Erken yaş meme kanserli hastalarda CHEK2 genindeki genetik varyasyonların değerlendirilmesi
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Date
2019
Authors
Aksoy, Fuat
Journal Title
Journal ISSN
Volume Title
Publisher
Bursa Uludağ Üniversitesi
Abstract
BRCA1/2 gen mutasyonlarının meme kanseri riskini arttırdığı uzun süredir bilinmekte olup, meme kanseri hastalarının rutin BRCA taramalarında bu genlerin protein kodlayan bölgeleri ve intron-ekzon sınırlarındaki genetik değişimler araştırılmaktadır. Son dönemde gerçekleştirilen çalışmalar, genlerin 3' transle olmayan bölgelerindeki (3'UTR) polimorfizmlerin mikroRNA (miRNA) bağlanma fonksiyonunu etkilediklerini ve hastalarda kanser gelişimi riskinin belirlenmesinde değerlendirilebilecek genetik belirteçler olabileceklerini ortaya koymuştur. Bu nedenle çalışmamızda, ailesel / erken yaş meme kanseri hastalarında, BRCA1/2 genlerinin 3'UTR ’sindeki risk faktörü olabilecek genetik değişimleri belirlemeyi amaçladık. 46 BRCA1/2 mutasyonu taşıyan ve 54 BRCA1/2 mutasyonu taşımayan toplam 100 ailesel / erken yaş meme kanseri hastası ve 47 kontrolde BRCA1 ve BRCA2 genlerinin 3'UTR’ leri heterodupleks ve DNA dizi analizleri ile tarandı. Hastaların % 27’ sinin BRCA1 geninde c.*1287C>T (rs12516), ve hastaların % 24’ ünün BRCA2 geninde c.*105A>C (rs15869) polimorfizleri belirlendi. Ayrıca, gerçekleştirilen Fisher’s Exact Test’ i ile hastalarda BRCA1 mutasyonu ile 3'UTR bölgesindeki c.*1287C>T (rs12516) polimorfizminin anlamlı bir sıklıkla birlikte görüldüğü saptandı (p =0.035). Bulgularımız BRCA1 geni 3'UTR ’sindeki c.*1287C>T (rs12516) polimorfizminin meme kanseri gelişme riskinin belirlenmesinde genetik bir belirteç olma potansiyelini ve BRCA1 geninin kodlanmayan bölgelerindeki genetik varyasyonların bu genin fonksiyonunu etkileyerek ailesel / erken yaş meme kanseri gelişme riskini arttırabileceğini destekler niteliktedir
Mutations in the BRCA1/BRCA2 gene confer a substantial increase in breast cancer risk, yet routine clinical genetic screening is limited to the coding regions and intronexon boundaries, precluding the identification of mutations in noncoding and untranslated regions. Because 3' untranslated region (3'UTR) polymorphisms disrupting microRNA (miRNA) binding can be functional and can act as genetic markers of cancer risk, we aimed to determine genetic variation in the 3'UTR of BRCA1/BRCA2 in familial and early-onset breast cancer patients with and without mutations in the coding regions of BRCA1/BRCA2 and to identify specific 3'UTR variants that may be risk factors for cancer development. The 3'UTRs of the BRCA1 and BRCA2 genes were screened by heteroduplex analysis and DNA sequencing in 100 patients from 46 BRCA1/2 families, 54 non-BRCA1/2 families, and 47 geographically matched controls. SNPs c.*1287C>T (rs12516) (BRCA1) and c.*105A>C (rs15869) (BRCA2) were identified in 27% and 24% of patients, respectively. These 2 variants were also identified in controls with no family history of cancer (23.4% and 23.4%, respectively). In addition, there was a statistically significant relationship between the BRCA1 gene polymorphism c.*1287C>T (rs12516) and BRCA1 mutations (p=0.035) by Fisher’s Exact Test. We suggest that, SNP c.*1287C>T (rs12516) of the BRCA1 gene may have potential use as a genetic marker of an increased risk of developing breast cancer and likely represents a non-coding sequence variation in BRCA1 that impacts BRCA1 function and leads to increased familial and/or early-onset breast cancer risk in the Turkish population.
Mutations in the BRCA1/BRCA2 gene confer a substantial increase in breast cancer risk, yet routine clinical genetic screening is limited to the coding regions and intronexon boundaries, precluding the identification of mutations in noncoding and untranslated regions. Because 3' untranslated region (3'UTR) polymorphisms disrupting microRNA (miRNA) binding can be functional and can act as genetic markers of cancer risk, we aimed to determine genetic variation in the 3'UTR of BRCA1/BRCA2 in familial and early-onset breast cancer patients with and without mutations in the coding regions of BRCA1/BRCA2 and to identify specific 3'UTR variants that may be risk factors for cancer development. The 3'UTRs of the BRCA1 and BRCA2 genes were screened by heteroduplex analysis and DNA sequencing in 100 patients from 46 BRCA1/2 families, 54 non-BRCA1/2 families, and 47 geographically matched controls. SNPs c.*1287C>T (rs12516) (BRCA1) and c.*105A>C (rs15869) (BRCA2) were identified in 27% and 24% of patients, respectively. These 2 variants were also identified in controls with no family history of cancer (23.4% and 23.4%, respectively). In addition, there was a statistically significant relationship between the BRCA1 gene polymorphism c.*1287C>T (rs12516) and BRCA1 mutations (p=0.035) by Fisher’s Exact Test. We suggest that, SNP c.*1287C>T (rs12516) of the BRCA1 gene may have potential use as a genetic marker of an increased risk of developing breast cancer and likely represents a non-coding sequence variation in BRCA1 that impacts BRCA1 function and leads to increased familial and/or early-onset breast cancer risk in the Turkish population.
Description
Keywords
Meme kanseri, BRCA1, BRCA2, 3'UTR, SNP, Erken yaş, Türkiye, Breast cancer, Early onset, Turkey
Citation
Aksoy, F. (2019). Erken yaş meme kanserli hastalarda CHEK2 genindeki genetik varyasyonların değerlendirilmesi. Yayınlanmamış tıpta uzmanlık tezi. Bursa Uludağ Üniversitesi Tıp Fakültesi.