Today, a very limited number of reports describe possible associations between FDG uptake and SNPs, rendering this field poorly explored and clarified [13–18]. Our study investigated the possible simultaneous association between polymorphisms in GLUT1, HIF-1a, EPAS1, APEX1,VEGFA and MTHFR genes and the FDG-PET uptake. To our knowledge, this is the first work that evaluates the collective impact of the abovementioned SNPs on PET tracer uptake in BC patients. FDG uptake, expressed in terms of SUVmax or SUVpvc, is largely dependent on glucose metabolism. High values are associated with reduced overall survival in cancer patients .
GLUT1 is the primary transporter of glucose metabolism and its over-expression has an important role in the survival and rapid growth of cancer cells. The rs841853 polymorphism of GLUT1 is located on the second intron of the gene and as suggested by Kim SJ et al. , no change would be expected in the GLUT1 protein sequence and expression. However, the GG genotype, which occurs in about 52% of the European population (data derived by dbSNP Short Genetic Variations database) seems to be related to FDG uptake in BC patients . In our work, although we did not observe deviation from the Hardy–Weinberg equilibrium, we did not find the association between this SNP and the FDG tumour uptake in BC.
The promoter region of the GLUT1 gene harbours another SNP, rs710218 (named also SLC2A1 Hpy CH4V), positioned 400 bp upstream of a putative HIF-1a binding site. Its close proximity to the hypoxia response elements (HRE) may modify the binding affinity of HIF-1 and thus alter the efficiency of the promoter and expression of GLUT1 . In our study, the allele frequencies of rs710218 SNP did not differ significantly from those available in NCBI dbSNP database and no association between this genetic alteration and SUVmax or SUVpvc was found in BC patients, confirming similar data recently obtained in NSCLC . No significant association with FDG uptake exists also when we examined this SNP in combination with the APEX1 rs1130409 genotypes.
APEX1 promotes transcriptional activation of HIF-1 and its reduced levels are related to a decrease in tumour volume and FDG uptake, suggesting that it affects glucose metabolism and cellular proliferation . Homozygosity (TT genotype) for the rs1130409 APEX1 SNP was significantly associated with a poor overall cancer survival . Here, this genotype was not significantly associated with SUV, compared with the GG/TG genotypes, as previously shown by by Kim SJ et al. .
HIF1a itself has an SNP (rs11549465) that we studied for possible association with FDG uptake. However, we observed no association in BC disease, in agreement with data previously obtained in NSCLC .
VEGFA rs3025039 polymorphism has been related with BC risk and a C > T polymorphism at position 936 in the 3’ untranslated region of the VEGFA gene has been associated with VEGF plasma levels. Specifically, the T-variant is linked to lower VEGF level and associated with increased BC risk  and worse outcome  compared to the wildtype allele. Wolf G. and co-workers  suggested a potential role of this VEGFA polymorphism on the variability of FDG uptake in tumour tissue. However, our study and data reported by Lorenzen S. et al.  do not confirm this association.
The MTHFR rs1801133 SNP is highly represented in the Caucasian population  and it is related to increased BC risk [36–38]. Nevertheless, its role in PET has not been studied yet. Here, we evaluated its importance in FDG uptake, for the first time, finding no associations. Considering its great importance in BC, we still believe that additional studies are needed to clarify its relevance.
Unfortunately, the genotype distributions for the remaining HIF1a: rs11549467, EPAS1: rs137853037 and rs137853036 SNPs did not allow us to evaluate their possible association with SUV.
The possible association between FDG uptake and SNPs is described by a limited number of studies, due to the need for multidisciplinary team and expertise. Moreover, this research field is characterized by controversial reports.
Moreover a strong variability of FDG-PET uptake on BC tissue has been reported , but the reason for this variability is not fully understood and may involve various cellular processes and risk factors such as genetic predisposition. Overall, our analysis succeeded to reproduce some previous findings, while we failed to confirm others, which still need to be further investigated. These discrepancies can be explained by the shortage of patients assayed both in our work and previous studies [13–15].
In addition these works looked at different groups of people from various European countries. Therefore it is harder to compare findings and to draw conclusions: the geographical and racial/ethnic distribution of an allele and associated genotypes are considered extremely important to fully understand the risk and the development of treatments related to gene polymorphisms (sometimes the allele frequency varies from region to region in the same country) .
Concluding, none of the reported analyses included functional evaluation of SNPs in FDG PET uptake. In our work, the potentially useful polymorphisms were not found associated with FDG uptake, using both SUVmax and SUVpvc.
Taking into consideration the clinical impact of a significant association between genetic alterations and PET-CT could have in BC treatment and since current knowledge is limited, additional and larger studies are required to assess the importance of these genotypic variants in the phenotypes or biological functions. Additionally, we cannot exclude the possibility that unknown or known SNPs, not investigated yet, in the same genes could have an important role.