Publication: Kolorektal kanserli hastaların farklı ilaç yanıtlarında vitamin D reseptör gen rolünün araştırılması
Abstract
Kolorektal kanser (KRK) gerek ülkemizde gerek dünya çapında en yaygın kanser türleri içerisinde olup kanser kaynaklı ölüm nedenlerinin başında yer almaktadır. Bu sebeple KRK karsinogenezinde görev alan genetik risk faktörlerinin belirlenmesinin hastalığın patolojisinin anlaşılmasında, muhtemel terapötik hedeflerin belirlenmesinde ve farklı tedavi seçeneklerinin ortaya çıkarılmasında önemlidir. Vitamin D reseptörü (VDR) gen anlatımının düzenlenmesine aracılık ederek proliferasyon, apoptoz, farklılaşma, inflamasyon, invazyon, metastaz, anjiyogenez gibi karsinogenezde etkili hücresel olayları kontrol eder. Yaşamsal ve karsinogenik faaliyetlerdeki rolü nedeni ile çalışmamızda VDR BsmI (rs1544410), ApaI (rs7975232) ve TaqI (rs731236) polimorfizmlerinin KRK hastalara ait klinik ve patolojik karakteristikler ile olan ilişkilerini ortaya çıkarmayı hedefledik. Çalışmamızda aynı zamanda primer tümör yerinin ve 5-FU tabanlı kemoterapi sonrası gözlenen yan etkilerin VDR polimorfizmleri, kan hücre sayıları ve serumdaki moleküllerin konsantrasyonları ile ilişkilerini incelemeyi de hedefledik. Çalışma grubumuz immunohistokimyasal yöntemler ile doğrulanmış KRK hastalarından oluşmaktadır. Genotip analizleri hastalara ait periferik kandan DNA izolasyonu sonrası polimeraz zincir reaksiyonu (PZR) ve restriksiyon parça uzunluk polimorfizmi (RFLP) yöntemleri kullanılarak gerçekleştirilmiştir. Çalışma grubumuzda yer alan KRK hastalarının eozinofil sayıları ortalamaları ApaI heterozigot (GT) (p=0.019); kreatinin ortalamaları ApaI homozigot mutant (TT) (p<0.001); RDW ortalamaları ise GT genotipli hastalarda (p=0.007) yüksek tespit edilmiştir. TaqI homozigot mutant (CC) hastaların kreatinin ortalamaları (p=0.007) ile TaqI heterozigot (TC) hastaların RDW ortalamaları (p=0.007) diğer genotiplere kıyasla yüksek bulunmuştur. TaqI CC genotipli hastalarda nötrofil sayıları (p=0.026) ile albümin (p=0.023) ve kreatinin ortalamaları (p=0.036) TaqI TT+TC genotipli hastalara kıyasla yüksek bulunmuştur. Çalışmamızda BsmI, ApaI ve TaqI polimorfizmleri primer tümör yeri ile ilişkili bulunmamıştır. Ancak rektum hastalarına kıyasla kolon hastalarında eritrosit sayısı (p=0.029), hemoglobin (p=0.034) ve albümin (p=0.047) seviyeleri yüksek tespit edilmiştir. Çalışmamızda VDR BsmI, ApaI ve TaqI polimorfizmleri ile 5-FU tabanlı kemoterapi sonrası gözlenen yan etkiler arasında belirgin bir ilişki tespit edilmemiştir. Sonuç olarak elde ettiğimiz veriler ApaI ve TaqI polimorfizmlerinin KRK’da inflamasyon ve sağ kalım süreçlerini doğrudan etkileyebileceğine işaret etmektedir. Karşılaştırmalı kolon ve rektum analizlerinden elde ettiğimiz verilerin ise kolon ve rektum kanserlerinin farklı birer patoloji olarak ele alınmaları hususunda literatüre katkı sağlayacağını düşünüyoruz. Sonuçlarımız daha geniş popülasyonlarda ileri çalışmalar ile desteklenmelidir.
Colorectal cancer (CRC) is one of the most common cancers in both our country and worldwide and one of the leading causes of cancer-related death. For this reason, the determination of genetic risk factors involved in CRC carcinogenesis is important for understanding the pathology of the disease, determining possible therapeutic targets and revealing different treatment options. Vitamin D receptor (VDR) controls the cellular events such as proliferation, apoptosis, differentiation, inflammation, invasion, metastasis, angiogenesis, which are also effective in carcinogenesis by mediating gene expression regulation. Due to its role in vital and carcinogenic activities, in the present study we aimed to reveal the relationships of VDR BsmI (rs1544410), ApaI (rs7975232) and TaqI (rs731236) polymorphisms with clinical and pathological characteristics of CRC patients. We also aimed to reveal the relationship between primary tumor location and 5-FU related side effects with VDR polymorphisms, blood cell counts and concentrations of spesific serum molecules. Our study group consists of immunohistochemically confirmed CRC patients. Genomic DNAs were isolated from peripheral blood. Genotype analyzes were performed using polymerase chain reaction (PCR) and restriction fragment length polymorphism (RFLP) methods. Patients with ApaI heterozygous (GT) genotypes were found to have higher eosinophil counts (p=0.019) and RDW levels (p=0.007), whereas ApaI homozygous mutant (TT) patients were found to have higher creatinine levels (p<0.001). TaqI homozygous mutant (CC) patients had higher creatinine (p=0.007); TaqI heterozygous (TC) patients had higher RDW (p=0.007) levels compared to other TaqI genotypes. Neutrophil counts (p=0.026), mean albumin (p=0.023) and creatinine (p=0.036) levels were found to be higher in patients with TaqI CC genotype compared to TaqI TT+TC genotypes. In the present study BsmI, ApaI and TaqI polymorphisms were not found to be associated with primary tumor location. However, erythrocyte count (p=0.029), hemoglobin (p=0.034) and albumin (p=0.047) levels were found to be higher in colon cancer patients compared to rectal cancer. Finally, no significant relationship was found between VDR BsmI, ApaI and TaqI polymorphisms and 5-FU chemotherapy related side effects. In conclusion, our results may indicate that ApaI and TaqI polymorphisms could directly affect inflammation and survival processes in CRC. We also suggest that results from comparative colon and rectum analyzes would contribute to the literature on the consideration of colon and rectal cancers as different pathologies. Our results should be supported by further studies in larger populations.
Colorectal cancer (CRC) is one of the most common cancers in both our country and worldwide and one of the leading causes of cancer-related death. For this reason, the determination of genetic risk factors involved in CRC carcinogenesis is important for understanding the pathology of the disease, determining possible therapeutic targets and revealing different treatment options. Vitamin D receptor (VDR) controls the cellular events such as proliferation, apoptosis, differentiation, inflammation, invasion, metastasis, angiogenesis, which are also effective in carcinogenesis by mediating gene expression regulation. Due to its role in vital and carcinogenic activities, in the present study we aimed to reveal the relationships of VDR BsmI (rs1544410), ApaI (rs7975232) and TaqI (rs731236) polymorphisms with clinical and pathological characteristics of CRC patients. We also aimed to reveal the relationship between primary tumor location and 5-FU related side effects with VDR polymorphisms, blood cell counts and concentrations of spesific serum molecules. Our study group consists of immunohistochemically confirmed CRC patients. Genomic DNAs were isolated from peripheral blood. Genotype analyzes were performed using polymerase chain reaction (PCR) and restriction fragment length polymorphism (RFLP) methods. Patients with ApaI heterozygous (GT) genotypes were found to have higher eosinophil counts (p=0.019) and RDW levels (p=0.007), whereas ApaI homozygous mutant (TT) patients were found to have higher creatinine levels (p<0.001). TaqI homozygous mutant (CC) patients had higher creatinine (p=0.007); TaqI heterozygous (TC) patients had higher RDW (p=0.007) levels compared to other TaqI genotypes. Neutrophil counts (p=0.026), mean albumin (p=0.023) and creatinine (p=0.036) levels were found to be higher in patients with TaqI CC genotype compared to TaqI TT+TC genotypes. In the present study BsmI, ApaI and TaqI polymorphisms were not found to be associated with primary tumor location. However, erythrocyte count (p=0.029), hemoglobin (p=0.034) and albumin (p=0.047) levels were found to be higher in colon cancer patients compared to rectal cancer. Finally, no significant relationship was found between VDR BsmI, ApaI and TaqI polymorphisms and 5-FU chemotherapy related side effects. In conclusion, our results may indicate that ApaI and TaqI polymorphisms could directly affect inflammation and survival processes in CRC. We also suggest that results from comparative colon and rectum analyzes would contribute to the literature on the consideration of colon and rectal cancers as different pathologies. Our results should be supported by further studies in larger populations.