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Article

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

1
Section of Genetics, International Agency for Research on Cancer (IARC-WHO), 69372 Lyon, France
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Gustave Roussy, Département de Biopathologie, 94805 Villejuif, France
3
Department of Dermatology, AP-HP, Hôpital Avicenne, University Paris 13, 93000 Bobigny, France
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UMRS-1124, Campus Paris Saint-Germain-des-Prés, University of Paris, 75006 Paris, France
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Centre National de Recherche en Génomique Humaine, Université Paris-Saclay, CEA, 91057 Evry, France
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Association Robert Debré pour la Recherche Médicale, 75006 Paris, France
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INSERM U1279, Tumor Cell Dynamics, 94805 Villejuif, France
*
Authors to whom correspondence should be addressed.
These authors contributed equally.
Academic Editor: Elaine Dunlop
Cancers 2021, 13(9), 2243; https://doi.org/10.3390/cancers13092243
Received: 10 March 2021 / Revised: 26 April 2021 / Accepted: 28 April 2021 / Published: 7 May 2021
Patients with malignant melanoma have an increased risk of being affected by kidney cancer and vice versa. Lifestyle risk factors contributing to these cancers differ. Instead, our study aims to assess whether common genetic predispositions may be at play. Here we reveal the clinical and germline genetic characteristics of a series of 125 patients diagnosed with both malignant melanoma and renal cell carcinoma (RCC), the most common type of kidney cancer. Clinical testing of known predisposing genes only explains a minority of either or both cancer occurrences. Instead, a wide exploration of all coding genes identified 13 novel susceptibility candidates more prone to rare deleterious germline mutations than expected in cancer-free controls, and converging to a common signaling pathway. This research highlights methods to better characterize cancer (co-)heritability. It also provides a basis to better understand and diagnose melanoma and RCC, which is essential for adequate clinical management.
Background: 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. Results: 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 MITF (p.E318K locus, N = 9 cases), BAP1 (N = 3), CDKN2A (N = 2), FLCN (N = 2), and PTEN (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 (<0.01%) within genes displaying strong evolutionary mutational constraints along the PI3K/mTOR pathway, including PIK3CD, NFRKB, EP300, MTOR, and related epigenetic modifier SETD2. The screening of independently processed germline exomes from The Cancer Genome Atlas confirmed an association with melanoma and RCC but not with cancers of established differing etiology such as lung cancers. Conclusions: Our study highlights that an exome-wide case-control enrichment approach may better characterize the rare variant-based missing heritability of multiple primary cancers. In our series, the co-occurrence of malignant melanoma and RCC was associated with germline variation in the PI3K/mTOR signaling cascade, with potential relevance for early diagnostic and clinical management. View Full-Text
Keywords: melanoma; renal cell carcinoma; genetic susceptibility; rare variants enrichment; WES melanoma; renal cell carcinoma; genetic susceptibility; rare variants enrichment; WES
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MDPI and ACS Style

Hubert, J.-N.; Suybeng, V.; Vallée, M.; Delhomme, T.M.; Maubec, E.; Boland, A.; Bacq, D.; Deleuze, J.-F.; Jouenne, F.; Brennan, P.; McKay, J.D.; Avril, M.-F.; Bressac-de Paillerets, B.; Chanudet, E. The PI3K/mTOR Pathway Is Targeted by Rare Germline Variants in Patients with Both Melanoma and Renal Cell Carcinoma. Cancers 2021, 13, 2243. https://doi.org/10.3390/cancers13092243

AMA Style

Hubert J-N, Suybeng V, Vallée M, Delhomme TM, Maubec E, Boland A, Bacq D, Deleuze J-F, Jouenne F, Brennan P, McKay JD, Avril M-F, Bressac-de Paillerets B, Chanudet E. The PI3K/mTOR Pathway Is Targeted by Rare Germline Variants in Patients with Both Melanoma and Renal Cell Carcinoma. Cancers. 2021; 13(9):2243. https://doi.org/10.3390/cancers13092243

Chicago/Turabian Style

Hubert, Jean-Noël, Voreak Suybeng, Maxime Vallée, Tiffany M. Delhomme, Eve Maubec, Anne Boland, Delphine Bacq, Jean-François Deleuze, Fanélie Jouenne, Paul Brennan, James D. McKay, Marie-Françoise Avril, Brigitte Bressac-de Paillerets, and Estelle Chanudet. 2021. "The PI3K/mTOR Pathway Is Targeted by Rare Germline Variants in Patients with Both Melanoma and Renal Cell Carcinoma" Cancers 13, no. 9: 2243. https://doi.org/10.3390/cancers13092243

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