Morgese Francesca, Soldato Davide, Pagliaretta Silvia, Giampieri Riccardo, Brancorsini Donatella, Torniai Mariangela, Rinaldi Silvia, Savini Agnese, Onofri Azzurra, Scarpelli Marina, Berardi Rossana
Clinica Oncologica, Università Politecnica delle Marche, Azienda Ospedaliero-Universitaria Ospedali Riuniti "Umberto I°-G.M. Lancisi-G. Salesi", Ancona, Italy.
Section of Pathological Anatomy and Histopathology, Deparment of Neuroscience, Università Politecnica delle Marche, Azienda Ospedaliero-Universitaria Ospedali Riuniti "Umberto I°-G.M. Lancisi-G. Salesi", Ancona, Italy.
Oncotarget. 2017 May 30;8(44):75914-75923. doi: 10.18632/oncotarget.18304. eCollection 2017 Sep 29.
Several studies associating single nucleotide polymorphisms (SNPs) frequencies with tumors outcome have been conducted, nevertheless malignant melanoma literature data are inconclusive.Therefore we evaluate the impact of different genotypes for phosphoinositide-3-kinase (PI3K) and vitamin D3 nuclear receptor (VDR) SNPs on melanoma patients' outcome.
Genomic DNA of 88 patients was extracted from blood and tumor samples. SNPs were determined by PCR using TaqMan assays. We selected polymorphisms of the regulatory and catalytic subunit of PI3K (PIK3R1 and PIK3CA genes, respectively), analyzing rs2699887C>T of and rs3730089G>A of SNPs. Furthermore we considered the following SNPs: rs2228570A>G (Fok1), rs731236A>G (Taq1) and rs1544410C>T (Bsm1).Progression free survival (PFS) and overall survival (OS) were estimated with the Kaplan-Meier method and with Mantel-Haenszel log-rank test.
The statistical analysis for Fok1 of showed a significant difference in PFS after the first line therapy (median PFS= 21.2 months in the homozygous recessive genotype group vs. 3.3 months of homozygous dominant and heterozygous ones, = 0.03). In particular, in homozygous recessive patients for Fok1 SNPs of a high rate of histological regression and BRAF (B- Rapidly Accelerated Fibrosarcoma gene) mutation were observed. Furthermore, more efficacy of BRAF +/- MEK (MAPK-ERK-Kinase) inhibitors therapies in homozygous recessive patients vs. homozygous dominant and heterozygous ones was shown.
Our study showed a significant correlation between homozygous recessive genotype of Fok1 SNPs of VDR gene and an increased PFS in patients who underwent a first line therapy with BRAF inhibitors.
已经开展了多项将单核苷酸多态性（SNP）频率与肿瘤预后相关联的研究，然而恶性黑色素瘤的文献数据尚无定论。因此，我们评估了磷脂酰肌醇-3-激酶（PI3K）和维生素D3核受体（VDR）SNP的不同基因型对黑色素瘤患者预后的影响。
从88例患者的血液和肿瘤样本中提取基因组DNA。使用TaqMan分析法通过聚合酶链反应（PCR）确定SNP。我们选择了PI3K调节亚基和催化亚基的多态性（分别为PIK3R1和PIK3CA基因），分析了PIK3R1基因的rs2699887C>T和PIK3CA基因的rs3730089G>A SNP。此外，我们还考虑了以下VDR SNP：rs2228570A>G（Fok1）、rs731236A>G（Taq1）和rs1544410C>T（Bsm1）。采用Kaplan-Meier法和Mantel-Haenszel对数秩检验估计无进展生存期（PFS）和总生存期（OS）。
对VDR基因Fok1的统计分析显示一线治疗后的PFS存在显著差异（纯合隐性基因型组的中位PFS = 21.2个月，而纯合显性和杂合基因型组为3.3个月，P = 0.03）。特别是，在VDR基因Fok1 SNP的纯合隐性患者中，观察到较高的组织学消退率和BRAF（B-快速进展性纤维肉瘤基因）突变率。此外，与纯合显性和杂合患者相比，BRAF +/- MEK（丝裂原活化蛋白激酶细胞外信号调节激酶激酶）抑制剂疗法在纯合隐性患者中显示出更高的疗效。
我们的研究表明，VDR基因Fok1 SNP的纯合隐性基因型与接受BRAF抑制剂一线治疗的患者PFS增加之间存在显著相关性。
