© Borgis - Postępy Nauk Medycznych 10/2012, s. 771-776
Małgorzata Drobnicka-Stępień1, Joanna Narbutt2, Irmina Olejniczak2, Anna Sysa-Jędrzejowska2, *Aleksandra Lesiak2
Niskie stężenie kwasu foliowego jako jeden z czynników predysponujących do rozwoju raków podstawnokomórkowych skóry
Low folic acid serum concentration as one of the factors leading to basal cell carcinoma development**
1Infectious and liver diseases ward, Bieganski Hospital, Łódź
Head of Department: prof. Zbigniew Deroń, MD, PhD
2Department of Dermatology, Medical University of Łódź
Head of Department: prof. Anna Sysa-Jędrzejowska, MD, PhD
Rak podstawnokomórkowy skóry jest najczęściej występującym nowotworem wśród ludzi rasy białej, stanowi 80% nowo zdiagnozowanych guzów. Niedobór kwasu foliowego został ostatnio uznany za czynnik ryzyka w przypadku kilku nowotworów złośliwych.
Cel. Ocena roli metabolizmu kwasu foliowego w procesie karcynogenezy u pacjentów z rakiem podstawnokomórkowym skóry poprzez oznaczenie stężenia kwasu foliowego w surowicy pacjentów chorych na raka podstawnokomórkowego i w grupie kontrolnej.
Materiały i metody. Grupa doświadczalna liczyła 125 pacjentów rasy białej, 79 osób (41 kobiet i 38 mężczyzn, średnia wieku – 60,2 lata, fototyp I/II – 20, III – 52, IV – 7) ze zdiagnozowanym na podstawie badania histopatologicznego rakiem podstawnokomórkowym skóry oraz 46 zdrowych ochotników (21 kobiet, 25 mężczyzn, średnia wieku – 58,4 lata. fototyp I/II – 10, III – 28, IV – 8). U wszystkich pacjentów pomiar stężenia kwasu foliowego w surowicy został przeprowadzony za pomocą Vitamin Folic Acid Test (DRG Vitamin Folic Acid, Mountainside, USA).
Wyniki. Stężenie kwasu foliowego było znacząco wyższe w grupie kontrolnej niż w grupie pacjentów z rakiem podstawnokomórkowym skóry (odpowiednio: mediana 16,5 μg/l vs. mediana 9,6 μg/l; p < 0,001). U większości badanych zarówno z grupy kontrolnej, jak i z grupy chorych na raka podstawnokomórkowego skóry stężenie kwasu foliowego w surowicy mieściło się w normalnych granicach.
Wnioski. Na podstawie otrzymanych wyników i danych zawartych w literaturze możemy stwierdzić, że kwas foliowy bierze udział w rozwoju raka podstawnokomórkowego skóry i jego niedobór może być uznany za jeden z czynników zwiększających ryzyko wystąpienia karcynogenezy skóry.
Basal cell carcinoma (BCC) is the most common neoplasm in Caucasian population, it represents over 80% of newly diagnosed tumors. Folic acid insufficiency has been recently considered as a risk factor for several cancers.
Aim. To assess the contribution of folic acid metabolism in the process of carcinogenesis in patients with BCC by determining the concentration of folic acid in the serum of patients with BCC and in control group.
Material and methods. Study group included 125 Caucasian subjects, 79 persons (41 women, 38 men, median age – 60.2 years, phototype: I/II – 20, III – 52, IV – 7) with BCC diagnosed on the basis of histopathological examination and 46 healthy volunteers (21 women, 25 men, median age – 58.4 years, phototype: I/II – 10, III – 28, IV – 8). In all patients serum folic acid concentration was measured with the use of Vitamin Folic Acid Test (DRG Vitamin Folic Acid, Mountainside, USA).
Results. Folic acid concentration was significantly higher in a control group than in BCC patients (median 16.5 μg/l vs. median 9.6 μg/l; respectively; p < 0.001). In most of the subjects both from control group and with BCC folic acid serum concentration was within normal limit.
Conclusions. Based on the obtained results and literature data we may conclude that the folic acid is involved in BCC development and its insufficiency may be concerned as one of the risk factors leading to skin cancerogenesis.
Recently increase in frequency of non-melanoma skin cancers (NMSC) which include basal cell carcinomas (BCC) and squamous cell carcinomas (SCC) has been observed (1-3). Basal cell carcinoma is the most common neoplasm in Caucasians and in Australian population and it represents over 80% of newly diagnosed cancers (4). In white race its frequency estimates between 18 and 40% (5, 6).
Despite of low mortality, NMSC, as the most common tumors in USA, Europe and Australia, are the major medical, social and economic problem (5, 7, 8).
Folic acid is a complex of folates, among which pteroil-1glutamic acid is the most stable form, therefore it is used in diet supplements, while it is rarely found in nature. Folates are sensible to high temperature, sun radiation and low pH. The active folates in the organism that act as coenzymes in many metabolic reactions are 5-tetrahydrofolate derivatives. They transfer one-carbon units in synthesis of purine and pyrimidine nucleotides, are involved in the synthesis of deoxyribonucleic acid (DNA) and therefore are essential for the correct cell division. They also play an important role in the metabolism of amino acids. One of the major reaction is the methylation of homocysteine to methionine – an amino acid which is an important substrate for the methylation reactions (9). Methionine derived from food undergoes remethylation into homocysteine. Disconnected methyl group is used for methylation of various compounds such as phospholipids, proteins, DNA and RNA. Approximately 50% of homocysteine is converted with the participation of vitamin B6, to cysteine. The remaining 50% is remethylated to methionine. 5-methylenetetrahydrofolate and vitamin B12 are necessary for this reaction (10) (fig. 1).
Fig. 1. Folate metabolic pathway (9).
The active form of folic acid (5-methylenetetrahydrofolate) is involved in the synthesis of purines, pyrimidines and DNA synthesis, amino acid metabolism and in the synthesis and transformation of formates. It also plays an important role in tissues with high rates of cell division, especially in the hematopoietic system, gastrointestinal tract epithelia and fetal tissues. In addition, it is important in the process of myelination of nerve fibers. During pregnancy it prevents neural tube birth defects in the fetus (11, 12).
The role of folate in preventing the development of cancer is not fully elucidated. Epidemiological studies suggest an inverse relationship between folate intake and the occurrence of cancer of the colon, lung, pancreas, esophagus, stomach, cervix, prostate, ovarian, breast cancer and leukemia (13, 16).
Most of data concerns the role of folic acid in preventing colon cancer. Recent studies showed an inverse relationship between folate intake or blood folate levels and risk of colorectal cancer. The postulated link between folate deficiency and carcinogenesis is likely due to the participation of this vitamin in the synthesis of DNA. Folate deficiency is responsible for impairment of DNA methylation, increased chromosome fragility and decreased ability to repair damaged DNA fragments, which contributes to mutagenesis (15, 17-19).
There are only scarce data on the role of folate insufficiency in BCC development. Thus, the aim of the study was to assess the contribution of folic acid metabolism in the process of carcinogenesis in patients with BCC by determining the concentration of folic acid in the serum of patients with BCC and in control group.
Material and methods
Study group consisted of 125 Caucasian subjects, including 79 (41 women, 38 men, median age – 60.2 years, phototype: I/II – 20, III – 52, IV – 7) persons with BCC diagnosed on the basis of histopathological examination and 46 healthy volunteers (21 women, 25 men, median age – 58.4 years, phototype: I/II – 10, III – 28, IV – 8). The control group was randomly selected (tab. 1). The inclusion criterion was negative history for any neoplasms. Exclusion criteria were the use of tanning bath or increased exposure to sunlight within two months prior the study. Patients with BCC were treated in Outpatient Clinic of Dermatology and Venereology Medical University of Łódź between 2005 and 2008. None of the them was transplant recipient, was treated with immunosupresants, nor suffered from internal organs neoplasm. In all the subjects risk factors for BCC development were evaluated. They included lesion localization, chronic sunlight exposure, using of sunbeds, past history of sunburn, smoking, alcohol abuse. The patients’ skin types were defined according to the Fitzpatrick classification (1988). From all patients blood samples in order to determine serum folic acid concentration, were taken. Sampled sera were stored at -25°C until the measurement. Measurement of the total folic acid serum level was performed with the use of Vitamin Folic Acid Test (DRG Vitamin Folic Acid, Mountainside, USA). This assay is a microtiter plate test kit based on a microbiological assay. Serum samples were diluted with a buffer solution. The diluted samples were added into the microtiter plate wells [coated with Lactobacillus rhamnosus which metabolizes folic acid]. The addition of folic acid in either standards or samples gave a folic acid-dependent growth response until it was consumed. After incubation at 37°C for 48 h, the growth of Lactobacillus rhamnosus was measured turbidimetrically at 610-630 nm (alternative at 540-550 nm) in an ELISA-reader and a standard curve was generated from the dilution series. The amount of folic acid was directly proportional to the turbidity.The reference values of folate concentrations in this method were 3.8-23.2 ug/l. The obtained results were statistically evaluated with the use of STATISTICA 6.0 Software (Statsoft, Tulusa, USA).
Table 1. Clinical characteristic of BCC patients and control group.
| ||Group 1|
|Female/Male [n]||41/38||21/25 |
|Hair ||Fair 47, dark 32||Fair 29, dark 17|
|Eyes||Fair 44, dark 35||Fair 24, dark 22|
|Skin phototype ||I/II n = 20|
III n = 52
IV n = 7
|I/II n = 10|
III n = 28
IV n = 8
In most cases (n = 67, 84.8%) basal cell carcinomas were located on the body areas exposed to sunlight (face, neck, dorsal side of hands), only in 12 (15.2%) cases tumor was located on unexposed surfaces (back, lower limbs). In 47 patients (59.5%) there was significant medical history concerning sunburn, in 68 subjects (86.1%) – erythema after sun exposure. In analyzed BCC-group 49 patients (62.0%) suffered had at least 1 incidence of sunburn, while 30 (38.0%) did not notice this side effect after sunlight exposure. 53.2% of patients (n = 42) were smoking.
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