Genotyping and differential expression analysis of inflammasome genes in sporadic malignant melanoma reveal novel contribution of CARD8, IL1B and IL18 in melanoma susceptibility and progression.
Sporadic melanoma malignancy is correlated with constitutive secretion of IL-1β in transformed melanocytes suggesting the involvement of inflammasome in melanoma. Common variants in inflammasome genes are known to affect IL-1β expression. To investigate the contribution of inflammasome genetics in melanoma development and progression and to identify a potential prognostic marker, the distribution of selected inflammasome SNPs was analysed in a Brazilian case/control cohort of sporadic malignant melanoma (SMM) and then the expression of inflammasome components was evaluated in melanoma biopsies. Allele and gene-specific Taqman assays were implied for genotyping of case/control DNA samples and for relative expression analysis in skin biopsies respectively. CARD8 rs6509365 was found to be significantly more common in healthy volunteers than in SMM patients suggesting a protection effect of this variant towards melanoma development. Accordingly, CARD8 expression was found to be reduced in nevus compared to melanoma biopsies. Upon stratification, NLRP1 rs11651270 and CARD8 rs2043211 were found associated with nodular melanoma; IL1B rs1143643 to a lower value of Breslow index; IL18 rs5744256 to melanoma development in sun sensitive individuals. As expected, IL1B expression was up-regulated in tumour biopsies especially in metastatic samples, whereas IL18 was down-regulated compared to nevus. Our results demonstrated for the first time the contribution of inflammasome genes CARD8, IL1B and IL18 in SMM.
Laboratory of Medical Investigation in Dermatology and Immunodeficiences-LIM 56, Department of Dermatology, Faculty of Medicine, University of Sao Paulo, Avenida Dr Eneas de Carvalho Aguiar, 470 - Prédio 2-3° andar, 05403-000 Cerqueira César, Sao Paulo, Brazil. Electronic address: wanessacardoso@yahoo.com.br.
Wanessa Cardoso
WC
da Silva
Laboratory of Medical Investigation in Dermatology and Immunodeficiences-LIM 56, Department of Dermatology, Faculty of Medicine, University of Sao Paulo, Avenida Dr Eneas de Carvalho Aguiar, 470 - Prédio 2-3° andar, 05403-000 Cerqueira César, Sao Paulo, Brazil.
Telma Miyuki
TM
Oshiro
Department of Dermatology, Faculty of Medicine, University of Sao Paulo, Avenida Dr. Eneas de Carvalho Aguiar 500, 05403-000 Cerqueira Cesar, Sao Paulo, Brazil.
Daniel Coelho
DC
de Sá
Department of Dermatology, Faculty of Medicine, University of Sao Paulo, Avenida Dr. Eneas de Carvalho Aguiar 500, 05403-000 Cerqueira Cesar, Sao Paulo, Brazil.
Dilcilea D G S
DD
Franco
Department of Dermatology, Faculty of Medicine, University of Sao Paulo, Avenida Dr. Eneas de Carvalho Aguiar 500, 05403-000 Cerqueira Cesar, Sao Paulo, Brazil.
Cyro
C
Festa Neto
Laboratory of Immunogenetics, Department of Immunology, Institute of Biomedical Sciences, University of Sao Paulo, Avenida Prof. Lineu Prestes 1730, 05508-000 Cidade Universitaria, Sao Paulo, Brazil.
Alessandra
A
Pontillo
D000368:Aged; D000483:Alleles; D014408:Biomarkers, Tumor / Q000235:genetics; D001938:Brazil; D053468:CARD Signaling Adaptor Proteins / Q000235:genetics*; D016022:Case-Control Studies; D018450:Disease Progression; D005260:Female; D005500:Follow-Up Studies; D020022:Genetic Predisposition to Disease; D005838:Genotype; D006801:Humans; D058847:Inflammasomes / Q000235:genetics*; D020382:Interleukin-18 / Q000235:genetics*; D053583:Interleukin-1beta / Q000235:genetics*; D008207:Lymphatic Metastasis; D008297:Male; D008545:Melanoma / Q000235:genetics* / Q000276:immunology / Q000556:secondary; D008875:Middle Aged; D009361:Neoplasm Invasiveness; D009363:Neoplasm Proteins / Q000235:genetics*; D009367:Neoplasm Staging; D020641:Polymorphism, Single Nucleotide / Q000235:genetics*; D011379:Prognosis; D012307:Risk Factors; D012878:Skin Neoplasms / Q000235:genetics / Q000276:immunology / Q000473:pathology; D000096142:Cutaneous Malignant Melanoma
D014408:Biomarkers, Tumor; D053468:CARD Signaling Adaptor Proteins; C455623:CARD8 protein, human; C508585:IL1B protein, human; D058847:Inflammasomes; D020382:Interleukin-18; D053583:Interleukin-1beta; D009363:Neoplasm Proteins
CARD8; IL1B; Melanoma; SNPs; inflammasome