Folate-related polymorphisms in gastrointestinal stromal tumours: susceptibility and correlation with tumour characteristics and clinical outcome

Abstract

The folate metabolism pathway has a crucial role in tumorigenesis as it supports numerous critical intracellular reactions, including DNA synthesis, repair, and methylation. Despite its importance, little is known about the influence of the folate pathway on gastrointestinal stromal tumour (GIST), a rare tumour with an incidence ranging between 6 and 19.6 cases per million worldwide. The importance of folate metabolism led us to investigate the influence of polymorphisms in the genes coding folate-metabolising enzymes on GIST susceptibility, tumour characteristics and clinical outcome. We investigated a panel of 13 polymorphisms in 8 genes in 60 cases and 153 controls. The TS 6-bp deletion allele (formerly rs34489327, delTInsTTAAAG) was associated with reduced risk of GIST (OR = 0.20, 95% CI 0.05-0.67, P = 0.0032). Selected polymorphisms in patients stratified by age, gender, and other main molecular and clinical characteristics showed that few genotypes may show a likely correlation. We also observed a significant association between the RFC AA/AG genotype and time to progression (HR = 0.107, 95% CI 0.014-0.82; P = 0.032). Furthermore, we observed a tendency towards an association between the SHMT1 variant allele (TT, rs1979277) and early death (HR = 4.53, 95% CI 0.77-26.58, P = 0.087). Aware of the strengths and limitations of the study, these results suggest that polymorphisms may modify the risk of GIST and clinical outcome, pointing to the necessity for further investigations with information on folate plasma levels and a larger study population. INTRODUCTIONFolate metabolism supports numerous critical intracellular reactions, including DNA synthesis, repair, and methylation. DNA methylation status is essential for normal development and maintenance of cellular homeostasis and functions in adult organisms, including silencing of repetitive DNA elements, proper expression of genetic information and maintenance of genomic structural integrity. 1 The accurate maintenance of DNA synthesis, repair, and methylation patterns is fundamental, and its balance in mature cells is maintained by the concerted action of more than 30 enzymes. 2 These enzymes are highly polymorphic, and several functional genetic polymorphisms have been attracting research interest, as they may be responsible for altered DNA synthesis, repair and methylation processes, all of which are crucial in relation to carcinogenesis. Aberrant methylation patterns have been associated with various diseases including cancer and neurodegenerative diseases. 3,4 In addition, polymorphisms in genes involved in the folate metabolisms have been associated with cancer risk, including colorectal and gastric cancer, vascular disease, depression, and Down's syndrome. 5 Currently, there are evidences of an association between DNA methylation level and polymorphisms in folate metabolism genes. 6,7

Plasma Homocysteine and Polymorphisms of Genes Involved in Folate Metabolism Correlate with DNMT1 Gene Methylation Levels

“…The genotype distribution of the investigated polymorphisms is shown in Table 2. Genotype frequencies are in agreement with those previously observed in healthy Caucasians [19,22], and conformed to Hardy-Weinberg equilibrium (HWE) expectations (p > 0.05). Figure 3 shows the correlation between DNMT1 promoter methylation and circulating folate, Hcy, and vitamin B12 levels.…”

KIT exon 10 variant (c.1621 A > C) single nucleotide polymorphism as predictor of GIST patient outcome

“…Besides, a few germline genetic variants of receptor tyrosine kinase (IGF1R, VEGFR) were previously found to be associated with clinical outcome [ 2 , 9 – 12 ], suggesting the importance of somatic genome in GIST. Results of Angelini et al [ 11 ] suggest that polymorphisms in the genes coding folate-metabolising enzymes may modify the risk of GIST and clinical outcome and results of Haller et al [ 28 ] suggest SPP1 promoter methylation as a novel and independent prognostic parameter in GIST. KIT L541 belongs to this novel class of predictor of the risk of relapse in patients with GIST.…”

Somatic pharmacogenomics of gastrointestinal stromal tumor

“…Therefore, it is conceivable that polymorphisms or gene expression regulation through methylation/miRNA mechanisms could represent key players in affecting the final clinical outcome. By virtue of this consideration, possible pharmacogenetic [57][58][59][60][61][62] and epigenetic [63][64][65][66] mechanisms of imatinib and sunitinib resistance have been broadly investigated in GISTs [67][68][69][70][71] . Despite the extensive research, data are controversial and to date none of them supports the use of pharmacogenetic or pharmacoepigenetic tests to optimize treatment outcome in GIST patients.…”