Differences in Clinicopathological Features and Distribution of Risk Factors in Italian Melanoma Patients

Fava, Paolo; Astrua, Chiara; Chiarugi, Alessandra; Crocetti, Emanuele; Pimpinelli, Nicola; Fargnoli, Maria Concetta; Maurichi, Andrea; Rubegni, Pietro; Manganoni, Ausilia Maria; Bottoni, Ugo; Catricalà, Caterina; Cavicchini, S.; Santinami, Mario; Alaibac, Mauro; Annetta, Alessandro; Borghi, Alessandro; Calzavara‐Pinton, Piergiacomo; Capizzi, Rodolfo; Clerico, Rita; Colombo, Enrico; Corradin, Maria Teresa; Simone, Paola De; Fantini, Fabrizio; Ferreli, Caterina; Filosa, Giorgio; Girgenti, V.; Giulioni, Erika; Guarneri, Claudio; Lamberti, Arianna; Lisi, Paolo; Nardini, Paolo; Papini, Manuela; Peris, Ketty; Pizzichetta, Maria Antonietta; Salvini, Camilla; Savoia, Paola; Strippoli, Davide; Tolomio, Elena; Tomassini, Marco; Veña, Gino Antonio; Zichichi, Leonardo; Patrizi, Annalisa; Argenziano, Giuseppe; Simonacci, Marco; Quaglino, Pietro

doi:10.1159/000368775

Cited by 5 publications

(3 citation statements)

References 18 publications

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“…In contrast with these findings, in our series, we did not find a significant difference in terms of skin type between MUTs and WTs. In our patients, the phototype distribution is comparable to that of the Mediterranean area population, regardless of CDKN2A gene status [15]. This finding could depend on the fact that the CDKN2A gene encodes two distinct proteins (p16INN4 p16INK4a and p14ARF) that act as tumour suppressors, while they have no direct influence on the skin phototype.…”

Section: Discussionsupporting

confidence: 59%

Melanoma-prone families: new evidence of distinctive clinical and histological features of melanomas in CDKN2A mutation carriers

et al. 2018

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Germline mutations on the CDKN2A gene, the most important known genetic factors associated with cutaneous melanomas (CMs), predispose carriers to multiple primary CMs (MPMs) with higher frequency and younger onset compared to non-carriers. Most of the largest published studies concerning clinical and histological characteristics of CMs with CDKN2A mutation carriers did not specify if the described CMs are first or subsequent to the first, and they used sporadic CMs from non-genotyped patients as controls. We conducted a single-centre observational study to compare clinical and histological CM features of 32 unrelated carriers (MUT) of 5 germline CDKN2A mutations (one of which was never previously described) compared to 100 genotyped wild-type (WT) patients. We stratified the data based on time of diagnosis, anatomical site and histological subtype of CMs, demonstrating several significant unreported differences between the two groups. MUT developed a higher number of dysplastic nevi and MPMs. We proved for the first time that anatomical distribution of CMs in MUT was independent of gender, unlike WTs. MUTs developed in situ and superficial spreading melanomas (SSMs) more frequently, with significantly higher number of SSMs on the head/neck. In MUTs, Breslow thickness was significantly lower for all invasive CMs. When CMs were stratified on the basis of the time of occurrence, statistical significance was maintained only for SSMs subsequent to the first. In WTs, Clark level was significantly higher, and ulceration was more prevalent than in MUTs. Significant differences in ulceration were observed only in SSMs. In nodular CMs, we did not find differences in terms of Breslow thickness or ulceration between WTs and MUTs. In situ CMs developed 10 years earlier in MUTs with respect to WTs, whereas no significant differences were observed in invasive CMs. In contrast to those reported previously by other authors, we did not find a difference in skin phototype.

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Section: Discussionsupporting

confidence: 59%

Melanoma-prone families: new evidence of distinctive clinical and histological features of melanomas in CDKN2A mutation carriers

et al. 2018

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“…Among all skin tumors, melanoma is the most aggressive form because of rapid metastasis and resistance to conventional radio- and chemotherapy ( 1 – 3 ). The advances in understanding the microenvironment of melanoma and cell biology make it obvious that the treatment needs to be multi-directional.…”

Section: Introductionmentioning

confidence: 99%

FOXP3 expression is modulated by TGF‑β1/NOTCH1 pathway in human melanoma

et al. 2018

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Forkhead box protein 3 (FOXP3) transcription factor is expressed by immune cells and several human cancers and is associated with tumor aggressiveness and unfavorable clinical outcomes. NOTCH and transforming growth factor-β (TGF-β) protumorigenic effects are mediated by FOXP3 expression in several cancer models; however, their interaction and role in melanoma is unknown. We investigated TGF-β-induced FOXP3 gene expression during NOTCH1 signaling inactivation. Primary (WM35) and metastatic melanoma (A375 and A2058) cell lines and normal melanocytes (NHEM) were used. FOXP3 subcellular distribution was evaluated by immuno cytochemical analysis. Gene expression levels were assessed by reverse transcription-quantitative polymerase chain reaction. Protein levels were assessed by western blot analysis. The γ-secretase inhibitor (GSI) was used for NOTCH1 inhibition and recombinant human (rh)TGF-β was used for melanoma cell stimulation. Cell proliferation and viability were respectively assessed by MTT and Trypan blue dye assays. FOXP3 mRNA and protein levels were progressively higher in WM35, A375 and A2058 cell lines compared to NHEM and their levels were further increased after stimulation with rh-TGF-β. TGF-β-mediated FOXP3 expression was mediated by NOTCH1 signaling. Inhibition of NOTCH1 with concomitant rh-TGF-β stimulation determined the reduction in gene expression and protein level of FOXP3. Finally, melanoma cell line proliferation and viability were reduced by NOTCH1 inhibition. The results show that nn increase in FOXP3 expression in metastatic melanoma cell lines is a potential marker of tumor aggressiveness and metastasis. NOTCH1 is a central mediator of TGF-β-mediated FOXP3 expression and NOTCH1 inhibition produces a significant reduction of melanoma cell proliferation and viability.

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“…The incidence of cutaneous melanoma is increasing (1,2). Although much progress has been made in terms of immuno- and chemotherapy, the mortality rate for patients with melanoma remains very high, as it is a very aggressive disease (3,4).…”

Section: Introductionmentioning

confidence: 99%

NF-κB inhibition is associated with OPN/MMP-9 downregulation in cutaneous melanoma

et al. 2017

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The development of cutaneous melanoma is influenced by genetic factors, including BRAF mutations and environmental factors, such as ultraviolet exposure. Its progression has been also associated with the involvement of several tumour microenvironmental molecules. Among these, nuclear factor-κB (NF-κB) has been indicated as a key player of osteopontin (OPN) and matrix metalloproteinase-9 (MMP-9) activation. However, whether NF-κB plays a role in the development and progression of melanoma in association with the OPN/MMP-9 axis according to the BRAFV600E mutation status has not been investigated in detail to date. Thus, in the present study, in order to shed light on this matter, 148 patients with melanoma and 53 healthy donors were recruited for the analysis of OPN, MMP-9 and NF-κB. Significantly higher circulating levels of OPN and MMP-9 were observed in the patients with melanoma when compared to the healthy donors. Similar data were obtained for NF-κB p65 activity. The OPN levels did not differ significantly between melanomas with or without BRAFV600E mutation. However, as regards NF-κB and MMP-9, significant differences were observed between the melanomas with or without BRAFV600E mutation. To determine whether NF-κB inhibition is associated with a decrease in the levels of OPN and MMP-9, peripheral blood mononuclear cells from 29 patients with melanoma were treated with the NF-κB inhibitor, dehydroxymethylepoxyquinomycin (DHMEQ), with or without OPN. As expected, the inhibition of NF-κB induced a marked decrease in both the OPN and MMP-9 levels. Furthermore, the decrease in MMP-9 levels was higher among melanomas harbouring the BRAFV600E mutation. Overall, our data suggest that the activation of MMP-9 is associated with the BRAFV600E mutation status. Furthermore, such an activation is mediated by NF-κB, suggesting its role as therapeutic target in patients with melanoma.

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Differences in Clinicopathological Features and Distribution of Risk Factors in Italian Melanoma Patients

Cited by 5 publications

References 18 publications

Melanoma-prone families: new evidence of distinctive clinical and histological features of melanomas in CDKN2A mutation carriers

Melanoma-prone families: new evidence of distinctive clinical and histological features of melanomas in CDKN2A mutation carriers

FOXP3 expression is modulated by TGF‑β1/NOTCH1 pathway in human melanoma

NF-κB inhibition is associated with OPN/MMP-9 downregulation in cutaneous melanoma

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