Genetic susceptibility to cutaneous melanoma in southern Switzerland: role ofCDKN2A,MC1RandMITF

Mangas, Cristina; Potrony, Míriam; Mainetti, Carlo; Bianchi, Elena; Merlani, P. Carrozza; Eberhardt, Anaïs; Maspoli-Postizzi, E.; Marazza, G.; Marcollo-Pini, A.; Pelloni, F.; Sessa, Cristiana; Bulgarelli, S.; Puig-Butillé, Joan Antón; Badenas, Cèlia; Puig, Susana

doi:10.1111/bjd.14897

Cited by 16 publications

(14 citation statements)

References 33 publications

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“…Although CDKN2A mutations confer an increased risk of melanoma, not all carriers of the mutation develop this pathology, suggesting that other environmental, clinical, and genetic factors contribute to increase the risk of melanoma [26][27][28]. Indeed, when assessing the relationship between geographical location and individual risk of bearing a CDKN2A mutation, it is important to take into account the variability of melanoma incidence in the general population and the degree of penetrance of CDKN2A mutations for each specific country considered [7,16,17]. It appears, in fact, that in regions with higher incidence of melanoma there is a greater possibility of finding multiple family members with melanoma or multiple primary melanomas caused by reasons other than CDKN2A mutations.…”

Section: Cdkn2amentioning

confidence: 99%

See 1 more Smart Citation

Familial Melanoma and Susceptibility Genes: A Review of the Most Common Clinical and Dermoscopic Phenotypic Aspect, Associated Malignancies and Practical Tips for Management

Zocchi

Lontano

Merli

et al. 2021

JCM

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A family history of melanoma greatly increases the risk of developing cutaneous melanoma, a highly aggressive skin cancer whose incidence has been steadily increasing worldwide. Familial melanomas account for about 10% of all malignant melanomas and display an inheritance pattern consistent with the presence of pathogenic germline mutations, among which those involving CDKN2A are the best characterized. In recent years, a growing number of genes, such as MC1R, MITF, CDK4, POT1, TERT, ACD, TERF2IP, and BAP1, have been implicated in familial melanoma. The fact that individuals harboring these germline mutations along with their close blood relatives have a higher risk of developing multiple primary melanomas as well as other internal organ malignancies, especially pancreatic cancer, makes cascade genetic testing and surveillance of these families of the utmost importance. Unfortunately, due to a polygenic inheritance mechanism involving multiple low-risk alleles, genetic modifiers, and environmental factors, it is still very difficult to predict the presence of these mutations. It is, however, known that germline mutation carriers can sometimes develop specific clinical traits, such as high atypical nevus counts and specific dermoscopic features, which could theoretically help clinicians predict the presence of these mutations in prone families. In this review, we provide a comprehensive overview of the high- and intermediate-penetrance genes primarily linked to familial melanoma, highlighting their most frequently associated non-cutaneous malignancies and clinical/dermoscopic phenotypes.

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Section: Cdkn2amentioning

confidence: 99%

“…The genes that predispose to melanoma are classified as low, medium, and high penetrance genes (Table 1) [13][14][15][16][17]. Each of these genes has a different intrinsic mechanism whose mutations can lead to the inactivation of fundamental biological mechanisms regulating cellular integrity.…”

Section: Introductionmentioning

confidence: 99%

Familial Melanoma and Susceptibility Genes: A Review of the Most Common Clinical and Dermoscopic Phenotypic Aspect, Associated Malignancies and Practical Tips for Management

Zocchi

Lontano

Merli

et al. 2021

JCM

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“…These analyses included melanoma-prone families and individuals with multiple cutaneous melanomas. A recent study reported the analysis of 27 melanoma-prone families, showing: CDKN2A V126D mutation in 7/27; CDKN2A A148T was observed in 7/27 (this germline mutation was observed in 7/146 normal healthy blood donors); MC1R melanoma-associated polymorphism was detected in 78% of cases (and 66% in healthy donors); the MITF E318K mutant was observed in 7% of cases (and in 0.7% of healthy controls) [ 114 ].…”

Section: Molecular Abnormalitiesmentioning

confidence: 99%

Melanoma: Genetic Abnormalities, Tumor Progression, Clonal Evolution and Tumor Initiating Cells

Testa

Castelli

2017

Medical Sciences

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Melanoma is an aggressive neoplasia issued from the malignant transformation of melanocytes, the pigment-generating cells of the skin. It is responsible for about 75% of deaths due to skin cancers. Melanoma is a phenotypically and molecularly heterogeneous disease: cutaneous, uveal, acral, and mucosal melanomas have different clinical courses, are associated with different mutational profiles, and possess distinct risk factors. The discovery of the molecular abnormalities underlying melanomas has led to the promising improvement of therapy, and further progress is expected in the near future. The study of melanoma precursor lesions has led to the suggestion that the pathway of tumor evolution implies the progression from benign naevi, to dysplastic naevi, to melanoma in situ and then to invasive and metastatic melanoma. The gene alterations characterizing melanomas tend to accumulate in these precursor lesions in a sequential order. Studies carried out in recent years have, in part, elucidated the great tumorigenic potential of melanoma tumor cells. These findings have led to speculation that the cancer stem cell model cannot be applied to melanoma because, in this malignancy, tumor cells possess an intrinsic plasticity, conferring the capacity to initiate and maintain the neoplastic process to phenotypically different tumor cells.

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“…A rare functional variant of MITF(E318K) has been shown to disrupt a conserved SUMOylation site and to confer a two-to fourfold risk for cutaneous melanoma 1,2 . Moreover, there have been small studies suggesting that this variant is also associated with other cancers such as renal cell carcinoma (RCC) [1][2][3][4][5][6][7][8][9][10][11][12][13] . However, since epidemiologic observations have documented an association between cutaneous melanoma and many other malignancies, including RCC, it is possible that MITF(E318K) represents a germline "passenger" mutation in these other cancers without directly impacting the risk of these other cancers such as RCC.…”

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confidence: 99%

Cancer risks associated with the germline MITF(E318K) variant

Guhan

Artomov

McCormick

et al. 2020

Sci Rep

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The MITF(E318K) variant confers moderate risk for cutaneous melanoma. While there are small studies suggesting that this risk is associated with other malignancies (e.g. renal cell carcinoma), little is known about the role of this variant in specifying risk for other cancers. In this study, we perform a systematic review and meta-analysis of the published data as a backdrop to a whole-exome sequence(WES)-based characterization of MITF(E318K) risk for various cancers in sporadic samples from the TCGA and several genetically-enriched patient cohorts. We found minimal evidence of MITF(E318K)’s contribution to non-melanoma cancer risk among individuals with low inherited risks of melanoma (OR 1.168; 95% CI 0.78–1.74; p = 0.454), suggesting that earlier reports of an association between this variant and other malignancies may be related to shared environmental or polygenic risk factors rather than MITF(E318K). Interestingly, an association was observed with uterine carcinosarcoma, (OR 9.24; 95% CI 2.08–37.17; p = 0.024), which was not previously described. While more research needs to be completed, this study will help update cancer screening recommendations for patients with the MITF(E318K) variant.

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Genetic susceptibility to cutaneous melanoma in southern Switzerland: role ofCDKN2A,MC1RandMITF

Cited by 16 publications

References 33 publications

Familial Melanoma and Susceptibility Genes: A Review of the Most Common Clinical and Dermoscopic Phenotypic Aspect, Associated Malignancies and Practical Tips for Management

Familial Melanoma and Susceptibility Genes: A Review of the Most Common Clinical and Dermoscopic Phenotypic Aspect, Associated Malignancies and Practical Tips for Management

Melanoma: Genetic Abnormalities, Tumor Progression, Clonal Evolution and Tumor Initiating Cells

Cancer risks associated with the germline MITF(E318K) variant

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