Gemma Tell-Marti

The MC1R melanoma risk variant p.R160W is associated with Parkinson disease

Epidemiological studies have reported the co‐occurrence of Parkinson disease (PD) and melanoma. Common genetic variants in the MC1R (melanocortin 1 receptor) gene, which determines skin and hair color, are associated with melanoma. Here we investigated whether genetic variants in MC1R modulate the risk of PD by sequencing the entire gene in 870 PD patients and 736 controls ascertained from Spain. We found that the MC1R variant p.R160W (rs1805008) is marginally associated with PD (odds ratio = 2.10, gender‐ and age‐adjusted p = 0.009, Bonferroni‐corrected p = 0.063). Our results suggest that MC1R genetic variants modulate the risk of PD disease in the Spanish population. Ann Neurol 2015;77:889–894

Mutational status of naevus-associated melanomas

The origin of melanoma has always been a debated subject, as well as the role of adjacent melanocytic naevi. Epidemiological and histopathological studies point to melanomas arising either de novo or from a naevus.

Multiple BRAF Wild-Type Melanomas During Dabrafenib Treatment for Metastatic BRAF-Mutant Melanoma

IMPORTANCE BRAF inhibitors have become the standard of care in metastatic BRAF-mutant melanomas. Compared with chemotherapies, BRAF inhibitors improve overall and disease-free survival and speed the recovery of symptomatic patients with metastatic disease. The most worrisome finding is the possible development of resistance to new malignant tumors. OBSERVATIONS A patient in her 30s developed massive BRAFV600E melanoma metastasis during her 30th week of pregnancy. After emergency cesarean delivery, oral dabrafenib treatment was initiated, and a partial radiologic response was confirmed within 1 month. At dermatologic digital follow-up aided by confocal microscopy 8 weeks after initiation of dabrafenib treatment, 4 melanomas were detected. Unfortunately, within the next month, the melanoma rapidly progressed. The 4 new melanomas were wild-type BRAFmelanomas, whereas the new metastasis carried a different BRAF mutation (S467L). CONCLUSIONS AND RELEVANCE Cutaneous malignant tumors are the most frequent adverse events of BRAF inhibitors; therefore, strict dermatologic surveillance in a referral center aided by digital follow-up is mandatory, especially when multiple nevi are present and these drugs are used in an adjuvant setting. In view of our findings, the pathogenesis of the development of new melanomas seems to be different from therapy resistance. Whether paradoxical RAF activation could explain these BRAF wild-type secondary malignant tumors is still unknown.

Prevalence of MITF p.E318K in Patients With Melanoma Independent of the Presence of CDKN2A Causative Mutations

IMPORTANCE The main high-penetrance melanoma susceptibility gene is CDKN2A, encoding p16INK4A and p14ARF. The gene MITF variant p.E318K also predisposes to melanoma and renal cell carcinoma. To date, the prevalence of MITF p.E318K and its clinical and phenotypical implications has not been previously assessed in a single cohort of Spanish patients with melanoma or in p16INK4A mutation carriers. OBJECTIVES To evaluate the prevalence of MITF p.E318K in Spanish patients with melanoma and assess the association with clinical and phenotypic features. DESIGN, SETTING, AND PARTICIPANTS A hospital-based, case-control study was conducted at the Melanoma Unit of Hospital Clinic of Barcelona, with MITF p.E318K genotyped in all patients using TaqMan probes. We included 531 patients: 271 patients with multiple primary melanoma (MPM) without mutations affecting p16INK4A (wild-type p16INK4A); 191 probands from melanoma-prone families with a single melanoma diagnosis and without mutations affecting p16INK4A, and 69 probands from different families carrying CDKN2A mutations affecting p16INK4A. A population-based series of 499 age- and sex-matched cancer-free individuals from the Spanish National Bank of DNA were included as controls. Patients were recruited between January 1, 1992, and June 30, 2014; data analysis was conducted from September 1 to November 30, 2014. MAIN OUTCOMES AND MEASURES The genetic results of the MITF p.E318K variant were correlated with clinical and phenotypic features. RESULTS Among the 531 patients, the prevalence of the MITF p.E318K variant was calculated among the different subsets of patients included and was 1.9% (9 of 462) in all melanoma patients with wild-type p16INK4A, 2.6% (7 of 271) in those with MPM, and 2.9% (2 of 69) in the probands of families with p16INK4A mutations. With results reported as odds ratio (95% CI), the MITF p.E318K was associated with an increased melanoma risk (3.3 [1.43-7.43]; P < .01), especially in MPM (4.5 [1.83-11.01]; P < .01) and high nevi count (>200 nevi) (8.4 [2.14-33.19]; P < .01). Two fast-growing melanomas were detected among 2 MITF p.E318K carriers during dermatologic digital follow-up. CONCLUSIONS AND RELEVANCE In addition to melanoma risk, MITF p.E318K is associated with a high nevi count and could play a role in fast-growing melanomas. Testing for MITF p.E318K should not exclude patients with known mutations in p16INK4A. Strict dermatologic surveillance, periodic self-examination, and renal cell carcinoma surveillance should be encouraged in this context.

Association of Melanocortin-1 Receptor Variants with Pigmentary Traits in Humans: A Pooled Analysis from the M-Skip Project

Bishop, J; Polsky, D; Lazovich, D; Kumar, R; Ghiorzo, P; Ferrucci, L; Gruis, NA; Puig, S; Kanetsky, PA; Motokawa, T; Ribas, G; Landi, MT; Fargnoli, MC; Wong, TH; Stratigos, A; Helsing, P; Guida, G; Autier, P; Han, J; Little, J; Sera, F; Raimondi, S; M-SKIP Study group, ; , COLLABORATORS; Raimondi, S; Autier, P; Fargnoli, MC; Garca-Borrn, JC; Han, J; Kanetsky, PA; Landi, MT; Little, J; Newton-Bishop, J; Sera, F; Caini, S; Gandini, S; Maisonneuve, P; Hofman, A; Kayser, M; Liu, F; Nijsten, T; Uitterlinden, AG; Kumar, R; Scherer, D; Bishop, T; Newton-Bishop, J; Elliott, F; Nagore, E; Lazovich, D; Polsky, D; Hansson, J; Hoiom, V; Ghiorzo, P; Pastorino, L; Gruis, NA; Bouwes Bavinck, JN; Aguilera, P; Badenas, C; Carrera, C; Gimenez-Xavier, P; Malvehy, J; Potrony, M; Puig, S; Puig-Butille, JA; Tell-Marti, G; Dwyer, T; Blizzard, L; Cochrane, J; Fernandez-de-Misa, R; Branicki, W; Debniak, T; Morling, N; Johansen, P; Mayne, S; Bale, A; Cartmel, B; Ferrucci, L; Pfeiffer, R; Palmieri, G; Ribas, G; Menin, C; Stratigos, A; Kypreou, K; Bowcock, A; Cornelius, L; Council, ML; Motokawa, T; Anno, S; Helsing, P; Andresen, PA; Guida, G; Guida, S; Wong, TH (2016) Association of Melanocortin-1 Receptor Variants with Pigmentary Traits in Humans: A Pooled-Analysis from the M-SKIP Project. The Journal of investigative dermatology, 136 (9). pp. 1914-7. ISSN 0022-202X DOI: https://doi.org/10.1016/j.jid.2016.05.099

Inherited functional variants of the lymphocyte receptor CD5 influence melanoma survival

Despite the recent progress in treatment options, malignant melanoma remains a deadly disease. Besides therapy, inherited factors might modulate clinical outcome, explaining in part widely varying survival rates. T‐cell effector function regulators on antitumor immune responses could also influence survival. CD5, a T‐cell receptor inhibitory molecule, contributes to the modulation of antimelanoma immune responses as deduced from genetically modified mouse models. The CD5 SNPs rs2241002 (NM_014207.3:c.671C > T, p.Pro224Leu) and rs2229177 (NM_014207.3:c.1412C > T, p.Ala471Val) constitute an ancestral haplotype (Pro224‐Ala471) that confers T‐cell hyper‐responsiveness and worsens clinical autoimmune outcome. The assessment of these SNPs on survival impact from two melanoma patient cohorts (Barcelona, N = 493 and Essen, N = 215) reveals that p.Ala471 correlates with a better outcome (OR= 0.57, 95% CI = 0.33–0.99, Adj. p = 0.043, in Barcelona OR = 0.63, 95% CI = 0.40–1.01, Adj. p = 0.051, in Essen). While, p.Leu224 was associated with increased melanoma‐associated mortality in both cohorts (OR = 1.87, 95% CI = 1.07–3.24, Adj. p = 0.030 in Barcelona and OR = 1.84, 95% CI = 1.04–3.26, Adj. p = 0.037, in Essen). Furthermore survival analyses showed that the Pro224‐Ala471 haplotype in homozygosis improved melanoma survival in the entire set of patients (HR = 0.27, 95% CI 0.11–0.67, Adj. p = 0.005). These findings highlight the relevance of genetic variability in immune‐related genes for clinical outcome in melanoma.

Genomic analysis and clinical management of adolescent cutaneous melanoma

Melanoma in young children is rare; however, its incidence in adolescents and young adults is rising. We describe the clinical course of a 15‐year‐old female diagnosed with AJCC stage IB non‐ulcerated primary melanoma, who died from metastatic disease 4 years after diagnosis despite three lines of modern systemic therapy. We also present the complete genomic profile of her tumour and compare this to a further series of 13 adolescent melanomas and 275 adult cutaneous melanomas. A somatic BRAFV600E mutation and a high mutational load equivalent to that found in adult melanoma and composed primarily of C>T mutations were observed. A germline genomic analysis alongside a series of 23 children and adolescents with melanoma revealed no mutations in known germline melanoma‐predisposing genes. Adolescent melanomas appear to have genomes that are as complex as those arising in adulthood and their clinical course can, as with adults, be unpredictable.

IRF4 rs12203592 functional variant and melanoma survival

Inherited genetic factors may modulate clinical outcome in melanoma. Some low‐to‐medium risk genes in melanoma susceptibility play a role in melanoma outcome. Our aim was to assess the role of the functional IRF4 SNP rs12203592 in melanoma prognosis in two independent sets (Barcelona, N = 493 and Essen, N = 438). Genotype association analyses showed that the IRF4 rs12203592 T allele increased the risk of dying from melanoma in both sets (Barcelona: odds ratio [OR] = 6.53, 95% CI 1.38–30.87, Adj p = 0.032; Essen: OR = 1.68, 95% CI 1.04–2.72, Adj p = 0.035). Survival analyses only showed significance for the Barcelona set (hazard ratio = 4.58, 95% CI 1.11–18.92, Adj p = 0.036). This SNP was also associated with tumour localization, increasing the risk of developing melanoma in head or neck (OR = 1.79, 95% CI 1.07–2.98, Adj p = 0.032) and protecting from developing melanoma in the trunk (OR = 0.59, 95% CI 0.41–0.85, Adj p = 0.004). These findings suggest for the first time that IRF4 rs12203592 plays a role in the modulation of melanoma outcome and confirms its contribution to the localization of the primary tumour.

Time and tumor type (primary or metastatic) do not influence the detection of BRAF/NRAS mutations in formalin fixed paraffin embedded samples from melanomas

Abstract Background: BRAF and NRAS mutation detection is crucial for advanced melanoma treatment. Our aim was to evaluate how different characteristics from formalin-fixed paraffin-embedded (FFPE) samples, age of the block or DNA concentration could influence the success of BRAF and NRAS mutational screening. Methods: DNA was obtained from 144 FFPE samples (62 primary melanoma, 43 sentinel lymph nodes [SLN] and 39 metastasis). BRAF and NRAS were sequenced by Sanger sequencing. Results: Complete sequencing results were obtained from 75% (108/144) of the samples, and at least one gene was sequenced in 89% (128/144) of them. BRAF was mutated in 55% (29/53) and NRAS in 11% (5/45) of the primary melanomas sequenced. DNA concentration correlated with the tumor area used for DNA extraction (mm2) (adj p-value<0.01, r=0.73). The age of the block did not affect sequencing success. In 60% of samples kept for more than 10 years, both BRAF and NRAS were successfully sequenced. Conclusions: Preserving sufficient tumor area in FFPE blocks is important. It is necessary to keep the FFPE blocks, no matter their age, as they are necessary to decide the best treatment for the melanoma patient.

KIT Mutations and CD117 Overexpression Are Markers of Better Progression‐Free Survival in Vulvar Melanomas

Few studies have addressed prognostic markers and none has correlated molecular status and prognosis in vulvar melanomas.