Abstract 228: Association analysis across different populations identifies 26 new cutaneous melanoma risk loci

Autor: Cristina Pellegrini, Matthew Law, Mark Iles, Mitch Machiela, Alex Stratigos, Tongwu Zhang, Kevin Brown, Julia Newton-Bishop, Nick Hayward, Nick Martin, Alisa Goldstein, Rose Yang, Stephen Chanock, Florence Demenais, Susana Puig, Eduardo Nagore, Jianxin Shi, Tim Bishop, Stuart McGregor, Maria Teresa Landi, GenoMEL Consortium, MelaNostrum Consortium
Rok vydání: 2018
Předmět:
Zdroj: Cancer Research. 78:228-228
ISSN: 1538-7445
0008-5472
Popis: Heritability of cutaneous melanoma is among the highest across cancer types and is mostly determined by common, noncoding genetic variants. Previous genome-wide association studies (GWAS), mostly including subjects from Australia and Northern European countries, had identified twenty genetic loci associated with melanoma risk. To characterize the genetic landscape of cutaneous melanoma across different populations, we conducted a new association study in Southern European countries including 6,043 melanoma cases and 10,383 controls from the MelaNostrum Consortium. Moreover, we largely expanded the analyses of melanoma cases and controls from other populations, for a total of 27,450 histologically confirmed melanoma cases and 49,888 controls from Northern Europe, Southern Europe, USA and Australia. Imputation was done using the Haplotype Reference Consortium as a reference panel. We assessed the association between cutaneous melanoma risk and single-nucleotide polymorphisms (SNPs) adjusting for country and ancestry-informative principal components. We identified 26 new genetic loci associated with melanoma risk achieving genome-wide significance. The pigmentation pathway, with TYRP1 and MITF, and the telomere-related pathway with RTEL1, TERC, and POT1 among the candidate genes, continued to show an important role for melanoma susceptibility. Additional candidate pathways emerged, including signaling (with GPRC5A and DOCK8), cell-cell junction (with CDH1), immune-related functions (with DCST2, involved in antigen processing), transcriptional regulation (with FOXD3, which represses MITF expression), or tumor-suppressor genes (TP53). Adding genotype data from 6,130 self-reported melanoma cases in a sensitivity analysis identified eight additional novel genetic loci involved in the HLA region, signaling transduction and transcription factor functions. A combined analysis of the melanoma GWAS with the GWAS of pigmentation characteristics from the UK Biobank including 500,000 UK persons, and with a GWAS of nevus density including over 52,000 persons, revealed substantial overlap across phenotypes. Although the effect size of the SNPs on melanoma risk was consistent across populations, substantial differences in minor allele frequency (MAF) were observed in pigmentation-related genes between Northern and Southern European populations; for example, MC1R, SLC45A2, and ASIP SNP MAF was 8.2, 3.1 and 14.2 in Northern and 2.6, 8.8, and 5.5 in Southern European subjects, respectively. Additional analyses based on melanoma histologic subtypes and body site distribution are ongoing. These results provide further insight into genetic susceptibility to cutaneous melanoma and provide the opportunity for genetic risk scores in risk-prediction models for early detection and targeted prevention of the disease. Citation Format: Cristina Pellegrini, Matthew Law, Mark Iles, Mitch Machiela, Alex Stratigos, Tongwu Zhang, Kevin Brown, Julia Newton-Bishop, Nick Hayward, Nick Martin, Alisa Goldstein, Rose Yang, Stephen Chanock, Florence Demenais, Susana Puig, Eduardo Nagore, Jianxin Shi, Tim Bishop, Stuart McGregor, Maria Teresa Landi, GenoMEL Consortium, MelaNostrum Consortium. Association analysis across different populations identifies 26 new cutaneous melanoma risk loci [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 228.
Databáze: OpenAIRE
Externí odkaz: