a new melanoma susceptibility locus at 1q21.3

We performed a genome-wide association study of melanoma in a discovery cohort of 2,168 Australian individuals with melanoma and 4,387 control individuals. In this discovery phase, we confirm several previously characterized melanoma-associated loci at MC1R, ASIP and MTAP–CDKN2A. We selected variants at nine loci for replication in three independent case-control studies (Europe: 2,804 subjects with melanoma, 7,618 control subjects; United States 1: 1,804 subjects with melanoma, 1,026 control subjects; United States 2: 585 subjects with melanoma, 6,500 control subjects). The combined meta-analysis of all case-control studies identified a new susceptibility locus at 1q21.3 (rs7412746, P = 9.0 × 10−11, OR in combined replication cohorts of 0.89 (95% CI 0.85–0.95)). We also show evidence suggesting that melanoma associates with 1q42.12 (rs3219090, P = 9.3 × 10−8). The associated variants at the 1q21.3 locus span a region with ten genes, and plausible candidate genes for melanoma susceptibility include ARNT and SETDB1. Variants at the 1q21.3 locus do not seem to be associated with human pigmentation or measures of nevus density.

Genome-wide meta-analysis identifies five new susceptibility loci for cutaneous malignant melanoma

Thirteen common susceptibility loci have been reproducibly associated with cutaneous malignant melanoma (CMM). We report the results of an international 2-stage meta-analysis of CMM genome-wide association studies (GWAS). This meta-analysis combines 11 GWAS (5 previously unpublished) and a further three stage 2 data sets, totaling 15,990 CMM cases and 26,409 controls. Five loci not previously associated with CMM risk reached genome-wide significance (P < 5 × 10−8), as did 2 previously reported but unreplicated loci and all 13 established loci. Newly associated SNPs fall within putative melanocyte regulatory elements, and bioinformatic and expression quantitative trait locus (eQTL) data highlight candidate genes in the associated regions, including one involved in telomere biology.

Guidelines for practical use of MAL-PDT in non-melanoma skin cancer.

Methyl aminolaevulinate photodynamic therapy is increasingly practiced in the treatment of actinic keratoses, Bowen’s disease and basal cell carcinomas. This method is particularly suitable for treating multiple lesions, field cancerization and lesions in areas where a good cosmetic outcome is of importance. Good treatment routines will contribute to a favourable result. The Norwegian photodynamic therapy (PDT) group consists of medical specialists with long and extensive PDT experience. With support in the literature, this group presents guidelines for the practical use of topical PDT in non‐melanoma skin cancer.

A variant in FTO shows association with melanoma risk not due to BMI

We report the results of an association study of melanoma that is based on the genome-wide imputation of the genotypes of 1,353 cases and 3,566 controls of European origin conducted by the GenoMEL consortium. This revealed an association between several SNPs in intron 8 of the FTO gene, including rs16953002, which replicated using 12,313 cases and 55,667 controls of European ancestry from Europe, the USA and Australia (combined P = 3.6 × 10−12, per-allele odds ratio for allele A = 1.16). In addition to identifying a new melanoma-susceptibility locus, this is to our knowledge the first study to identify and replicate an association with SNPs in FTO not related to body mass index (BMI). These SNPs are not in intron 1 (the BMI-related region) and exhibit no association with BMI. This suggests FTOs function may be broader than the existing paradigm that FTO variants influence multiple traits only through their associations with BMI and obesity.

Comparison of cyclosporin and UVAB phototherapy for intermittent one-year treatment of atopic dermatitis.

Although cyclosporin is effective for the treatment of severe atopic dermatitis, phototherapy is the standard second-line treatment for this disease. An open, randomized, controlled, parallel-group study was conducted to compare the efficacy, influence on quality of life and safety of cyclosporin and UVAB phototherapy during 1 year of intermittent treatment of atopic dermatitis in adult patients. The main endpoints of the study were the number of days in remission and the influence on quality of life. Seventy-two patients were treated, 36 in each group. Cyclosporin produced significantly more days in remission than UVAB phototherapy during the 1-year study period. At the end of the study no difference between the 2 groups was noted in terms of quality of life. A significant increase in serum creatinine occurred in 2 patients and 7 patients developed mild or moderate hypertension during cyclosporin treatment. It can be concluded that intermittent cyclosporin seems to be more effective than UVAB and is reasonably safe for the treatment of atopic dermatitis over a 1-year treatment period.

Intensified fractional CO2 laser‐assisted photodynamic therapy vs. laser alone for organ transplant recipients with multiple actinic keratoses and wart‐like lesions: a randomized half‐side comparative trial on dorsal hands

Photodynamic therapy (PDT) is a well‐documented treatment for actinic keratosis (AK), but achieves inferior efficacy in organ transplant recipients (OTRs), particularly in acral regions. Ablative fractional laser (AFXL) intensifies the PDT response and may improve the efficacy of AK clearance when used as monotherapy.

Population-based prevalence of CDKN2A and CDK4 mutations in patients with multiple primary melanomas

The presence of multiple primary cutaneous melanomas (MPM) has been advocated as guidance to identifying melanoma families. Frequencies of CDKN2A mutations in materials of sporadic MPM cases from pigmented lesion clinics vary between 8 and 15%. Patients with MPM have therefore been regarded as good candidates for CDKN2A mutational screening. We describe a population‐based study where all persons in Norway diagnosed with MPM between 1953 and 2004 (n = 738 alive per April 2004) were invited to participate. Three‐hundred‐and‐ninety patients (52.8%) responded confidentially. Mutations in CDKN2A were found in 6.9% of the respondents. Eighty‐one MPM patients (20.8%) reported that they belonged to melanoma families, and 17 (21.0%) of these harboured a CDKN2A mutation, compared to 3.2% of the nonfamilial cases. The probability of finding a CDKN2A mutation increased when the patients had three or more melanomas, or a young age of onset of first melanoma. We identified five novel CDKN2A variants (Ala57Gly, Pro81Arg, Ala118Val, Leu130Val, and Arg131Pro) and four that previously have been reported in melanoma families (Glu27X, Met53Ile, Arg87Trp, and Ala127Pro). A large deletion (g.13623_23772del10150) encompassing exon 1α and the 5′ part of exon 2 was detected in six patients with a family history of melanoma. Three patients, belonging to the same family, had the CDK4 Arg24His mutation. The frequency of CDKN2A mutations was lower than previously reported in other studies, an observation which probably is due to the population‐based design of our study.

Clinical and Histopathological Features of Folliculotropic Mycosis Fungoides: a Norwegian Patient Series

Folliculotropic mycosis fungoides is a variant of cutaneous T-cell lymphoma with distinct clinicopathological features. We describe here the clinical presentation, pathology findings and treatment outcome in 15 Norwegian patients. All patients were diagnosed between 1997 and 2010 at Oslo University Hospital. A spectrum of skin lesions, both typical and atypical, such as leonine facies, acneiform lesions, psoriasiform plaques, purulent ulcerations and cystic milia-like lesions for mycosis fungoides, were seen. Histological examination revealed characteristic infiltration of hair follicles with neoplastic T cells associated with partial destruction of the former. A CD4+ immunophenotype of the neoplastic T cells with loss of one or more T-cell markers was demonstrated. In general, the patients were given more aggressive therapeutic regimens than those with conventional mycosis fungoides, and showed a trend towards more rapid disease progression. In conclusion, this case series confirms the distinct clinical and histological features of folliculotropic mycosis fungoides.

Hepatocellular focal nodular hyperplasia after danazol treatment for hereditary angio-oedema.

Hereditary angio-oedema (HAE) is a potentially life-threatening disease manifesting as recurrent attacks of laryngeal, intra-abdominal, facial or peripheral oedema. The disease is caused by mutations in the gene coding for C1-inhibitor, resulting in low antigenic or functional concentrations of this inhibitor of complement and kinin systems. Long-term prophylactic treatment is indicated in patients with frequent or severe attacks. Attenuated androgens, anti-fibrinolytic agents and C1-inhibitor concentrates may be used prophylactically. Attenuated androgens are usually effective, but are associated with adverse effects, such as weight gain, virilization in women , arterial hypertension and hepatotoxicity. Danazol is considered a significant risk factor for atherosclerosis, caused by unfavourable changes in the serum lipid profile (1). More recently, hepatocellular adenomas and carci-nomas have been reported in patients with HAE, taking danazol for long-term prophylaxis (2, 3). Focal nodular hyperplasia (FNH) is a common benign tumour of the liver, with unknown pathogenesis (4). There are a few reports linking FNH to use of anabolic androgens (5, 6) and high endogenous sex steroids (7), even to prolonged therapy with ketoconazole (8). We report here a patient with HAE on long-term prophylaxis with danazol, who developed FNH. CASE rEpOrT A 32-year-old woman was diagnosed with HAE at the age of 16 years. Since then she has been taking danazol (Danol ® , Sanofi-Synthelabo, New York) on a regular basis at a dosage of 400 mg daily. At lower dosages, she experienced abdominal cramps and swellings in the skin. She gained weight and stopped menstruating after introduction of danazol. At the age of 30 years she was diagnosed with polycystic ovarian syndrome, and clinical examination showed an atrophic uterus. She showed signs of virilization, with acne and hirsutism. Her serum lipid profile was abnormal with high total and low-density lipoprotein (LDL) cholesterol, and she was under treatment for arterial hypertension. The patientsíiver was monitored by transaminases and an annual ultrasonography. Transaminases were normal, but a tumour was found in the right liver lobe located centrally. Magnetic resonance tomography (Fig. 1) could not differentiate between a hepatocellu-lar adenoma and FNH, but an ultrasonography guided biopsy showed FNH. Danazol was then reduced to 100 mg daily, and the patient was instructed to administer infusions of C1-inhibitor concentrate (Berinert ® , ZLB-Behring. Marburg, Germany) intravenously. Disease control was obtained by 1000 IE Berinert ® every fourth day. Ultrasonographic follow-up showed no progression of the tumour after 1 year. DISCUSSION recent reports have …

Fine mapping of genetic susceptibility loci for melanoma reveals a mixture of single variant and multiple variant regions

At least 17 genomic regions are established as harboring melanoma susceptibility variants, in most instances with genome‐wide levels of significance and replication in independent samples. Based on genome‐wide single nucleotide polymorphism (SNP) data augmented by imputation to the 1,000 Genomes reference panel, we have fine mapped these regions in over 5,000 individuals with melanoma (mainly from the GenoMEL consortium) and over 7,000 ethnically matched controls. A penalized regression approach was used to discover those SNP markers that most parsimoniously explain the observed association in each genomic region. For the majority of the regions, the signal is best explained by a single SNP, which sometimes, as in the tyrosinase region, is a known functional variant. However in five regions the explanation is more complex. At the CDKN2A locus, for example, there is strong evidence that not only multiple SNPs but also multiple genes are involved. Our results illustrate the variability in the biology underlying genome‐wide susceptibility loci and make steps toward accounting for some of the “missing heritability.”