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. 2020 Dec 11;21(24):9432.
doi: 10.3390/ijms21249432.

A Single Center Retrospective Review of Patients from Central Italy Tested for Melanoma Predisposition Genes

Paola De Simone  1 , Irene Bottillo  2 , Michele Valiante  2 , Alessandra Iorio  1 , Carmelilia De Bernardo  2 , Silvia Majore  2 , Daniela D'Angelantonio  2 , Tiziana Valentini  2 , Isabella Sperduti  3 , Paolo Piemonte  1 , Laura Eibenschutz  1 , Angela Ferrari  1 , Anna Carbone  1 , Pierluigi Buccini  1 , Alessandro Paiardini  4 , Vitaliano Silipo  1 , Pasquale Frascione  1 , Paola Grammatico  2
Affiliations

A Single Center Retrospective Review of Patients from Central Italy Tested for Melanoma Predisposition Genes

Paola De Simone et al. Int J Mol Sci. .

Abstract

Background: Cutaneous malignant melanoma (CMM) is one of the most common skin cancers worldwide. CMM pathogenesis involves genetic and environmental factors. Recent studies have led to the identification of new genes involved in CMM susceptibility: beyond CDKN2A and CDK4, BAP1, POT1, and MITF were recently identified as potential high-risk melanoma susceptibility genes.

Objective: This study is aimed to evaluate the genetic predisposition to CMM in patients from central Italy.

Methods: From 1998 to 2017, genetic testing was performed in 888 cases with multiple primary melanoma and/or familial melanoma. Genetic analyses included the sequencing CDKN2A, CDK4, BAP1, POT1, and MITF in 202 cases, and of only CDKN2A and CDK4 codon 24 in 686 patients. By the evaluation of the personal and familial history, patients were divided in two clinical categories: "low significance" and "high significance" cases.

Results: 128 patients (72% belonging to the "high significance" category, 28% belonging to the "low significance" category) were found to carry a DNA change defined as pathogenic, likely pathogenic, variant of unknown significance (VUS)-favoring pathogenic or VUS.

Conclusions: It is important to verify the genetic predisposition in CMM patients for an early diagnosis of further melanomas and/or other tumors associated with the characterized genotype.

Keywords: familial melanoma; melanoma susceptibility genes; multiple primary melanoma.

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Conflict of interest statement

The authors declare no conflict of interest.

Figures

Figure 1
Figure 1
Distribution of other cancers than cutaneous melanoma in the patients’ cohort. The type of tumor is given on the x-axis, the percentage of patients is given on the y-axis. ca: cancer; H: Hodgkin; nH: non Hodgkin; n.a.: not assessed.
Figure 2
Figure 2
Spectrum of genetic alterations identified in “low significance” and “high significance” cutaneous melanoma patients by the use of both Sanger and NGS testing approach. The percentage of cases is given nearby each data series represented in the pie charts.
Figure 3
Figure 3
Patients with positive genetic testing results. The proportion of “high significance” and “low significance” patients carrying Pathogenic (P), Likely Pathogenic (LP), VUS-favoring pathogenic (VUS-3B), and VUS variants is shown for each of the analyzed genes. H: high significance patients, L: low significance patients.
Figure 4
Figure 4
CDKN2A variants mapped over the genic structure and over the 4 coded isoforms. Exons are in scale and are represented as grey rectangles on the top. Introns are not in scale and they are represented by a black line through the genic sequence. The CDKN2A isoforms (i.e., p12, p14, p16 and p16γ) are shown on the bottom as colored rectangles. The DNA variants are name according the hg19 Human Genome Assembly.
Figure 5
Figure 5
Molecular modeling analysis and localization of missense changes affecting p16 CDKN2A isoform. Proteins are represented as ribbons and colored according to protein chain. Wild-type and mutant residues are represented in blue and red sticks, respectively.
Figure 6
Figure 6
Flow chart on the therapeutic diagnostic path of the patient with familial melanoma or/and multiple primary melanoma.
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