Multiple primary melanomas (MPMs) and criteria for genetic assessment: MultiMEL, a multicenter study of the Italian Melanoma Intergroup

Bruno, William; Pastorino, Lorenza; Ghiorzo, Paola; Andreotti, Virginia; Martinuzzi, Claudia; Menin, Chiara; Elefanti, Lisa; Stagni, Camilla; Vecchiato, Antonella; Rodolfo, Monica; Maurichi, Andrea; Manoukian, Siranoush; Giorgi, Vincenzo De; Savarese, Imma; Gensini, Francesca; Borgognoni, Lorenzo; Testori, Alessandro; Spadola, Giuseppe; Mandalà, Mario; Imberti, Gianlorenzo; Savoia, Paola; Astrua, Chiara; Ronco, A.; Farnetti, Alessandra; Tibiletti, Maria Grazia; Lombardo, M.; Palmieri, Giuseppe; Ayala, Fabrizio; Ascierto, Paolo A.; Ghigliotti, Giovanni; Muggianu, M.; Spagnolo, Francesco; Picasso, Virginia; Tanda, Enrica T.; Queirolo, Paola; Bianchi‐Scarrǎ, Giovanna

doi:10.1016/j.jaad.2015.09.053

Cited by 35 publications

(40 citation statements)

References 55 publications

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“…For instance, it is unclear how environment, other prognostic risk factors such as the hair, eye, and skin color, and/or ethnicity contribute to the overall risk in individuals with CDKN2A (or other melanoma gene) mutations. Furthermore, in Italy, it has been determined that in situ melanomas can be included in the “rule of two” criteria applied to the Italian population [44, 45], while in the USA, this data is based on invasive melanomas and individuals with melanoma in situ should be evaluated on an individual basis.…”

Section: Identification and Selection Of Melanoma Genetic Testing Canmentioning

confidence: 99%

Identification, genetic testing, and management of hereditary melanoma

Leachman

Lucero

Sampson

et al. 2017

Cancer Metastasis Rev

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103

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Several distinct melanoma syndromes have been defined, and genetic tests are available for the associated causative genes. Guidelines for melanoma genetic testing have been published as an informal “rule of twos and threes,” but these guidelines apply to CDKN2A testing and are not intended for the more recently described non-CDKN2A melanoma syndromes. In order to develop an approach for the full spectrum of hereditary melanoma patients, we have separated melanoma syndromes into two types: “melanoma dominant” and “melanoma subordinate.” Syndromes in which melanoma is a predominant cancer type are considered melanoma dominant, although other cancers, such as mesothelioma or pancreatic cancers, may also be observed. These syndromes are associated with defects in CDKN2A, CDK4, BAP1, MITF, and POT1. Melanoma-subordinate syndromes have an increased but lower risk of melanoma than that of other cancer(s) seen in the syndrome, such as breast and ovarian cancer or Cowden syndrome. Many of these melanoma-subordinate syndromes are associated with well-established predisposition genes (e.g., BRCA1/2, PTEN). It is likely that these predisposition genes are responsible for the increased susceptibility to melanoma as well but with lower penetrance than that observed for the dominant cancer(s) in those syndromes. In this review, we describe our extension of the “rule of twos and threes” for melanoma genetic testing. This algorithm incorporates an understanding of the spectrum of cancers and genes seen in association with melanoma to create a more comprehensive and tailored approach to genetic testing.

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Section: Identification and Selection Of Melanoma Genetic Testing Canmentioning

confidence: 99%

Identification, genetic testing, and management of hereditary melanoma

Leachman

Lucero

Sampson

et al. 2017

Cancer Metastasis Rev

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103

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“…All melanoma patients had been referred to our center for germline testing either for diagnostic (familial and multiple melanoma cases) or research purposes (sporadic cases from an ongoing case-control study [26–28]). All the patients signed an informed consent under local IRB approved protocols for both germline testing and other research purposes dealing with the archived melanoma tissues in the pathology department.…”

Section: Methodsmentioning

confidence: 99%

Heterogeneity and frequency of BRAF mutations in primary melanoma: Comparison between molecular methods and immunohistochemistry

et al. 2016

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Finding the best technique to identify BRAF mutations with a high sensitivity and specificity is mandatory for accurate patient selection for target therapy. BRAF mutation frequency ranges from 40 to 60% depending on melanoma clinical characteristics and detection technique used.Intertumoral heterogeneity could lead to misinterpretation of BRAF mutational status; this is especially important if testing is performed on primary specimens, when metastatic lesions are unavailable.Aim of this study was to identify the best combination of methods for detecting BRAF mutations (among peptide nucleic acid – PNA-clamping real-time PCR, immunohistochemistry and capillary sequencing) and investigate BRAF mutation heterogeneity in a series of 100 primary melanomas and a subset of 25 matched metastatic samples.Overall, we obtained a BRAF mutation frequency of 62%, based on the combination of at least two techniques. Concordance between mutation status in primary and metastatic tumor was good but not complete (67%), when agreement of at least two techniques were considered. Next generation sequencing was used to quantify the threshold of detected mutant alleles in discordant samples. Combining different methods excludes that the observed heterogeneity is technique-based. We propose an algorithm for BRAF mutation testing based on agreement between immunohistochemistry and PNA; a third molecular method could be added in case of discordance of the results. Testing the primary tumor when the metastatic sample is unavailable is a good option if at least two methods of detection are used, however the presence of intertumoral heterogeneity or the occurrence of additional primaries should be carefully considered.

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“…Germline mutations instead, can be found in multiple or familial cases of CM. The most frequently described germline mutation is in CDKN2A (cyclin-dependent kinase inhibitor 2A) gene occurring in 8-15% of subjects diagnosed with multiple primary melanomas (MPMs) without familial history and up to 40% of patients with hereditary CM 6,25,40,44 . Mutations in other susceptibility genes such as CDK4 (cyclin-dependent kinase 4), MITF (microphtalmia-associated transcription factor) and POT1 (protection of telomeres 1) are less frequently detected 4,14 .…”

Section: Introductionmentioning

confidence: 99%

Unraveling the Role of microRNA and isomiRNA Networks in Multiple Primary Melanoma Pathogenesis

Dika

Broseghini

Porcellini

et al. 2020

Preprint

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Background Malignant cutaneous melanoma (CM) is a potentially lethal form of skin cancer whose worldwide incidence has been constantly increasing over the past decades. During their lifetime about 8% of patients with CM will develop multiple primary melanomas (MPM). Patients affected by MPM could have a genetically determined susceptibility, though germline mutations in hereditary melanoma genes are rarely detected. Methods To better characterize the biology of this subset of melanomas, we explored the miRNome of 24 single and multiple primary melanomas, including multiple tumors from the same patient, using a smallRNA sequencing approach and bioinformatic detection of miRNA isoforms. The differential expression of specific miRNAs/isomiRs was obtained using quantitative PCR.Results From a supervised analysis, 22 miRNAs were differentially expressed in MPM compared to single CM, including key miRNAs involved in epithelial-mesenchymal transition (EMT). Moreover, the first and second melanoma from the same patient presented a different miRNA profile. Ten miRNAs, including miR-25-3p, 149-5p, 92b-3p, 211-5p, 125a-5p, 125b-5p, 205-5p, 200b-3p, 21-5p and 146a-5p, were further validated in a larger cohort of single and multiple melanoma samples (N=47). Overall, the Pathway Enrichment Analysis revealed a more differentiated and less invasive status of MPMs. Analyzing our smallRNA seq data, we detected a panel of melanoma-specific miRNA isoforms (isomiRs), which were validated in The Cancer Genome Atlas SKCM cohort. Specifically, we identified hsa-miR-125a-5p|0|-2 isoform as 10-fold over-represented in melanoma and differentially expressed in MPMs. IsomiR-specific target analysis revealed that the miRNA shortening confers a novel pattern of target gene regulations, including genes implicated in melanocyte differentiation and cell adhesion. Conclusions Overall we provided a comprehensive characterization of the miRNA/isomiRNA regulatory network of multiple primary melanomas, highlighting mechanisms of tumor development and correlating miRNA expression with MPM clinical characteristics.

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Multiple primary melanomas (MPMs) and criteria for genetic assessment: MultiMEL, a multicenter study of the Italian Melanoma Intergroup

Cited by 35 publications

References 55 publications

Identification, genetic testing, and management of hereditary melanoma

Identification, genetic testing, and management of hereditary melanoma

Heterogeneity and frequency of BRAF mutations in primary melanoma: Comparison between molecular methods and immunohistochemistry

Unraveling the Role of microRNA and isomiRNA Networks in Multiple Primary Melanoma Pathogenesis

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