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


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.

SUBMITTER: Pastorino L 

PROVIDER: S-EPMC7226507 | biostudies-literature | 2020 Apr

REPOSITORIES: biostudies-literature

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

Pastorino Lorenza L   Andreotti Virginia V   Dalmasso Bruna B   Vanni Irene I   Ciccarese Giulia G   Mandalà Mario M   Spadola Giuseppe G   Pizzichetta Maria Antonietta MA   Ponti Giovanni G   Tibiletti Maria Grazia MG   Sala Elena E   Genuardi Maurizio M   Chiurazzi Pietro P   Maccanti Gabriele G   Manoukian Siranoush S   Sestini Serena S   Danesi Rita R   Zampiga Valentina V   La Starza Roberta R   Stanganelli Ignazio I   Ballestrero Alberto A   Mastracci Luca L   Grillo Federica F   Sciallero Stefania S   Cecchi Federica F   Tanda Enrica Teresa ET   Spagnolo Francesco F   Queirolo Paola P   Italian Melanoma Intergroup (IMI)   Goldstein Alisa M AM   Bruno William W   Ghiorzo Paola P  

Cancers 20200419 4


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 <i>CDKN2A/ARF</i> and <i>CDK4-</i>negative probands through a custom-designed targeted gene panel that included <i>CDKN2A/ARF, CDK4, ACD, BAP1, MITF, POT1, TERF2IP, ATM,</i> and <i>PALB2.</i> Co-segregation, loss of heterozygosity (LOH)/prote  ...[more]

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