Dinata, Mulya (2019) Polimorfisme NRAS, RUNX1, NPM1, FLT3, Dan Delesi Kromosom 5 Del(5q) Sebagai Prediktor Myelodysplastic Syndrome Related Acute Myeloid Leukemia (Mds-Related Aml) Di Surabaya. Doctor thesis, Universitas Brawijaya.
Abstract
Myelodysplastic syndrome (MDS) adalah sekelompok kelainan haematopoeitic stem cells (HSC) yang ditunjukkan dengan kegagalan sumsum tulang (displastik) yang meningkat. Penyakit yang didominasi orang tua antara 70 tahun dan dapat dikatakan kira-kira 1 orang menderita MDS pada 500 populasi diatas 60 tahun. Jumlah kasus MDS lebih kurang 20-30% berkembang menjadi Acute Myelocytic Leukemia (AML), prevalensi risiko menjadi AML cukup tinggi, diperlukan diagnosis sedini mungkin sebelum transformasi menjadi AML. Etiologi kasus Leukemia sampai saat ini belum diketahui penyebabnya dengan pasti. Banyak penelitian telah dilakukan untuk mengetahui faktor risiko. Berbagai faktor risiko yaitu penggunaan pestisida, medan listrik, bahan kimia (Benzena), virus, abnormalitas sitogenetik (contoh: Down syndrome), usia ibu yang relatif tua saat melahirkan, ibu yang merokok saat hamil, konsumsi alkohol saat hamil, medan magnet, pekerjaan orang tua, radiasi prenatal dan postnatal. Data penelitian pendahuluan didapatkan bagian Patologi Klinik RSUD dr Soetomo atau Fakultas Kedokteran Universitas Airlangga Surabaya, Jawa Timur, jumlah pasien 228 orang selama 10 bulan pada tahun 2014, ikut serta penelitian 181 orang, kasus AML 37,28%, rentang umur terbanyak 46 - 61 tahun 11,40% sedangkan Kasus MDS 3,95%. Hasil penelitian pasien rawat jalan atau inap di instalasi Ilmu Penyakit Dalam Hematologi-Onkologi FK Universitas Airlangga, RSUD dr Soetomo, Surabaya, Indonesia, tahun 2017 - 2018 (satu tahun), sebanyak 36 subyek sampel, 31 sampel dengan diagnosis AML sedangkan 5 sampel diagnosis MDS dikeluarkan dari penelitian. Usia 47- 57 tahun dan 58 – 68 tahun masing-masing sebanyak 19,35% dan 22,58%, sedangkan usia tua yaitu 80-90 tahun (3,24%). Jenis kelamin laki-laki lebih banyak dari perempuan yaitu laki-laki (70,97%), perempuan (29,03%). Hasil pemeriksaan immunophenotyping yaitu myeloid lineage 96,76%. Tujuan penelitian ini adalah membuktikan pengaruh polimorfisme NRAS, RUNX1, NPM1, FLT3, dan delesi kromosom 5 del(5q) sebagai prediktor Myelodisplastic Syndrome related Acute Myeloid Leukemia (MDS-related AML) pada penderita di Surabaya. Diagnosis pasien (klasifikasi Leukemia FAB, WHO 2008) berdasarkan pemeriksaan klinik, immunophenotyping, hapusan aspirasi sumsum tulang (BMA) yaitu pertama AML (86,11%), dan Non AML (MDS) sebanyak 13,89%, abnormalitas genetik (PCR), abnormalitas kromosom (CISH). Metode penelitian ini cross sectional analytic, uji analisis statistik yang dipergunakan Logistic Regression (Regresi Logistik), Receiver operating Characteristics (ROC), 24 sampel adalah delesi kromosom 5 del(5q) (positif) dan 7 sampel adalah kromosom 5q normal (negatif) dengan berbagai variasi mutasi gen. ROC didapatkan area dibawah kurva (AUC) 76,5%, confidence interval 95%, dan signifikan (P = 0,036), menunjukkan bahwa delesi kromosom 5 del(5q) atau kromosom 5 normal dengan berbagai variasi mutasi atau tidak ada mutasi NRAS, RUNX1, NPM1, FLT3 variasi tersebut sebanyak 16 macam variasi, sebagai prediktor MDS-related AML adalah valid dan bisa didapatkan cut-off x i i value (0,7825584010). Delesi kromosom 5 del(5q) dengan variasi gen cut-off probbilitas ≥ 0,7825584010 prediksi kuat MDS-related AML, sebaliknya kromosom 5 normal dengan variasi NRAS, RUNX1, NPM1, FLT3 ≤ probabilitas 0,7825584010 prediktor lemah MDS-related AML. Mutasi NRAS mempunyai β tertinggi 2,446, PR(Prealence Risk) 11,543 adalah PR tertinggi berarti meningkatkan risiko MDS-related AML sebesar 11,543 kali; mutasi RUNX1 β (-) 1,694, PR 0,184 adalah PR terendah, berarti menghambat risiko MDS-related AML sebesar 0,184 kali sedangkan Mutasi NPM1 mempunyai β 1,618, PR 5,043; mutasi FLT3 β 0,147; PR 1,158 meningkatkan risiko MDS-related AML. Hasil penelitian didapatkan prediktor kuat MDS-related AML yaitu delesi kromosom 5 del(5q) dengan variasi gen cut-off probbilitas > 0,7825584010, sedangkan Prediktor lemah untuk MDS-related AML yaitu kromosom q normal dengan variasi gen cut-off < probabilitas 0,7825584010. Mutasi gen RUNX1 mempunyai aktivitas menghambat 0,184 kali terjadinya MDS–related AML, sebaliknya mutasi gen NRAS, NPM1, FLT3 mempunyai aktivitas meningkat risiko MDS-related AML tertinggi adalah NRAS 11,543 kali. Kesimpulan: variasi RUNX1, NPM1, FLT3, N-RAS dan delesi kromosom 5 del(5q) sebagai prediktor kuat MDS–related AML di Surabaya. Progresivitas MDS-related AML sebagai prediktor lemah ditunjukan oleh sitogenatik normal yaitu kromosom 5, mutasi gen RUNX1 bersifat menghambat progresivitas sedangkan mutasi gen NRAS, NPM1, FLT3 meningkatkan progresivitas MDS-related AML. Masing-masing prediktor lemah atau kuat besarnya risiko prediktor ditentukan oleh masing-masing gen yang mutasi, setiap mutasi gen NRAS, RUNX1, NPM1, FLT3, sesuai urutan sebagai berikut NRAS (1), NPM1 (2), FLT3 (3), RUNX1 (4).
English Abstract
Myelodysplastic syndrome (MDS) is a group of haematopoeitic stem cells (HSC) abnormality which is showed by the increase fail in bone marrow (dysplastic). A disease dominated by 70 years old people can be one in 500 population over 60 years. The number of MDS case grows more less 20-30% into Acute Myelocytic Leukemia (AML), the risk prevalency to be AML is high enough. It needs earlier diagnosis before the transformation into AML. The previous research data of Clinical Patology of dr Soetomo hospital or Medical faculty of Airlangga University, Surabaya, East Java states that there are 228 patients during 10 months in 2014 with 37,28% of AML case, 11,40% mostly with age range between 46 – 61 years old. Meanwhile, the MDS case is about 3.95%. Based on the research result from in or outpatients in Hematology and Medical oncology department of Internal Medicine, Airlangga University, School of Medical Dr. Soetomo Hospital, Surabaya, Indonesia, there are 36 subject of sample, 31 sample with AML diagnosis and 5 sample of MDS diagnosis that is issued by the researcher. There are 19,35% and 22,58% of Each of age 47-57 years old and 58-68 years old, besides 3,24% of age 80-90 years old. The number of man (70,97%) is more than the woman (29,03%). The immunophenotyping checkup result and myeloid lineage 96,76%. The patient diagnosis based on the clinical checkup, immunophenotyping, Bone marrow aspiration is first AML(86,11%), and there are 13,89% Non AML (MDS), genetic abnormality (PCR), chromosome abnormality (CISH). This research is cross sectional analytic using statistic Logistic Regression, Receiver operating Characteristics (ROC), 24 samples are deletion of 5 del(5q) chromosome as possitive and 7 samples are normal 5 chromosome as negative with many kinds of genetic mutation. ROC that is found in the area of under curve (AUC) is 76.5%, confidence interval 95%, and the significance is (P = 0.036), shows that deletion of 5 del(5q) chromosome or normal 5 chromosome with various mutation or no NRAS, RUNX1, NPM1, FLT3 mutation. There are 16 kinds of mutation which influence to MDS-related AML in which it is valid and can be found cut-off value (0.7825584010). Deletion of 5 del(5q) chromosome with variety of gen cut-off probability is > 0.7825584010 will be strongly predicted to be MDS-related AML, otherwise normal 5 chromosome with various mutation of RUNX1, FLT3, NRAS, NPM1 which are < 0.7825584010 probability in which the weak predictor becomes MDS-related AML. NRAS mutation has highest β 2.446, PR 11.543. The highest PR means increasing 11.543 times of MDS-related AML; the mutation of RUNX1 β (-) 1.694, PR 0.184 is the lowest PR. it means that it increases 0.184 times of MDS-related AML. Whereas, NPM1 mutation has β 1.618, PR 5.043; FLT3 β 0.147 mutation; PR 1.158. The variable of β (-)1.694, inhibits the risk of MDS-related AML. Otherwise, the mutation of FLT3 β variable: 0.147, NRAS β 2.446 and NPM1 β 1.618 increases the risk of MDS-related AML. The research result found that strong predictor will be MDS-related AML , that is deletion of del(5q) chromosome 5 with genetic variation of cut-off probability > 0.7825584010. Meanwhile, the weak predictor for MDS-related AML x iv is normal 5 chromosome with genetic variation of cut-off that is < 0.7825584010 probability for being MDS-related AML. RUNX1 gene mutation has activity to inhibit the occurrence of MDS-related AML as much as 0.184 times. On the contrary, NRAS gene mutation, NPM1 and FLT3 have activities to increase higher than others such as NRAS 11.543 times. The conclusion: the variation of N-RAS, RUNX1, NPM1, FLT3, and chromosome 5 del(5q) deletion are strong predictors MDS–related AML patients in Surabaya. RUNX1 has activity to inhibit the process of MDS-related AML; while NRAS, NPM1 and FLT3 have activity to increase the probability of MDS-related AML occurrence. Each of weak or strong predictors risk is determined by each of mutated genes. Every gene mutation of NRAS, RUNX1, NPM1, FLT3 is based on its order as follow NRAS (1), NPM1 (2), FLT3 (3), RUNX1 (4).
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| Item Type: | Thesis (Doctor) |
|---|---|
| Identification Number: | DIS/616.994 19/DIN/p/2019/062002043 |
| Uncontrolled Keywords: | LEUKIMIA |
| Subjects: | 600 Technology (Applied sciences) > 616 Diseases > 616.9 Other disease > 616.99 Tumors and miscellaneous communicable diseases > 616.994 Cancers |
| Divisions: | S2/S3 > Doktor Ilmu Kedokteran, Fakultas Kedokteran |
| Depositing User: | Endang Susworini |
| Date Deposited: | 16 Feb 2022 07:35 |
| Last Modified: | 16 Feb 2022 07:35 |
| URI: | http://repository.ub.ac.id/id/eprint/189789 |
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