Insights into Genetic Susceptibility to Melanoma by Gene Panel Testing: Potential Pathogenic Variants in ACD, ATM, BAP1, and POT1

Maurizio Genuardi, Pietro Chiurazzi, Giorgio Spadola, Elisabetta Sala, Maria Francesca Grillo, Lorenza Pastorino, Virginia Andreotti, Bruna Dalmasso, Irene Vanni, Giulia Ciccarese, Mario Mandalà, Giuseppe Spadola, Maria Antonietta Pizzichetta, Giovanni Ponti, Maria Grazia Tibiletti, Elena Sala, Gabriele Maccanti, Siranoush Manoukian, Serena Sestini, Rita DanesiValentina Zampiga, Roberta La Starza, Ignazio Stanganelli, Alberto Ballestrero, Luca Mastracci, Federica Grillo, Stefania Sciallero, Federica Cecchi, Enrica Teresa Tanda, Francesco Spagnolo, Paola Queirolo, Alisa M. Goldstein, William Bruno, Paola Ghiorzo

Risultato della ricerca: Contributo in rivistaArticolo in rivista

5 Citazioni (Scopus)

Abstract

The contribution of recently established or candidate susceptibility genes to melanoma missing heritability has yet to be determined. Multigene panel testing could increase diagnostic yield and better define the role of candidate genes. We characterized 273 CDKN2A/ARF and CDK4-negative probands through a custom-designed targeted gene panel that included CDKN2A/ARF, CDK4, ACD, BAP1, MITF, POT1, TERF2IP, ATM, and PALB2. Co-segregation, loss of heterozygosity (LOH)/protein expression analysis, and splicing characterization were performed to improve variant classification. We identified 16 (5.9%) pathogenic and likely pathogenic variants in established high/medium penetrance cutaneous melanoma susceptibility genes (BAP1, POT1, ACD, MITF, and TERF2IP), including two novel variants in BAP1 and 4 in POT1. We also found four deleterious and five likely deleterious variants in ATM (3.3%). Thus, including potentially deleterious variants in ATM increased the diagnostic yield to about 9%. Inclusion of rare variants of uncertain significance would increase the overall detection yield to 14%. At least 10% of melanoma missing heritability may be explained through panel testing in our population. To our knowledge, this is the highest frequency of putative ATM deleterious variants reported in melanoma families, suggesting a possible role in melanoma susceptibility, which needs further investigation.
Lingua originaleEnglish
pagine (da-a)1-17
Numero di pagine17
RivistaCancers
DOI
Stato di pubblicazionePubblicato - 2020

Keywords

  • melanoma

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