Allele and genotype distributions
For the study of angiogenesis-related genes, 34 patients (9 responders
and 25 non-responders) were genotyped using the TaqMan allelic
discrimination method. The distribution of rs2010963, rs4604006,
rs12434438, rs55633437, and rs2070744 alleles and genotypes in responder
(R) and non-responder (NR) groups is shown in Table 1. Only the C allele
(p = 0.004) (Table 1), and CC genotype (p = 0.046) ofVEGF-A (rs2010963) were significantly associated with sorafenib
response.
The genotyping by DMETTM SNP panel allowed the
identification, among 1,936 markers, of 10 SNPs in seven genes as
significantly associated with sorafenib response: ADH1A (alcohol
dehydrogenase 1A), ADH6 (alcohol dehydrogenase 6), SULT1A2/CCDC101
(Sulfotransferase Family 1A Member 2)/CCDC101 (Coiled-Coil
Domain-Containing Protein 101), CYP26A (Cytochrome P450 Family 26
Subfamily A Member 1), DPYD (Dihydropyrimidine dehydrogenase), FMO2
(Flavin Containing Dimethylaniline Monoxygenase 2), and SLC22A14 (Solute
Carrier Family 22 Member 14) (Table 2).
The heterozygous genotypes of SLC22A14 rs171248, rs149738, and
rs183574 (p = 0.007), and the homozygous genotypes AA inSULT1A2/CCDC101 rs11401 (p = 0.019), DPYD rs2297595 (p =
0.011), and FMO2 rs2020863 (p = 0.004), and TT in DPYD*9rs1801265 (p = 0.0257), as well as the GG in ADH6 rs10008281 (p =
0.019) and CYP26A1 rs7905939 (p = 0.027), showed a significant
association to a lack of response to sorafenib. Instead, a significant
correlation to sorafenib efficacy was found for the CC genotype inADH1A rs6811453 (p = 0.005) and the heterozygous genotypes AG inSULT1A2/CCDC101 rs11401 (p = 0.019), DPYD rs2297595 (p =
0.011), and FMO2 rs2020863 (p = 0.004), and CT in DPYD*9rs1801265 (p = 0.026). The rs11401 is located on 16p11.2 region which
contains a splice site encompassing the SULT1A2 gene (500B Downstream
Variant), and the CCDC101 gene. In addition, the homozygous genotypes ofSLC22A14 rs171248 (TT), rs149738 (AA), and rs183574 (AA) were
found to be significantly associated to responder patients (p =
0.001).