Gülçin GÜNDEN, Sevgi IŞIK, Hava ÜSKÜDAR TEKE, Oğuz ÇİLİNGİR, Nur OGUZ DAVUTOGLU, Ebru ERZURUMLUOĞLU, Sinem KOCAGİL, Sevilhan ARTAN, Beyhan DURAK ARAS

İzole 13q Delesyonu Saptanan KLL Olgularında Notch1 ve Sf3b1 Genlerinde Mutasyon Analizi

Kronik lenfositik lösemi (KLL) klonal matür B lenfositten kaynaklanan ve genetik heterojenite gösteren bir lösemi tipi olarak bilinmektedir. KLL’nin genomunun aydınlatılması için birçok çalışma yapıldığı görülmektedir. Bu çalışmalarda, kromozomal aberasyonlardan en sık del(13q)’nun meydana geldiği bildirilmektedir. Bu anomali izole olduğu durumda iyi prognoz ile ilişkilendirilmesine rağmen, hastalar klinik heterojenite göstermektedir. Bunun yanında kötü prognoz ile ilişkilendirilen TP53, NOTCH1 ve SF3B1 gen mutasyonlarının da bulunduğu bir çok gende mutasyonlar tanımlanmış ve prognostik önemleri ortaya koyulmaya başlanmıştır. Biz de, bu veriler doğrultusunda FISH yöntemiyle izole del(13q) saptadığımız 43 olguda NOTCH1 ve SF3B1 genlerinin mutasyon oranını belirlemeyi ve prognoza (hastalık evreleri, TTFT ve OS) olan etkisini araştırmayı hedefledik. KLL’de en sık gözlenen NOTCH1 ve SF3B1 gen mutasyonlarını Sanger sekanslama yöntemi ile araştırdık. Klinik heterojeniteye sahip KLL olgu grubumuzun, 1/42’sinde NOTCH1 geninde frameshift 7541_7542delCT mutasyonu saptanırken, SF3B1 geninde mutasyon tespit edemedik. Çalışmamız sonucunda, NOTCH1 ve SF3B1 gen mutasyonlarının literatür verileri ile uyumlu olarak izole del(13q) ile ilişkili olmadığı gözlenmiştir. Çalışmamız Türk populasyonunda izole del(13q) KLL hastalarında prognostik parametreler ile birlikte NOTCH1 ve SF3B1 gen mutasyonlarının değerlendirildiği ilk çalışma olma özelliğindedir. Sonuç olarak; izole del(13q) vakalarının klinik heterojenitesinden sorumlu başka nedenlerin de olabileceği ve bunların ortaya çıkarılmasını amaçlayan daha fazla çalışmaya ihtiyaç olduğu sonucuna varılmıştır.

Anahtar Kelimeler:

Del13q, KLL, NOTCH1, Sanger, SF3B1

Analyzing The Mutations Of Notch1 And Sf3b1 Genes In Cases With CLL Detected Isolated 13q Deletion

Chronic lymphocytic leukemia (CLL) is known as type of leukemia originating from clonal mature B lymphocytes and has genetic heterogeneity. Many studies have been done to clarify the genome of CLL. In these studies, del(13q) is reported as the most common chromosomal aberration. Although this anomaly is associated with good prognosis when isolated, patients have clinical heterogeneity. In addition, in many gene mutations including TP53, NOTCH1 and SF3B1 gene mutations, poor prognosis has been identified. The prognostic significance of these genes has begun to be demonstrated. According to these data, we aimed to determine the mutation rate of NOTCH1 and SF3B1 genes and to investigate the prognostic effects (disease stages, TTFT and OS) in 43 cases with isolated del(13q) by using FISH method. We investigated the most common mutations of NOTCH1 and SF3B1 gene in CLL by using Sanger sequencing method. While frameshift 7541_7542delCT mutation was detected in the NOTCH1 gene in 1 out of 42 CLL cases with clinical heterogeneity, mutation in the SF3B1 gene couldn’t be detected. As a result of our study, it was observed that NOTCH1 and SF3B1 gene mutations weren’t associated with isolated del(13q) which is compatible with the literature data. Our study is the first study that evaluates NOTCH1 and SF3B1 gene mutations with prognostic parameters of isolated del(13q) with CLL patients in the Turkish population. As a result; It was concluded that there may be different reasons responsible for the clinical heterogeneity of isolated del(13q) cases and further studies are needed to reveal these reasons

Keywords:

CLL, Del13q, NOTCH1, Sanger, SF3B1,

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