Neural crest-derived tumor neuroblastoma and melanoma share 1p13.2 as susceptibility locus that shows a long-range interaction with the SLC16A1 gene

Marianna Avitabile, Mariangela Succoio, Alessandro Testori, Antonella Cardinale, Zalman Vaksman, Vito Alessandro Lasorsa, Sueva Cantalupo, Matteo Esposito, Flora Cimmino, Annalaura Montella, Daniela Formicola, Jan Koster, Virginia Andreotti, Paola Ghiorzo, Maria Fiammetta Romano, Stefania Staibano, Massimiliano Scalvenzi, Fabrizio Ayala, Hakon Hakonarson, Maria Valeria CorriasMarcella Devoto, Matthew H Law, Mark M Iles, Kevin Brown, Sharon Diskin, Nicola Zambrano, Achille Iolascon, Mario Capasso

Research output: Contribution to journalArticle

Abstract

Neuroblastoma (NB) and malignant cutaneous melanoma (CMM) are neural crest cells (NCC)-derived tumors and may have a shared genetic basis, but this has not been investigated systematically by genome-wide association studies (GWAS). We took a three-staged approach to conduct cross-disease meta-analysis of GWAS for NB and CMM (2101 NB cases and 4202 controls; 12 874 CMM cases and 23 203 controls) to identify shared loci. Findings were replicated in 1403 NB cases and 1403 controls of European ancestry and in 636 NB, 508 CMM cases and 2066 controls of Italian origin. We found a cross-association at locus 1p13.2 (rs2153977, odds ratio = 0.91, P = 5.36 × 10-8). We also detected a suggestive (P < 10-7) NB-CMM cross-association at 2q37.1 with opposite effect on cancer risk. Pathway analysis of 110 NB-CMM risk loci with P < 10-4 demonstrated enrichment of biological processes such as cell migration, cell cycle, metabolism and immune response, which are essential of human NCC development, underlying both tumors. In vitro and in silico analyses indicated that the rs2153977-T protective allele, located in an NB and CMM enhancer, decreased expression of SLC16A1 via long-range loop formation and altered a T-box protein binding site. Upon depletion of SLC16A1, we observed a decrease of cellular proliferation and invasion in both NB and CMM cell lines, suggesting its role as oncogene. This is the largest study to date examining pleiotropy across two NC cell-derived tumors identifying 1p13.2 as common susceptibility locus for NB and CMM risk. We demonstrate that combining genome-wide association studies results across cancers with same origins can identify new loci common to neuroblastoma and melanoma arising from tissues which originate from neural crest cells. Our results also show 1p13.2 confer risk to neuroblastoma and melanoma by regulating SLC16A1.

Original languageEnglish
JournalCarcinogenesis
DOIs
Publication statusE-pub ahead of print - Sep 7 2019

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    Avitabile, M., Succoio, M., Testori, A., Cardinale, A., Vaksman, Z., Lasorsa, V. A., Cantalupo, S., Esposito, M., Cimmino, F., Montella, A., Formicola, D., Koster, J., Andreotti, V., Ghiorzo, P., Romano, M. F., Staibano, S., Scalvenzi, M., Ayala, F., Hakonarson, H., ... Capasso, M. (2019). Neural crest-derived tumor neuroblastoma and melanoma share 1p13.2 as susceptibility locus that shows a long-range interaction with the SLC16A1 gene. Carcinogenesis. https://doi.org/10.1093/carcin/bgz153