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Identification of inherited susceptibility genes for cutaneous melanoma by large scale genotyping

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Cristiane de Oliveira
Total Authors: 1
Document type: Doctoral Thesis
Press: Campinas, SP.
Institution: Universidade Estadual de Campinas (UNICAMP). Faculdade de Ciências Médicas
Defense date:
Examining board members:
Carmen Silvia Passos Lima; Roger Chammas; Sérgio Vicente Serrano; Carmen Sílvia Bertuzzo; Fabio Rossi Torres
Advisor: Gustavo Jacob Lourenço; Carmen Silvia Passos Lima

Combinations of inherited genetic alterations, such as single nucleotide polymorphisms (SNPs) in association with cutaneous melanoma (CM) risk, clinical manifestation and prognosis in patients have not been clarified. Therefore, this was the aim of the present study. Genomic DNA was extracted of the peripheral blood samples of 103 CM patients and 103 controls. Each sample was genotyped using DNA high-resolution microarrays (Affymetrix® SNP 6.0). We observed 12.994 SNPs differentially between patients and controls groups. Among them, 6.814 SNPs (52.4%) were located in regulatory regions of DNA transcription (in 3¿ and 5¿ untranslated), 26 (0.2%) in coding sequence of amino acids regions, 6.042 (46.5%) in introns and 112 (0.9%) unidentified regions. Ten SNPs, located in regulatory regions of gene associated with melanogenesis pathway, WNT8B c.-101T>C (rs rs3793772), KIT c.67+12766T>C (rs rs2017472), GNAI1 g.80130766C>T (rs2079162), ADCY3 c.675+9196T>G (rs11900505), PLCB1 g.8908966C>A (rs4295085), PRKCA c.205+407G>A (rs12601850), PRKCA c.288+33994A>G (rs1806448), CALM2 g.47384601A>G (rs11884600), CREB1 c.303+373G>A (rs10932201) e MITF c.938-325A>G (rs7623610), were considered of interest for the study and validated by polymerase chain reaction in real time using TaqMan assays (Applied Biosystems®). All SNPs isolated and combined alter the risk for CM. SNPs ADCY3 c.675+9196T>G and MITF c.938-325A>G deserves highlight. The isolated genotypes ADCY3 TT and MITF AA and TT+GG + AA+AG combined were associated with 4,86, 3,13 and 19,17-fold increased risk for CM. During 60 months of observation, patients with MITF AA genotypes and ADCY3 + MITF TT+AA combined genotypes were associated with poor progression free survival (44,5% versus 68,2%, P= 0,007; 22,2% versus 61,3%, P= 0,006) and lower overall survival (67,7% versus 81,7%, P= 0,009; 44,4% versus 72,5%, P= 0,006) than the patients with others genotypes (Kaplan-Meier estimates). Carriers of the same genotypes had 2,40 and 3,53 more chances of disease progression and 2,85 and 3,84 more chances to evolve to death, respectively (Cox univariate). Our results suggest, for the first time, that SNPs related in melanogenesis pathway may contributed for identify people with high risk for CM and patients with poor prognosis, that need to receive more attention on preventing, early diagnosis or treatment (AU)

FAPESP's process: 12/16617-4 - Identification of inherited susceptibility genes for cutaneous melanoma by large scale genotyping
Grantee:Cristiane de Oliveira
Support type: Scholarships in Brazil - Doctorate