Publication: Kolorektal adenokarsinom hastalarında metastaz oluşumu ve terapiye yanıt farklılıklarındaki moleküler alt yapının araştırılması
Abstract
Çalışmamızda kanser gelişiminin farklı basamaklarında ve ilaç metabolizmasında görev alan dihidropirimidin dehidrogenaz (DPYD), metilentetrahidrofolat redüktaz (MTHFR), timidilat sentaz (TYMS), SNAI1, lisil oksidaz benzeri protein 2 (LOXL2), programlı hücre ölümü-1 (PD-1), programlı hücre ölümü ligandı 1 (PDL-1), vasküler endotelyal büyüme faktörü A (VEGF-A) genlerine ait spesifik polimorfizmlerin kolorektal kanser (KRK) ile ilişkilerini Türk toplumunda detaylı olarak ortaya çıkarmayı hedefledik. Çalışmamızdan elde edeceğimiz sonuçlar ile KRK etiyolojisinde tam olarak ortaya çıkarılmamış genetik etkileşimleri ve yeni terapötik hedefleri tespit etmeyi ve mevcut tedavi seçeneklerin iyileştirilmesine yönelik veriler elde etmeyi amaçladık. Çalışmaya toplamda histolojik olarak doğrulanmış 103 KRK hastası ve kanser veya otoimmün bozukluk öyküsü olmayan 86 gönüllü dahil edilmiştir. Genotip analizleri DPYD, MTHFR ve TYMS polimorfizmleri için mikrodizin bazlı Infiniti Plus analizörü (AutoGenomics Inc.); SNAI1, LOXL2, PD-1, PDL-1 ve VEGF-A polimorfizmleri için ise kütle spektrometresi temeline dayanan MassARRAY platformu (Agena Bioscience) kullanılarak yapılmıştır. Çalışma grubumuzda DPYD 496A>G polimorfizminin 5-FU kaynaklı 0-2 seviyede yan etkiler ile ilişkili olduğu tespit edilmiştir (p=0.02). PD-1 rs36084323 CT (p<0.001), PD-1 rs7421861 GA (p=0.007) ve PDL-1 rs2282055 GG (p=0.040) genotipleri azalan KRK riski ile ilişkili bulunmuştur. LOXL2 rs6999447 CT+TT ve SNAI1 rs6125849 GA+AA genotiplerinin sinerjetik birlikteliği artan metastaz riski ile ilişkili bulunmuştur (OR:5.739, p=0.019 ve OR:4.562, p=0.03). VEGF-A -460TT ve CT+TT genotiplerinin azalan karaciğer metastazı riski ile ilişkili olduğu saptanmıştır (OR:0.080 p=0.02 ve OR:0.191, p=0.04, sırası ile). VEGF-A +405GC+CC ve DPYD 496AG+GG genotipleri sol kolon kanseri geliştirme riski ile yakın ilişkili bulunmuşlardır (OR:5.208, p=0.04 ve OR:4.777, p=0.05). DPYD 85TC+CC genotiplerine sahip hastaların progresyonsuz ve genel sağ kalım sürelerinin daha uzun olduğu belirlenmiştir (Log rank=6.60, p=0.01 ve Log rank=4.40, p=0.04). PDL-1 rs2282055 TT genotipine sahip hastaların GG genotipinde olanlara kıyasla daha uzun progresyonsuz ve genel sağ kalım gösterdikleri saptanmıştır (Bonferroni düzeltilmiş Log rank p=0.013 ve p=0.009). VEGF-A +405GC+CC genotipine sahip hastalarda bevasizumab kullanımının daha kısa progresyonsuz sağ kalımla bağlantılı olduğu belirlenmiştir (Log rank=4.61, p=0.03). Araştırmamızda Türk toplumunda KRK hassasiyeti, metastazı, primer tümörün yeri, prognozu ve kemoterapi cevabında etkili genetik risk faktörleri ve yeni potansiyel terapötik bölgeler belirlenmiştir. Bulgularımızın KRK biyolojisi ve kemoterapisinde rol alan genetik mekanizmalarının anlaşılması yoluyla kişiselleştirilmiş tedavi rejimlerinin iyileştirilmesine katkı sağlayacağı öngörülmektedir.
In the present study, we aimed to reveal the detailed relationships between colorectal cancer (CRC) and specific genetic variations on dihydropyrimidine dehydrogenase (DPYD), methylenetetrahydrofolate reductase (MTHFR), thymidylate synthase (TYMS), SNAI1, lysyl oxidase-like protein 2 (LOXL2), programmed cell death-1 (PD-1), programmed cell death ligand 1 (PDL-1), vascular endothelial growth factor A (VEGF-A) genes, which are involved in different stages of cancer development and drug metabolism, in Turkish population. We intended to detect genetic interactions that have not been well established in CRC etiology and new therapeutic targets, and to obtain data to improve existing therapeutic options. A total of 103 histologically confirmed CRC patients and 86 volunteers without cancer or autoimmune disorder history were included in the study. Microarray based Infiniti Plus analyzer (AutoGenomics Inc.) was used for genotyping of DPYD, MTHFR and TYMS polymorphisms and mass spectrometry based MassARRAY platform (Agena Bioscience) was used for SNAI1, LOXL2, PD-1, PDL-1 and VEGF-A polymorphisms. In our study group, DPYD 496A>G polymorphism was found to be associated with 5-FU-induced grade 0-2 adverse events (p=0.02). PD-1 rs36084323 CT (p<0.001), PD-1 rs7421861 GA (p=0.007) and PDL-1 rs2282055 GG (p=0.040) genotypes were found to be associated with reduced CRC risk. The synergetic existing of LOXL2 rs6999447 CT+TT and SNAI1 rs6125849 GA+AA genotypes were related with increased metastasis risk (OR:5.739, p=0.019 and OR:4.562, p=0.03, respectively). VEGF-A -460TT and CT+TT genotypes were found to be involved in reduced liver metastasis risk (OR:0.080 p=0.02 and OR:0.191, p=0.04, respectively). Only VEGF-A +405GC+CC and DPYD 496AG+GG genotypes were closely related with left colon cancer risk (OR:5.208, p=0.04 and OR:4.777, p=0.05, respectively). The DPYD 85TC+CC genotypes was found to be related with longer progression-free and overall survival (Log rank=6.60, p=0.01 and Log rank=4.40, p=0.04, respectively). Patients with PDL-1 rs2282055 TT genotype showed longer progression-free and overall survival compared to GG genotype (Bonferroni corrected Log rank p=0.013 and p=0.009). We found that bevacizumab treatment resulted in shorter progression-free survival in patients with the VEGF-A +405GC+CC genotypes (Log rank=4.61, p=0.03). In our study, along with new potential therapeutic targets, genetic risk factors effective in CRC sensitivity, metastasis, primary tumor location, prognosis and chemotherapy response were determined in Turkish population. Our findings will contribute to understanding the genetic background of CRC biology and chemotherapy and provide data for improving of personalized therapy regimens.
In the present study, we aimed to reveal the detailed relationships between colorectal cancer (CRC) and specific genetic variations on dihydropyrimidine dehydrogenase (DPYD), methylenetetrahydrofolate reductase (MTHFR), thymidylate synthase (TYMS), SNAI1, lysyl oxidase-like protein 2 (LOXL2), programmed cell death-1 (PD-1), programmed cell death ligand 1 (PDL-1), vascular endothelial growth factor A (VEGF-A) genes, which are involved in different stages of cancer development and drug metabolism, in Turkish population. We intended to detect genetic interactions that have not been well established in CRC etiology and new therapeutic targets, and to obtain data to improve existing therapeutic options. A total of 103 histologically confirmed CRC patients and 86 volunteers without cancer or autoimmune disorder history were included in the study. Microarray based Infiniti Plus analyzer (AutoGenomics Inc.) was used for genotyping of DPYD, MTHFR and TYMS polymorphisms and mass spectrometry based MassARRAY platform (Agena Bioscience) was used for SNAI1, LOXL2, PD-1, PDL-1 and VEGF-A polymorphisms. In our study group, DPYD 496A>G polymorphism was found to be associated with 5-FU-induced grade 0-2 adverse events (p=0.02). PD-1 rs36084323 CT (p<0.001), PD-1 rs7421861 GA (p=0.007) and PDL-1 rs2282055 GG (p=0.040) genotypes were found to be associated with reduced CRC risk. The synergetic existing of LOXL2 rs6999447 CT+TT and SNAI1 rs6125849 GA+AA genotypes were related with increased metastasis risk (OR:5.739, p=0.019 and OR:4.562, p=0.03, respectively). VEGF-A -460TT and CT+TT genotypes were found to be involved in reduced liver metastasis risk (OR:0.080 p=0.02 and OR:0.191, p=0.04, respectively). Only VEGF-A +405GC+CC and DPYD 496AG+GG genotypes were closely related with left colon cancer risk (OR:5.208, p=0.04 and OR:4.777, p=0.05, respectively). The DPYD 85TC+CC genotypes was found to be related with longer progression-free and overall survival (Log rank=6.60, p=0.01 and Log rank=4.40, p=0.04, respectively). Patients with PDL-1 rs2282055 TT genotype showed longer progression-free and overall survival compared to GG genotype (Bonferroni corrected Log rank p=0.013 and p=0.009). We found that bevacizumab treatment resulted in shorter progression-free survival in patients with the VEGF-A +405GC+CC genotypes (Log rank=4.61, p=0.03). In our study, along with new potential therapeutic targets, genetic risk factors effective in CRC sensitivity, metastasis, primary tumor location, prognosis and chemotherapy response were determined in Turkish population. Our findings will contribute to understanding the genetic background of CRC biology and chemotherapy and provide data for improving of personalized therapy regimens.