Familial Melanoma: Diagnostic and Management Implications

Rossi, Michele; Pellegrini, Cristina; Cardelli, Ludovica; Ciciarelli, Valeria; Nardo, Lucia Di; Fargnoli, Maria Concetta

doi:10.5826/dpc.0901a03

Cited by 76 publications

(64 citation statements)

References 65 publications

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“…In this context, it will be interesting to analyze the rate of MGRN1 mutations in melanoma families without mutations in known susceptibility genes such as CDKN2A , CDK4 , BAP1 , TERT , POT1 , ACD , TERF2IP , and MITF . Interestingly, mutations in these genes are only found in 30–50% of melanoma families [ 61 ].…”

Section: Discussionmentioning

confidence: 99%

Mahogunin Ring Finger 1 Is Required for Genomic Stability and Modulates the Malignant Phenotype of Melanoma Cells

Martínez-Vicente

Abrisqueta

Herráiz

et al. 2020

Cancers

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The mouse mahoganoid mutation abrogating Mahogunin Ring Finger-1 (MGRN1) E3 ubiquitin ligase expression causes hyperpigmentation, congenital heart defects and neurodegeneration. To study the pathophysiology of MGRN1 loss, we compared Mgrn1-knockout melanocytes with genetically matched controls and melan-md1 (mahoganoid) melanocytes. MGRN1 knockout induced a more differentiated and adherent phenotype, decreased motility, increased the percentage of cells in the S phase of the cell cycle and promoted genomic instability, as shown by stronger γH2AX labelling, increased burden of DNA breaks and higher abundance of aneuploid cells. Lack of MGRN1 expression decreased the ability of melanocytes to cope with DNA breaks generated by oxidizing agents or hydroxyurea-induced replicative stress, suggesting a contribution of genomic instability to the mahoganoid phenotype. MGRN1 knockout in B16-F10 melanoma cells also augmented pigmentation, increased cell adhesion to collagen, impaired 2D and 3D motility and caused genomic instability. Tumors formed by Mgrn1-KO B16-F10 cells had lower mitotic indices, fewer Ki67-positive cells and showed a trend towards smaller size. In short-term lung colonization assays Mgrn1-KO cells showed impaired colonization potential. Moreover, lower expression of MGRN1 is significantly associated with better survival of human melanoma patients. Therefore, MGRN1 might be an important phenotypic determinant of melanoma cells.

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Section: Discussionmentioning

confidence: 99%

Mahogunin Ring Finger 1 Is Required for Genomic Stability and Modulates the Malignant Phenotype of Melanoma Cells

Martínez-Vicente

Abrisqueta

Herráiz

et al. 2020

Cancers

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“…Non-melanoma skin cancer, other cancer types, gender, race, a higher number of nevi (especially dysplastic nevi), actinic skin damage, and family history of melanoma are all risk factors for hereditary melanoma [5,7]. Furthermore, hereditary melanoma has been associated with germline mutations in high-risk melanoma susceptibility genes (CDKN2A, CDK4, TERT, POT1) [8][9][10][11][12][13], polymorphisms in intermediate-risk melanoma susceptibility genes (BAP1, ACD, TERF2IP, MC1R and MITF) [14][15][16], and germline missense substitutions in MITF [17]. Germline mutations in CDKN2A are present in~20-40% of multiple primary melanomas (MPM) cases [16].…”

Section: Introductionmentioning

confidence: 99%

“…Furthermore, hereditary melanoma has been associated with germline mutations in high-risk melanoma susceptibility genes (CDKN2A, CDK4, TERT, POT1) [8][9][10][11][12][13], polymorphisms in intermediate-risk melanoma susceptibility genes (BAP1, ACD, TERF2IP, MC1R and MITF) [14][15][16], and germline missense substitutions in MITF [17]. Germline mutations in CDKN2A are present in~20-40% of multiple primary melanomas (MPM) cases [16]. CDK4, POT1, ACD, TERF2IP, and MITF germline mutations were identified in~0.6-14.3% of MPM cases [16,18,19], while MC1R polymorphisms were detected in 60.5-82.1% [20,21] of MPM patients.…”

Section: Introductionmentioning

confidence: 99%

“…Germline mutations in CDKN2A are present in~20-40% of multiple primary melanomas (MPM) cases [16]. CDK4, POT1, ACD, TERF2IP, and MITF germline mutations were identified in~0.6-14.3% of MPM cases [16,18,19], while MC1R polymorphisms were detected in 60.5-82.1% [20,21] of MPM patients. Furthermore, despite being described in only two families, TERT mutations have been described as high-risk melanoma susceptibility genes.…”

Section: Introductionmentioning

confidence: 99%

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High-Throughput Sequencing Identifies 3 Novel Susceptibility Genes for Hereditary Melanoma

Campos¹,

Fragoso²,

Luís³

et al. 2020

Genes

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Cutaneous melanoma is one of the most aggressive human cancers due to its high invasiveness. Germline mutations in high-risk melanoma susceptibility genes have been associated with development hereditary melanoma; however, most genetic culprits remain elusive. To unravel novel susceptibility genes for hereditary melanoma, we performed whole exome sequencing (WES) on eight patients with multiple primary melanomas, high number of nevi, and negative for high and intermediate-risk germline mutations. Thirteen new potentially pathogenic variants were identified after bioinformatics analysis and validation. CDH23, ARHGEF40, and BRD9 were identified as the most promising susceptibility genes in hereditary melanoma. In silico analysis of CDH23 and ARHGEF40 variants provided clues for altered protein structure and function associated with the identified mutations. Then, we also evaluated the clinical value of CDH23, ARHGEF40, and BRD9 expression in sporadic melanoma by using the TCGA dataset (n = 461). No differences were observed in BRD9 expression between melanoma and normal skin samples, nor with melanoma stage, whereas ARHGEF40 was found overexpressed, and CDH23 was downregulated and its loss was associated with worse survival. Altogether, these results reveal three novel genes with clinical relevance in hereditary and sporadic melanoma.

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“…Familial melanoma (also known as familial melanoma syndrome, B-K mole syndrome or dysplastic nevus syndrome) is an inherited condition generally defined as presence of melanoma in two or more first degree relatives such as parents or siblings and characterised by atypical nevi and multiple inherited melanomas. About 10% of all melanomas are familial [251]. Two meta-analyses found a significant association between familial predisposition to melanoma and risk of developing melanoma in siblings [125,252] and estimated that the proportion of melanoma attributable to familial predisposition was around 7% [252].…”

Section: Family History Of Melanomamentioning

confidence: 99%

Epidemiologic studies of cancers of the skin

Dusingize¹

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Background Skin cancers are the most common form of cancer occurring in white populations. They account for approximately 40% of all cancer cases globally, with the highest incidence in Australia. The three most common histological types of skin cancer are basal cell carcinoma (BCC), cutaneous squamous cell carcinoma (cSCC) and melanoma. The risk of developing skin cancer depends on both environmental and constitutional factors. Exposure to ultraviolet radiation (UVR) is the major environmental risk factor for BCC, cSCC and melanoma, and skin phenotypic characteristics are the major constitutional risk factors. Cigarette smoking, obesity and height have been shown to have an etiologic effect for many cancers in humans, but their associations with skin cancer are unclear. Studies examining the relationships between these factors and skin cancer have been limited by factors such as lack of information on established skin cancer risk factors, inadequate approach to statistical analyses, and lack of exploration of other potential sources of bias, such as detection bias. Aim The overall aim of this thesis was to assess whether cigarette smoking, obesity (estimated by body mass index (BMI)) and height are independent risk factors for BCC, cSCC and melanoma using various epidemiological and statistical techniques. In particular, the research aimed to address some of the limitations arising from previous studies. Methods This research was conducted using data from the QSkin Sun and Health Study (n=43,794), supplemented by linkage to various health databases including the Australian national health insurance scheme (Medicare), pathology laboratories and the Queensland Cancer Registry. Smoking history, BMI and height were self-reported at baseline, with nearly perfect repeatability. Hazard ratios (HRs) and 95% confidence intervals (CIs) for associations between smoking, BMI and height were estimated using multivariable Cox proportional hazards regression, accounting for death as a competing event. viii Acknowledgements Undertaking this PhD journey has been a truly life-changing experience for me and the work presented in this thesis would not have been possible without the support that I received from many people. I would like to express my special appreciation and thanks to my principal supervisor Professor David Whiteman. Thank you for giving me your time and support over the years. Your advice on both research as well as on my career have been invaluable. You have taught me how to think critically, communicate more clearly and concisely and become a better researcher. Thank you for allowing me to pursue various projects without objection.

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Familial Melanoma: Diagnostic and Management Implications

Cited by 76 publications

References 65 publications

Mahogunin Ring Finger 1 Is Required for Genomic Stability and Modulates the Malignant Phenotype of Melanoma Cells

Mahogunin Ring Finger 1 Is Required for Genomic Stability and Modulates the Malignant Phenotype of Melanoma Cells

High-Throughput Sequencing Identifies 3 Novel Susceptibility Genes for Hereditary Melanoma

Epidemiologic studies of cancers of the skin

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