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E L If D a R B U K a Ist a N B U L Ü N Ive R Sit E Si Sa Ğ . B Il. E N St ELIF DARBUKA İSTANBUL ÜNİVERSİTESİ SAĞ. BİL. ENST. YÜKSEK LİSANS TEZİ İSTANBUL-2018 T.C. İSTANBUL ÜNİVERSİTESİ SAĞLIK BİLİMLERİ ENSTİTÜSÜ ( YÜKSEK LİSANS TEZİ ) KOLOREKTAL KANSERLİ HASTALARDA TCEAL7 GENİNİN ARAŞTIRILMASI ELİF DARBUKA DANIŞMAN PROF. DR. ALİ NUR TURGUT ULUTİN GENETİK ANABİLİM DALI GENETİK PROGRAMI İSTANBUL-2018 ii TEZ ONAYI iii BEYAN Bu tez çalışmasının kendi çalışmam olduğunu, tezin planlanmasından yazımına kadar bütün safhalarda etik dışı davranışımın olmadığını, bu tezdeki bütün bilgileri akademik ve etik kurallar içinde elde ettiğimi, bu tez çalışmasıyla elde edilmeyen bütün bilgi ve yorumlara kaynak gösterdiğimi ve bu kaynakları da kaynaklar listesine aldığımı, yine bu tezin çalışılması ve yazımı sırasında patent ve telif haklarını ihlal edici bir davranışımın olmadığı beyan ederim. Elif DARBUKA iv İTHAF Tez çalışmamı; Aileme ithaf ediyorum… v TEŞEKKÜR Tez süresince ilgisini ve desteğini esirgemeyen tez danışmanım Prof. Dr.Turgut ULUTİN’e, Tez çalışmam ve yüksek lisans eğitimim boyunca değerli bilgilerini, katkılarını ve sabrını esirgemeyen, her konuda tecrübesine sonuna kadar güvendiğim değerli hocam Prof. Dr. Nur BUYRU’ya, Tez çalışmamın gerçekleşmesi için gerekli dokuların temin edilmesini sağlayan ve bu süreçte bana destek olan Uzm. Dr. Süleyman DEMİRYAS’a ve patolojik incelemelerde uzmanlığından faydalandığım Uzm. Dr. Nuray KEPİL’e Moleküler Genetik Laboratuvarı’na ilk adımımı attığımdan beri her konuda yardımcı olan, yol gösteren ve sabırla destek veren Doç Dr. Onur BAYKARA’ya, Dr. Seda Ekizoğlu ERATAK’a, Dr. Filiz ÖZDEMİR’e, MSc. Asuman ÇELEBİ’ye ve Dr. Didem SEVEN’e, Doç Dr. Hikmet KÖSEOĞLU’na, Laboratuvar ve yüksek lisans eğitim arkadaşlığından öte benim için dost olan, MSc. Aslı KARACAN’a, BSc. Pelin BULUT’a, BSc. Ceren ORHAN’a, MSc. Betül SEYHAN’a ve BSc. Ayşegül SOYSAL’a, Hayatıma girdiklerinden beri dünyaya bakışımı değiştiren, saf sevginin ne demek olduğunu öğreten yeğenlerim Zeynep Nur BAY, Azra Lina BAY, Muhammed Yusuf PARLAK ve Ahsen Mina PARLAK’a, Hayatım boyunca daima sevgiyle yanımda olan, attığım her adımda en büyük destekçilerim annem Semra DARBUKA’ya, babam Ahmet DARBUKA’ya, ablalarım Neslihan PARLAK ve Aslı BAY’a, hayatı benim için daha güzel yapan tüm aileme ve arkadaşlarıma Sonsuz teşekkür ederim… Bu çalışma, İstanbul Üniversitesi Bilimsel Araştırma Projeleri Birimi tarafından desteklenmiştir. Proje No: 28691 vi İÇİNDEKİLER TEZ ONAYI .................................................................................................................... İİ BEYAN ........................................................................................................................... İİİ İTHAF ............................................................................................................................ İV TEŞEKKÜR ..................................................................................................................... V İÇİNDEKİLER .............................................................................................................. Vİ TABLOLAR LİSTESİ ................................................................................................... İX ŞEKİLLER LİSTESİ ..................................................................................................... Xİ SEMBOLLER / KISALTMALAR LİSTESİ ............................................................... Xİİ ÖZET .......................................................................................................................... XİV ABSTRACT .................................................................................................................. XV 1. GİRİŞ VE AMAÇ ......................................................................................................... 1 2. GENEL BİLGİLER ...................................................................................................... 2 2.1. Kolorektal Kanserler ................................................................................................ 3 2.1.1. Semptomlar ......................................................................................................... 4 2.1.2. Sıklığı ve Ölüm Oranları ..................................................................................... 5 2.1.3. Evreleme ............................................................................................................. 7 2.1.4. Histolojik Tip ve Derece ..................................................................................... 8 2.1.5. Kolorektal Kanser Çeşitleri ................................................................................. 8 2.1.5.1. Ailesel Kolorektal Kanser .............................................................................. 8 1. Ailesel Adenomatöz Polipozis (FAP) ................................................................... 10 2. Kalıtsal Nonpolipozis Kolorektal Kanser (HNPCC) ............................................ 11 3. MUTYH ile ilişkili polipozis (MAP) .................................................................... 13 4. Peutz-Jeghers Sendromu (PJS) ............................................................................. 13 5. Juvenil Polipozis Sendromu (JPS) ........................................................................ 14 6. Serrated (Tırtıklı) Polipozis Sendrom (SPS) ......................................................... 14 7. PTEN Hamartoma Tümör Sendromları ................................................................ 15 2.1.5.2. Sporadik Kolorektal Kanserler ..................................................................... 15 1. Çevresel Etmenler ................................................................................................. 15 2. Epigenetik Etmenler .............................................................................................. 17 a. Anormal DNA Metillenmesi ................................................................................. 17 vii b. Histon Değişimleri ................................................................................................ 18 c. Kodlama Yapmayan RNA’lar ............................................................................... 19 3. Genetik Etmenler .................................................................................................. 20 2.2. Yazılım Etmenleri ve Kanser ................................................................................. 28 2.2.1. TCEAL Gen Ailesi............................................................................................ 31 2.2.1.1. TCEAL7 Geni ve Proteini ............................................................................ 32 3. GEREÇ VE YÖNTEM ............................................................................................... 35 3.1. Gereç ...................................................................................................................... 35 3.1.1. Hasta Grubu ...................................................................................................... 35 3.1.2. Kullanılan Cihazlar ........................................................................................... 35 3.1.3. Kullanılan Malzemeler ve Kimyasal Maddeler ................................................ 36 3.2. Kullanılan Yöntemler ............................................................................................. 36 3.2.1. Dokudan RNA Eldesi........................................................................................ 36 3.2.2. RNA’nın Spektrofotometrik Analizi ................................................................. 38 3.2.3. Toplam RNA’dan cDNA eldesi ........................................................................ 38 3.2.4. TCEAL7 Geninin İfade Analizi ......................................................................... 39 3.2.5. Verilerin İstatistiksel Analizi ............................................................................ 41 4. BULGULAR ............................................................................................................... 42 4.1. Kolorektal Kanserli Dokularda TCEAL7 Gen İfade Analizi ................................ 42 4.2. Hastalara Ait Klinik Parametre Verileri ................................................................ 47 4.2.1. TCEAL7 Geninin İfade Değerlerinin Klinik Parametreler ile İlişkisi ............... 49 4.2.1.1. Cinsiyet ........................................................................................................ 49 4.2.1.2. Yaş................................................................................................................ 50 4.2.1.3. Tümör Yeri ................................................................................................... 52 4.2.1.4. Evre .............................................................................................................. 53 4.2.1.5. Histolojik Derece ......................................................................................... 54 4.2.1.6. Histolojik Tip ............................................................................................... 56 4.2.1.7. Lenfatik İnvazyon ........................................................................................ 57 4.2.1.8. Kan Damarı İnvazyonu ................................................................................ 58 4.2.1.9. Perinöral İnvazyon ....................................................................................... 60 5. TARTIŞMA ...............................................................................................................
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