Kodlama yapmayan uzun RNA HOTTIP’ in periampuller bölge tümörlerindeki klinik öneminin araştırılması
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Date
2016
Authors
Balçın, Özkan
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Publisher
Uludağ Üniversitesi
Abstract
Periampuller bölge tümörlerinde erken tanı ve prognozun tayini henüz çözülememiş bir problemdir. Bu çalışmada, son yıllarda keşfedilen ve kanser oluşumunda rol oynadığı bilinen bir kodlama yapmayan uzun RNA olan distal tipteki HOXA transkripti (HOXA transcript at the distal tip-HOTTIP) ‘nin periampuller bölge tümörlerindeki rolünün araştırılması amaçlanmıştır. Çalışmada 2006 - 2014 yılları arasında Uludağ Üniversitesi Tıp Fakültesi (U.Ü.T.F) Genel Cerrahi Anabilim Dalı ‘nda periampuller bölge tümörleri nedeniyle cerrahi uygulanan 100 hasta değerlendirildi. Spesmenlerdeki tümörlü ve tümörsüz dokularda Real-Time PCR yöntemi kullanılarak HOTTIP ekspresyon tayini ve DNA sekanslama yöntemi ile KRAS mutasyon durumu araştırıldı. Elde edilen bulgular ile patolojik parametreler karşılaştırıldı ve hastalıksız sağ kalım / genel sağ kalım ile ilişkileri web tabanlı Sabiosciences PCR-Data Analiz istatistik programı kullanılarak analiz edildi. Olguların ortalama yaşı 62 (26 – 91) olup 78 ’i erkek, 22 ’si kadındır. Olguların 46 ’sı pankreas başı, 34 ’ü ampulla vateri, 12 ’si distal koledok ve 8 ’i de duodenum tümörü idi. HOTTIP ekspresyonu, normal doku ile karşılaştırıldığında; tümöral dokuda 32 kat fazla idi (p=0,013). 100 olgunun 29 ‘unda KRAS kodon 13 mutasyonu saptandı. KRAS kodon 13 mutasyonu taşımayan 71 olgunun % 86 ’sında HOTTIP ’in yüksek ekspresyon gösterdiği belirlendi (p=0,03). HOTTIP ekspresyonu pankreas başı ve ampullada lokalize tümörlerde 8,3 ve 5,2 kat, infiltratif karakterlilerde 5 kat, lenfatik invazyonu olanlarda 8 kat ve rezeksiyon sonrası ilk 6 ayda ölenlerde 8,7 kat daha fazla idi (sırası ile p=0,0001, p=0,003, p=0,003, p=0,001 ve p=0,001) Bu çalışmanın sonucuna göre; periampuller bölge tümörlerinde, HOTTIP tayini prognoz takibinde etkili olabilecek bir biyobelirteç adayıdır. Ayrıca, KRAS mutasyonu bulunmayan periampuller bölge tümörlerinde, HOTTIP ekspresyonunun anlamlı derecede fazla olması bu tümörlerin oluşumunda sadece genetik değil epigenetik mekanizmaların da aktif olduğunu düşündürmektedir.
The medical and surgical treatment of periampullary tumors is difficult to estimate the impact of prognosis. Recent studies indicate that long non-coding RNAs (lncRNAs) play crucial roles in tumorigenesis. The objective of this study is to investigate the effect and role of long non coding RNA HOXA transcript at the distal tip (HOTTIP) on prognosis of periampullary region tumors. A total of 100 periampullary region cancer cases were determined at the Department of General Surgery, Uludag University Hospital from 2006 to 2014. Each patient was histopathologically diagnosed as any periampullary region tumors. HOTTIP expression profile was determined using Real-Time PCR in tumors and non-tumor tissues. KRAS gene were screened by DNA sequencing in 100 patients. Relationships between data, patient clinicopathological parameters and disease-free survival and overall survival were analysed by using Web-based Sabiosciences PCR-Data Analysis programme. The present study unrelated patients with periampullary region tumors, including 78 males and 22 females, aged 26-91 years; the median age at the time of diagnosis was 62 years. Primary tumors were localized in the head of the pancreas in 46 cases, the papilla of vateri in 34 cases, the duodenum in 8 cases and the distal bile duct in 12 cases. The expression level of HOTTIP was 32-fold upregulated in tumors (n=100) relative to normal tissues (n=92) (p=0,013). Point mutation in KRAS gene codon 13 was identified in 29 cases. HOTTIP expression was upregulated in mutation (-) tumors compared (n=71) to mutation (+) tumors (n=29) (p=0,03) The presence of the primary tumor in the pancreas head and papilla of vater was significantly associated with upregulated expression of HOTTIP compared to other primary tumor locations (p=0,0001; p=0,003). The expression of HOTTIP was 5,09-fold upregulated in patients with infiltrative growth tumors and 8,01-fold upregulated in patients with lymphatic invasion pozitive tumors (p=0,003; p=0,001). The expression level of HOTTIP was 8,75-fold upregulated in patients die during the 6 months after surgery. The elevated expression of HOTTIP may be involved in the progression of periampullary region tumors and may therefore be considered a prognostic factor for patients with poor prognosis. Furthermore, HOTTIP expression was observed high level in tumors without mutation of KRAS gene. This result shows that epigenetic mechanisms maybe as important as genetic mechanism in cancer progression.
The medical and surgical treatment of periampullary tumors is difficult to estimate the impact of prognosis. Recent studies indicate that long non-coding RNAs (lncRNAs) play crucial roles in tumorigenesis. The objective of this study is to investigate the effect and role of long non coding RNA HOXA transcript at the distal tip (HOTTIP) on prognosis of periampullary region tumors. A total of 100 periampullary region cancer cases were determined at the Department of General Surgery, Uludag University Hospital from 2006 to 2014. Each patient was histopathologically diagnosed as any periampullary region tumors. HOTTIP expression profile was determined using Real-Time PCR in tumors and non-tumor tissues. KRAS gene were screened by DNA sequencing in 100 patients. Relationships between data, patient clinicopathological parameters and disease-free survival and overall survival were analysed by using Web-based Sabiosciences PCR-Data Analysis programme. The present study unrelated patients with periampullary region tumors, including 78 males and 22 females, aged 26-91 years; the median age at the time of diagnosis was 62 years. Primary tumors were localized in the head of the pancreas in 46 cases, the papilla of vateri in 34 cases, the duodenum in 8 cases and the distal bile duct in 12 cases. The expression level of HOTTIP was 32-fold upregulated in tumors (n=100) relative to normal tissues (n=92) (p=0,013). Point mutation in KRAS gene codon 13 was identified in 29 cases. HOTTIP expression was upregulated in mutation (-) tumors compared (n=71) to mutation (+) tumors (n=29) (p=0,03) The presence of the primary tumor in the pancreas head and papilla of vater was significantly associated with upregulated expression of HOTTIP compared to other primary tumor locations (p=0,0001; p=0,003). The expression of HOTTIP was 5,09-fold upregulated in patients with infiltrative growth tumors and 8,01-fold upregulated in patients with lymphatic invasion pozitive tumors (p=0,003; p=0,001). The expression level of HOTTIP was 8,75-fold upregulated in patients die during the 6 months after surgery. The elevated expression of HOTTIP may be involved in the progression of periampullary region tumors and may therefore be considered a prognostic factor for patients with poor prognosis. Furthermore, HOTTIP expression was observed high level in tumors without mutation of KRAS gene. This result shows that epigenetic mechanisms maybe as important as genetic mechanism in cancer progression.
Description
Keywords
Periampuller bölge tümörleri, RNA, KRAS, HOTTIP, Prognoz, Periampullary region tumors, Prognosis
Citation
Balçın, Ö. (2016). Kodlama yapmayan uzun RNA HOTTIP’ in periampuller bölge tümörlerindeki klinik öneminin araştırılması. Yayınlanmamış uzmanlık tezi. Uludağ Üniversitesi Tıp Fakültesi.