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.

Identification of Germline Mutations in Melanoma Patients with Early Onset, Double Primary Tumors, or Family Cancer History by NGS Analysis of 217 Genes

“…A higher prevalence of mutations in ACD , TERF2IP , and POT1 was identified in 12/132 (9.1%) high-risk CDKN2A / CDK4 / TERT / BAP1 wild-type European and Australian patients with multiple melanoma (≥3) [ 44 ]. A higher prevalence of germline mutations in BAP1 (not identified in our patients) and POT1 was also reported in a recent study by Pastorino and colleagues who identified seven carriers (2.6%) of mutations in each of these two genes among 273 Italian melanoma patients [ 45 ]. The enrollment of 22 melanoma patients with atypical Spitz nevi with relatives developing BAP1 -related tumors can explain an increased prevalence of BAP1 mutation carriers in this Italian study.…”

Tumor Immune Microenvironment and Genetic Alterations in Mesothelioma

“…These genes mainly encode for tumor suppressor proteins involved in cell cycle regulation, apoptosis and DNA repair pathways; being involved in cancer development, they are called cancer susceptibility genes ( 113 ). The identification of these genes have paved the way for the development of targeted therapeutic approaches as well as for cancer prevention and surveillance ( 114 , 115 ). The most common inherited cancer risk factor associated with MPM is the aberration of BRCA1 Associated Protein 1 ( BAP1 ), a deubiquitinating enzyme located on chromosome 3p21.1 acting as tumor suppressor gene ( 116 , 117 ).…”

“…These alterations are more frequently detected in young adults with MPM: 4% in patients older than 75 years and 20% in the ones of 55 years of age or younger ( 121 ). Among the three histotypes of MPM, such as epithelioid, sarcomatoid, and biphasic, BAP1-germline mutations are found more frequently in the epithelioid and this correlates with a better prognosis ( 113 , 115 ).…”

The PI3K/mTOR Pathway Is Targeted by Rare Germline Variants in Patients with Both Melanoma and Renal Cell Carcinoma

“…ACD loss of function (LOF) mutations predispose to melanoma and a broader spectrum of cancers [ 59 ]. Despite the fact that no RCCs were reported in ACD carriers to date [ 59 , 60 , 61 ], a meta-analysis suggested that individuals with an inherited predisposition to longer telomere length are at increased risk of developing renal cell carcinoma [ 62 ]. Two other cases respectively harbored a novel 14-base-pair deletion (c.2228_2240del p.(Q743fs)) and a rare missense VUS (rs1588304158) in TSC1 .…”