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

: Malignant melanoma and RCC have different embryonic origins, no common lifestyle risk factors but intriguingly share biological properties such as immune regulation and radioresistance. An excess risk of malignant melanoma is observed in RCC patients and vice versa. This bidirectional association...

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Published in:Cancers 2021-05, Vol.13 (9), p.2243
Main Authors: Hubert, Jean-Noël, Suybeng, Voreak, Vallée, Maxime, Delhomme, Tiffany M, Maubec, Eve, Boland, Anne, Bacq, Delphine, Deleuze, Jean-François, Jouenne, Fanélie, Brennan, Paul, McKay, James D, Avril, Marie-Françoise, Bressac-de Paillerets, Brigitte, Chanudet, Estelle
Format: Article
Language:English
Subjects:
1-Phosphatidylinositol 3-kinase
Age
Biochemistry, Molecular Biology
Cell cycle
DNA damage
Embryos
Epigenetics
Etiology
Genes
Genetic counseling
Genetics
Genomes
Genomics
Heritability
Hypoxia
Immunoregulation
Informed consent
Kidney cancer
Life Sciences
Melanoma
Metabolism
Microphthalmia-associated transcription factor
Mutation
Oxidative stress
PTEN protein
Radioresistance
Renal cell carcinoma
Risk factors
Signal transduction
Skin cancer
TOR protein
Transcription factors
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Summary:: Malignant melanoma and RCC have different embryonic origins, no common lifestyle risk factors but intriguingly share biological properties such as immune regulation and radioresistance. An excess risk of malignant melanoma is observed in RCC patients and vice versa. This bidirectional association is poorly understood, and hypothetic genetic co-susceptibility remains largely unexplored. We hereby provide a clinical and genetic description of a series of 125 cases affected by both malignant melanoma and RCC. Clinical germline mutation testing identified a pathogenic variant in a melanoma and/or RCC predisposing gene in 17/125 cases (13.6%). This included mutually exclusive variants in (p.E318K locus, N = 9 cases), (N = 3), (N = 2), (N = 2), and (N = 1). A subset of 46 early-onset cases, without underlying germline variation, was whole-exome sequenced. In this series, thirteen genes were significantly enriched in mostly exclusive rare variants predicted to be deleterious, compared to 19,751 controls of similar ancestry. The observed variation mainly consisted of novel or low-frequency variants (
ISSN:2072-6694
2072-6694
DOI:10.3390/cancers13092243