Characterization of POT1 tumor predisposition syndrome: Tumor prevalence in a clinically diverse hereditary cancer cohort.

PURPOSE: Germline variants in POT1 have been implicated in predisposition to melanoma, sarcoma, and glioma in limited studies. Here, we determine the prevalence of cancer types in individuals with POT1 pathogenic variants (PVs) undergoing multigene panel testing (MGPT) for a broad variety of cancer indications. METHODS: We performed a retrospective review of data provided on clinical documents from individuals with POT1 PVs identified via MGPT over a 5-year period. Tumor prevalence in POT1 PV heterozygotes was compared with MGPT-negative wild-type (WT) controls using χ2 test. RESULTS: POT1 PVs were identified in 227 individuals. POT1 PV and WT (n = 13,315) cohorts had a similar proportion of reported tumors (69.6% and 69.2%, respectively); however, POT1 PV heterozygotes were more likely to be diagnosed with multiple tumors (18.9% vs 8.7%; P < .001). Compared with POT1 WT, we identified a significant increase in melanoma (odds ratio 7.03; 95% CI 4.7-10.5; P < .001) and sarcoma (odds ratio 6.6; 95% CI 3.1-13.9; P < .001). CONCLUSION: This analysis of the largest POT1 PV cohort to date validates the inclusion of POT1 in hereditary cancer MGPT and has the potential to impact clinical management recommendations, particularly for patients and families at risk for melanoma and sarcoma.

Molecular landscape of Hereditary Melanoma.

Melanoma is considered the most lethal skin cancer and its incidence has increased during the past decades. About 10 % of cases are classified as hereditary melanoma. Genetic predisposition usually manifests itself clinically as early onset and multiple cutaneous melanomas. Several genes have been identified as involved to melanoma susceptibility, some of them still with unknown clinical relevance. Beyond melanoma, the affected families are also more prone to develop other malignancies, such as pancreatic cancer. The identification of risk families and involved genes is of great importance, since different forms of oncological surveillance are recommended. However, well established guidelines to standardize both the selection of individuals and the genetic panel to be requested are still lacking. Given the importance of the genetic counseling and testing in the context of clinical suspicion of hereditary melanoma, this paper aims to review the literature regarding genetic panel indications worldwide.

Melanoma susceptibility: an update on genetic and epigenetic findings.

Malignant melanoma is one of the most highly ranked cancers in terms of years of life lost. Hereditary melanoma with its increased familial susceptibility is thought to affect up to 12% of all melanoma patients. In the past, only a few high-penetrance genes associated with familial melanoma, such as CDKN2A and CDK4, have been clinically tested. However, findings now indicate that melanoma is a cancer most likely to develop not only due to high-penetrance variants but also due to polygenic inheritance patterns, leaving no clear division between the hereditary and sporadic development of malignant melanoma. Various pathogenic low-penetrance variants were recently discovered through genome-wide association studies, and are now translated into polygenic risk scores. These can show superior sensitivity rates for the prediction of melanoma susceptibility and related mixed cancer syndromes than risk scores based on phenotypic traits of the patients, with odds ratios of up to 5.7 for patients in risk groups. In addition to describing genetic findings, we also review the first results of epigenetic research showing constitutional methylation changes that alter the susceptibility to cutaneous melanoma and its risk factors.

High-Throughput Sequencing Identifies 3 Novel Susceptibility Genes for Hereditary Melanoma.

Cutaneous melanoma is one of the most aggressive human cancers due to its high invasiveness. Germline mutations in high-risk melanoma susceptibility genes have been associated with development hereditary melanoma; however, most genetic culprits remain elusive. To unravel novel susceptibility genes for hereditary melanoma, we performed whole exome sequencing (WES) on eight patients with multiple primary melanomas, high number of nevi, and negative for high and intermediate-risk germline mutations. Thirteen new potentially pathogenic variants were identified after bioinformatics analysis and validation. CDH23, ARHGEF40, and BRD9 were identified as the most promising susceptibility genes in hereditary melanoma. In silico analysis of CDH23 and ARHGEF40 variants provided clues for altered protein structure and function associated with the identified mutations. Then, we also evaluated the clinical value of CDH23, ARHGEF40, and BRD9 expression in sporadic melanoma by using the TCGA dataset (n = 461). No differences were observed in BRD9 expression between melanoma and normal skin samples, nor with melanoma stage, whereas ARHGEF40 was found overexpressed, and CDH23 was downregulated and its loss was associated with worse survival. Altogether, these results reveal three novel genes with clinical relevance in hereditary and sporadic melanoma.

Role of Heredity in Melanoma Susceptibility: A Primer for the Practicing Surgeon.

Melanoma is a deadly skin cancer linked to ultraviolet radiation exposure. Heritable traits and sporadic mutations modify an individual's risk for melanoma that may be associated with phenotype. Familial/heritable melanomas are broadly used to describe families with an increased incidence of melanomas, although the underlying mutation may be unknown. Mutations associated with melanoma occur in cell cycle regulation, tumor suppression, chromosomal stability, DNA repair, pigmentation, and melanocyte differentiation genes. Genetic testing of individuals with a family history of melanoma may provide additional etiologic information and ensure patients with known markers for cancer development are closely monitored by physicians.

Familial atypical multiple mole melanoma (FAMMM) syndrome: history, genetics, and heterogeneity.

Approximately 5-10 % of cutaneous melanoma occurs in kindreds with a hereditary predisposition. Mutations in the CDKN2A gene are found to occur in approximately 20-40 % of these kindreds. The first historical mention of what is now called the familial atypical multiple mole melanoma syndrome appears to be from 1820, with more reports throughout the 1950s, 1960s, and later years. In 1991, Lynch and Fusaro described an association between familial multiple mole melanoma and pancreatic cancer and work continues to elucidate the syndrome's genotypic and phenotypic heterogeneity. Individuals at risk for familial melanoma need periodic screenings. Unfortunately, adequate screening for pancreatic cancer does not currently exist, but pancreatic cancer's prominence in the hereditary setting will hopefully act as a stimulus for development of novel screening measures.

Genética molecular del melanoma familiar: revisión del tema y aplicación clínica / Genetics of familial cutaneous melanoma

El melanoma maligno cutáneo (MMC) representa el 4 por ciento del total de los tumores malignos de piel, dando cuenta del 80 por ciento de las muertes producidas por cáncer cutáneo. La sobrevida a cinco años de individuos portadores de enfermedad metastásica se estima en 14 por ciento. Las formas de presentación incluyen una variante esporádica y otra familiar o hereditaria. En ambas el papel de diferentes mutaciones genéticas que otorgan susceptibilidad al desarrollo de MMC es indiscutido, así como la interacción entre las características genéticas del individuo y eventos ambientales. En el MMC familiar se han establecido dos genes de alta susceptibilidad con diferente penetrancia y frecuencia: CDK4 y CDKN2A. CDKN2A (Cyclin-dependent kinase inhibitor 2A) es el más importante gen de susceptibilidad a MMC, cuyas mutaciones se han identificado en aproximadamente un 40 por ciento de familias que presentan tres o más casos de MMC. Las características clínicas asociadas a la mutación de CDKN2A son número elevado de individuos afectados por MMC dentro de una familia, MMC primario múltiple y presencia conjunta de MMC y cáncer de páncreas dentro de una familia. En Chile de desconoce la frecuencia y tipos de mutaciones que afectan a CDKN2A en familias con predisposición a MMC familiar.

Cutaneous malignant melanoma (CMM) represents 4 percent of all malignant skin tumors and accounts for 80 percent of deaths related to cutaneous cancer. 5-year survival rates in individuals with metastatic disease is around 14 percent. An hereditary or familial variant of CMM has been identified. It is related to different mutations of so-called susceptibility genes as well as to interactions between genetic characteristics and environmental factors. Familial CMM is related to two genes of elevated susceptibility, penetrance, and frequency: CDK4 and CDKN2A (Cyclin-dependent kinase inhibitor 2A). CDKN2A is the most important susceptibility gene and its mutations have been identified in approximately 40 percent of the families bearing three or more members with CNM. Clinical features associated to CDKN2A mutations are elevated number of family members with CMN, multiple primary CMM, and the presence of both CMN and pancreatic cancer in the same family. In Chile, the incidence and mutation variants of CDKN2A in families with CMM is unknown.