Publication: Meme kanserinde sık görülen gen mutasyonlarının tamoksifene yanıt ile ilişkisi ve prognostik önemi
Abstract
Amaç: Meme kanseri kadınlarda görülen kanserler arasında prevalansı en yüksek kanserdir. Östrojen reseptörü pozitif (ER+) hastaların adjuvan tedavisinde tamoksifen standart tedavi olarak kullanılmaktadır ve CYP2D6 enzimi tarafından metabolize edilir. Bu projenin amacı, ER+ tamoksifen kullanan ve tamoksifen dirençli hastalarda, CYP2D6 allelik gruplarında, meme kanseri gelişiminde rol aldığı düşünülen PIK3CA, TP53, GSTP1, BRCA1/ 2 gen polimorfizmleri ile tamoksifenin etkinliği arasındaki ilişkinin belirlenmesidir.Gereç ve Yöntem: Çalışmaya katılan 43 hastadan alınan kan örneklerinden DNA izolasyonu sonrası CYP2D6 allelik gruplarının ve GST polimorfizmlerinin belirlenmesi için gerçek zamanlı qPZR yöntemi uygulanmıştır. PIK3CA ekzon 9 ve 20 ile p53 5-8 ekzonlarının taranması için PZR-HRM ve dizi analizi yapılmıştır. BRCA1/ 2 gen polimorfizmleri yeni nesil dizileme yöntemi ile taranmıştır.Bulgular: Çalışmamızda tamoksifen dirençli ve tamoksifen kullanan hastalar arasında BRCA1/ 2, PIK3CA ve GSTP1 polimorfizmleri ve CYP2D6 *2, *3, *4, *10, *17 allelik varyantarı arasında anlamlı bir fark saptanamamıştır. p53 geni 12383 (T>A) ve 12495 (G>C) varyasyonları tamoksifen dirençli grupta anlamlı bir şekilde yüksek bulunmuştur (sırasıyla p=0,045 ve p= 0,045). Sonuçlar: Çalışmamız tamoksifen kullanan ve dirençli hasta gruplarında CYP2D6 allelik varyantlarının ve BRCA1/ 2, PIK3CA, p53 ve GSTP1 polimorfizmlerinin birlikte incelendiği ilk çalışmadır. p53 geni varyasyonlarının tamoksifen dirençli grupta anlamlı bir şekilde yüksek görülmesi tamoksifen tedavisine başlanmadan önce ilaca direnci gösteren bir belirteç olarak kullanılabileceği yönünde öngürülebilir. Popülasyondaki örneklem sayısı arttırılarak ileri çalışmalarla verilerin desteklenmesi amaçlanmaktadır.
Objective: Breast cancer has the highest prevalence among cancers seen in women. Tamoxifen is used as standard therapy in the adjuvant therapy of estrogen receptor positive (ER+) patients and is metabolised by the CYP2D6 enzyme. The aim of this project is to determine the relationship between PIK3CA, TP53, GSTP1, BRCA1/ 2 gene polymorphisms, which are thought to play a role in the development of breast cancer in CYP2D6 allelic groups, and the efficacy of tamoxifen in ER + patients using tamoxifen and resistant to tamoxifen. Materials and Methods: Real time qPZR method was used to determine CYP2D6 allelic groups and GST polymorphisms after DNA isolation from blood samples obtained from 43 patients participating in the study. PZR-HRM and sequence analysis were performed to screen PIK3CA exons 9 and 20 and p53 exons 5-8. BRCA1/ 2 gene polymorphisms were screened by next generation sequencing method. Results: In our study, no significant difference was found between BRCA1 / 2, PIK3CA and GSTP1 polymorphisms and CYP2D6 * 2, * 3, * 4, * 10, * 17 allelic variants between tamoxifen resistant and tamoxifen using patients. The p53 gene 12383 (T> A) and 12495 (G> C) mutation rates were found to be significantly higher in the tamoxifen-resistant group (p = 0.045 and p = 0.045, respectively). Conclusion: Our study is the first study investigating CYP2D6 allelic variants and BRCA1/ 2, PIK3CA, p53 and GSTP1 polymorphisms in tamoxifen-using and resistant patient groups. The fact that p53 gene mutations were found to be significantly higher in the tamoxifen-resistant group shows in this study that it can be used as a marker to predict resistance before starting tamoxifen treatment. The accuracy of the data obtained should be verified by increasing the number of samples in the population.
Objective: Breast cancer has the highest prevalence among cancers seen in women. Tamoxifen is used as standard therapy in the adjuvant therapy of estrogen receptor positive (ER+) patients and is metabolised by the CYP2D6 enzyme. The aim of this project is to determine the relationship between PIK3CA, TP53, GSTP1, BRCA1/ 2 gene polymorphisms, which are thought to play a role in the development of breast cancer in CYP2D6 allelic groups, and the efficacy of tamoxifen in ER + patients using tamoxifen and resistant to tamoxifen. Materials and Methods: Real time qPZR method was used to determine CYP2D6 allelic groups and GST polymorphisms after DNA isolation from blood samples obtained from 43 patients participating in the study. PZR-HRM and sequence analysis were performed to screen PIK3CA exons 9 and 20 and p53 exons 5-8. BRCA1/ 2 gene polymorphisms were screened by next generation sequencing method. Results: In our study, no significant difference was found between BRCA1 / 2, PIK3CA and GSTP1 polymorphisms and CYP2D6 * 2, * 3, * 4, * 10, * 17 allelic variants between tamoxifen resistant and tamoxifen using patients. The p53 gene 12383 (T> A) and 12495 (G> C) mutation rates were found to be significantly higher in the tamoxifen-resistant group (p = 0.045 and p = 0.045, respectively). Conclusion: Our study is the first study investigating CYP2D6 allelic variants and BRCA1/ 2, PIK3CA, p53 and GSTP1 polymorphisms in tamoxifen-using and resistant patient groups. The fact that p53 gene mutations were found to be significantly higher in the tamoxifen-resistant group shows in this study that it can be used as a marker to predict resistance before starting tamoxifen treatment. The accuracy of the data obtained should be verified by increasing the number of samples in the population.