Genome-wide linkage analysis in Spanish melanoma-prone families identifies a new familial melanoma susceptibility locus at 11q

 

The main genetic factors for familial melanoma remain unknown in >75% of families. CDKN2A is mutated in around 20% of melanoma-prone families. Other high-risk melanoma susceptibility genes explain <3% of families studied to date. We performed the first genome-wide linkage analysis in CDKN2A-negative Spanish melanoma-prone families to identify novel melanoma susceptibility loci. We included 68 individuals from 2, 3, and 6 families with 2, 3, and at least 4 melanoma cases. We detected a locus with significant linkage evidence at 11q14.1-q14.3, with a maximum het-TLOD of 3.449 (rs12285365:A>G), using evidence from multiple pedigrees. The genes contained by the subregion with the strongest linkage evidence were: DLG2, PRSS23, FZD4, and TMEM135. We also detected several regions with suggestive linkage evidence (TLOD >1.9) (1q, 6p, 7p, 11q, 12p, 13q) including the region previously detected in melanoma-prone families from Sweden at 3q29. The family-specific analysis revealed three loci with suggestive linkage evidence for family #1: 1q31.1-q32.1 (max. TLOD 2.447), 6p24.3-p22.3 (max. TLOD 2.409), and 11q13.3-q21 (max. TLOD 2.654). Future next-generation sequencing studies of these regions may allow the identification of new melanoma susceptibility genetic factors.

https://www.ncbi.nlm.nih.gov/pubmed/29706638

#acralmelanoma  #melanoma  #susanapuig #josepmalvehy #cristinacarrera #skincancer #paulaaguilera  #thegooddoctor #topdoctors #familialmelanoma #cdkn2a #skincancer #skinmelanoma  

La ciencia de la salud - En tu propia piel (TVE La2)

Entrevista Dra Susana Puig

Es el órgano más grande y más visible del cuerpo humano, pero a menudo pasa desapercibido. Siempre sensible, la piel nos protege del mundo que nos rodea. Es el momento de empezar a protegerla a ella

http://www.rtve.es/alacarta/videos/la-ciencia-de-la-salud/ciencia-salud-tu-propia-piel/4643931/

#susanapuig #diagnosisdermatologica #cedilp #melanoma #carcinoma #hospitalclinic #cancerpiel #cancerdepiel #deteccioncancerdepiel #tratamientocancerdepiel #microscopia #aedv #topdoctors #fotoproteccionsolar #rayosuva #fotoenvejecimiento #cremassolares #entupropiapiel #protegerlapieldelsol #elsolylapiel #dermatólogo #dermatóloga

AURKA Overexpression Is Driven by FOXM1 and MAPK/ERK Activation in Melanoma Cells Harboring BRAF or NRAS Mutations: Impact on Melanoma Prognosis and Therapy

AURKA Overexpression Is Driven by FOXM1 and MAPK/ERK Activation in Melanoma Cells Harboring BRAF or NRAS Mutations: Impact on Melanoma Prognosis and Therapy

Abstract

The cell cycle-related genes AURKA and FOXM1 are overexpressed in melanoma. We show here that AURKA overexpression is associated with poor prognosis in three independent cohorts of melanoma patients and correlates with the presence of genomic amplification of AURKA locus and BRAF^V600E mutation. AURKA overexpression may also be driven by increased promoter activation through elements such as ETS and FOXM1 found within the 5' proximal promoter region. Activated MAPK/ERK signaling pathway mediates robust AURKA promoter activation, thereby knockdown of BRAF^V600E and ERK inhibition results in reduced AURKA transcription and expression. We show a positive correlation between FOXM1 and AURKA expression in three independent cohorts of melanoma patients. FOXM1 silencing decreases expression of AURKA and late cell cycle genes in melanoma cells. We further found that FOXM1 expression levels are significantly higher in tumors carrying the BRAF^V600E mutation compared with the wild-type BRAF (BRAF^wt). Accordingly, the knockdown of BRAF^V600E also reduces the expression of FOXM1 in BRAF^V600E cells. Moreover, Aurora kinase A and FOXM1 inhibition by either genetic knockdown or pharmacologic inhibitors impair melanoma growth and survival both in culture and in vivo, underscoring their therapeutic value for melanoma patients who fail to benefit from BRAF/MEK signaling inhibition.

https://www.ncbi.nlm.nih.gov/pubmed/28188776

#mutationsmelanoma #melanoma #malvehy #josepmalvehy #skincancer #aurka #braf

Sentinel lymph node biopsy versus observation in thick melanoma: A multicenter propensity score matching study.

Sentinel lymph node biopsy versus observation in thick melanoma: A multicenter propensity score matching study.

https://www.ncbi.nlm.nih.gov/pubmed/28960289

Abstract

The clinical value of sentinel lymph node (SLN) biopsy in thick melanoma patients (Breslow >4 mm) has not been sufficiently studied. The aim of the study is to evaluate whether SLN biopsy increases survival in patients with thick cutaneous melanoma, and, as a secondary objective, to investigate correlations between survival and lymph node status. We included 1,211 consecutive patients with thick melanomas (>4 mm) registered in the participating hospitals' melanoma databases between 1997 and 2015. Median follow-up was 40 months. Of these patients, 752 were matched into pairs by propensity scores based on sex, age, tumor location, histologic features of melanoma, year of diagnosis, hospital and adjuvant interferon therapy. The SLN biopsy vs. observation was associated with better DFS [adjusted hazard ratio (AHR), 0.74; 95% confidence interval (CI) 0.61-0.90); p = 0.002] and OS (AHR, 0.75; 95% CI, 0.60-0.94; p = 0.013) but not MSS (AHR, 0.84; 95% CI, 0.65-1.08; p = 0.165). SLN-negative patients had better 5- and 10-year MSS compared with SLN-positive patients (65.4 vs. 51.9% and 48.3 vs. 38.8%; p = 0.01, respectively). As a conclusion, SLN biopsy was associated with better DFS but not MSS in thick melanoma patients after adjustment for classic prognostic factors. SLN biopsy is useful for stratifying these patients into different prognostic groups.


#melanoma #josepmalvehy #susanapuig #Mohs #dermoscopy #sentinellymphnode #skincancer #topdoctors #dermatologiabarcelona #cutaneousbarcelona #diagnosisdermatologica
 

Melanocortin 1 receptor (MC1R) polymorphisms' influence on size and dermoscopic features of nevi.

Melanocortin 1 receptor (MC1R) polymorphisms' influence on size and dermoscopic features of nevi.

https://www.ncbi.nlm.nih.gov/pubmed/28950052

Abstract

The melanocortin 1 receptor (MC1R) is a highly polymorphic gene. The loss-of-function MC1R variants ("R") have been strongly associated with red hair color phenotype and an increased melanoma risk. We sequenced the MC1R gene in 175 healthy individuals to assess the influence of MC1R on nevus phenotype. We identified that MC1R variant carriers had larger nevi both on the back [p-value = .016, adjusted for multiple parameters (adj. p-value)] and on the upper limbs (adj. p-value = .007). Specifically, we identified a positive association between the "R" MC1R variants and visible vessels in nevi [p-value = .033, corrected using the FDR method for multiple comparisons (corrected p-value)], dots and globules in nevi (corrected p-value = .033), nevi with eccentric hyperpigmentation (corrected p-value = .033), a high degree of freckling (adj. p-value = .019), and an associative trend with presence of blue nevi (corrected p-value = .120). In conclusion, the MC1R gene appears to influence the nevus phenotype.

#melanocortin #josepmalvehy #susanapuig #dermoscopic #confocal #Mohs #dermatology #topdoctors #mc1r #melanoma #skincancer #dermatologiabarcelona #clinicadermatologica #cedilp