Cilt Kanserinde Sirkadiyen ile İlişkili Gen Mutasyonu ve Ekspresyon Paternlerinin Belirlenmesi

Öz

Amaç: Birçok periferal organın sirkadiyen ritim tarafından modüle edilen endojen ritimleri vardır; deri de bu periferik organlardan biridir. Ritimdeki düzensizlikler hücresel yolları yeniden programlayabilir ve hücre çoğalmasına, apoptoza direnç, metastaz, bağışıklık sistemi hücrelerinin yok edilmesi ve anjiyogenezin artmasına neden olabilir. Bu çalışmanın amacı, SKCM örneklerinde çekirdek sirkadiyen ritim genlerinin mutasyonel ve m-RNA profilini kapsamlı bir şekilde araştırmaktır. Method: Bu çalışmada; SKCM (n:462) hastalarının genom dizileri ve gen ekspresyon profilleri TCGA veri tabanından indirildikten sonra hedef genlerin mutasyon sıklığı ve mutasyon paternleri detaylı olarak belirlendi. SKCM için tespit ettiğimiz mutasyonların onkojenik özelliklerini tahmin etmek için PolyPhen-2 ve SNAP biyoinformatik araçları kullanıldı. Eş zamanlı olarak, sirkadiyen ritim genlerindeki mutasyonların fonksiyonel etkilerini değerlendirmek için m-RNA ekspresyon profilleri belirlendi. Son olarak, mutasyona uğramış proteinlerin hücresel süreçlerdeki fonksiyonel ilişkilerini daha iyi anlamak için STRING ağ analizi yapıldı. Bulgular: 10 gende bulunan 173 mutasyondan 152 missense (yanlış anlamlı) mutasyon, 13 nonsense (anlamsız) mutasyon, 6 splice bölge mutasyonu ve 2 füzyon gen mutasyonu vardı ve bunların 62'si patojenik özelliklere sahipti. BMAL1, CRY2, PER1, PER2 ve PER3'ün m-RNA ekspresyon seviyeleri, SKCM doku örneklerinde downregüle olurken, TIMELESS sağlıklı gruba kıyasla upregüle olduğu görüldü (p<0.01). Prognostik bir belirteç olarak kabul edilen m-RNA ekspresyonunun genel sağkalıma etkisi, azalan ARNTL (p=0.00038) seviyesi ve artan TIMELESS (p=0.00033) seviyesi için anlamlı bulundu. Sonuç: Bu moleküler bakış açısının belirlenmesi, hedefe yönelik ilaç tedavileri ve kişiselleştirilmiş tıp geliştirmede faydalı olabilir.

Anahtar Kelimeler

• sirkadiyen
• kriptokrom
• periyod
• cilt kanseri
• mutasyon
• saat genleri

Identification of circadian-related gene mutation and expression patterns in skin cancer

Abstract

Aim: Many peripheral organs have endogenous rhythms that are modulated by circadian rhythm; the skin is one of these peripheral organs. Irregularities in rhythm can reprogram cellular pathways and lead to cell proliferation, resistance to apoptosis, metastasis, elimination of immune system cells, and increased angiogenesis. The aim of this study was to comprehensively investigate the mutational and m-RNA profile of core circadian rhythm genes in SKCM samples. Methods: The genome sequences and gene expression profiles of SKCM (n:462) patients were downloaded from the TCGA database. Mutation frequency and mutation patterns of target genes were determined in detail. PolyPhen-2 and SNAP tools were used to estimate the oncogenic properties of the mutations we detected for SKCM. Simultaneously, m-RNA expression profiles were determined to asses the functional effects of mutations in circadian rhythm genes. Finally, STRING network analysis was performed to better understand the functional relationships of mutated proteins in cellular processes. Results: There were 152 missense mutations, 13 nonsense mutations, 6 splice region mutations and, 2 fusion gene mutations among the 173 mutations found in 10 genes, and 62 of them had pathogenic properties. The m-RNA expression levels of BMAL1, CRY2, PER1, PER2, and PER3 were down-regulated in SKCM tissue samples, while TIMELESS was up-regulated compared to the the healthy group (p<0.01). The effect of m-RNA expression, considered a prognostic marker, on overall survival was found to be significant for decreased ARNTL (p=0.00038) level and increased TIMELESS (p=0.00033) level. Conclusion: Determining this molecular perspective may be useful in developing targeted drug therapies and personalized medicine.

Keywords

• circadian
• cryptochrome
• period
• skin cancer
• clock genes

Kaynakça

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