Research Article: The role of the folate pathway in pancreatic cancer risk

Date Published: February 23, 2018

Publisher: Public Library of Science

Author(s): Shirisha Chittiboyina, Zhongxue Chen, E. Gabriela Chiorean, Lisa M. Kamendulis, Barbara A. Hocevar, Surinder K. Batra.


Pancreatic cancer is the third leading cause of cancer related deaths in the United States. Several dietary factors have been identified that modify pancreatic cancer risk, including low folate levels. In addition to nutrition and lifestyle determinants, folate status may be influenced by genetic factors such as single nucleotide polymorphisms (SNPs). In the present study, we investigated the association between folate levels, genetic polymorphisms in genes of the folate pathway, and pancreatic cancer.

Serum and red blood cell (RBC) folate levels were measured in pancreatic cancer and control subjects. Genotypes were determined utilizing Taqman probes and SNP frequencies between cases and controls were assessed using Fisher’s exact test. Logistic regression was used to estimate the odds ratio (OR) and corresponding 95% confidence intervals (CIs) to measure the association between genotypes and pancreatic cancer risk. The association between folate levels and SNP expression was calculated using one-way ANOVA.

Mean RBC folate levels were significantly lower in pancreatic cancer cases compared to unrelated controls (508.4 ± 215.9 ng/mL vs 588.3 ± 229.2 ng/mL, respectively) whereas serum folate levels were similar. Irrespective of cancer status, several SNPs were found to be associated with altered serum folate concentrations, including the D919G SNP in methionine synthase (MTR), the L474F SNP in serine hydroxymethyl transferase 1 (SHMT1) and the V175M SNP in phosphatidyl ethanolamine methyltransferase (PEMT). Further, the V allele of the A222V SNP and the E allele of the E429A SNP in methylene tetrahydrofolate reductase (MTHFR) were associated with low RBC folate levels. Pancreatic cancer risk was found to be significantly lower for the LL allele of the L78R SNP in choline dehydrogenase (CHDH; OR = 0.29; 95% CI 0.12–0.76); however, it was not associated with altered serum or RBC folate levels.

Partial Text

Pancreatic cancer, the third leading cause of cancer deaths in the United States, is an aggressive cancer with median 5 year survival rates of only 8% [1]. Detection late in the disease course, rapid metastasis, and chemo-resistance contribute to the poor prognosis for pancreatic cancer [2]. In the age of personalized medicine, identification of genetic and environmental factors that affect the risk for development of pancreatic cancer may aid in prevention or lead to increased surveillance of susceptible individuals. Environmental factors including tobacco and alcohol use, exposure to selected environmental chemicals, obesity, and diet, have been postulated to play a significant role in the etiology of sporadic pancreatic cancer [3]. Deficiencies in dietary sources of methyl groups, including choline, methionine, vitamin B-12 and folate, have been associated with pancreatic dysfunction in rodents [4,5]. In addition, risk of development of various cancer types in humans, including pancreatic cancer, has been shown to increase with low dietary folate intake [6–9].

Pancreatic cancer is a devastating disease, with a relative 5 year survival rate of 8%. One of the reasons for the dismal prognosis is that more than half of the cases are diagnosed at late stage, where the 5-year survival rate is only 3% [1]. As such, identification of risk susceptibility profiles for pancreatic cancer could greatly impact early diagnosis and prevention strategies. In a pilot study, we have previously shown that direct DNA damage was increased in pancreatic cancer patients as compared to control subjects who resided with the patient (i.e. shared the same environment) and also as compared to controls that are genetically related, but did not share the same environment [21]. As defects in the folate metabolic pathway have been linked to DNA damage, in this study we sought to determine (1) whether serum and RBC folate levels differ between pancreatic cancer patients and controls, (2) whether SNPs in key genes of the folate pathway associate with pancreatic cancer risk and (3) whether expression of specific SNPs correlates with serum or RBC folate levels.




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