Vpliv izbranih polimorfizmov matriksnih metaloproteinaz na odgovor na zdravljenje in potek bolezni pri bolnikih z malignim mezoteliomom

Štrbac, Danijela (author), Kovač, Viljem (mentor), Dolžan, Vita (co-mentor)

Ozadje: Maligni mezoteliom (MM) je redka bolezen s kratkim celokupnim preživetjem (CP). Matriksne metaloproteinaze (MMP) imajo širok biološki vpliv na napredovanje bolezni, nastanek zasevkov in apoptozo. Izražanje MMP je povezano s preživetjem pri MM. Cilj naše raziskave je bil preveriti vpliv genetske variabilnosti genov MMP na tveganje za nastanek in preživetje pri MM. Želeli smo tudi raziskati povezavo med genetskimi polimorfizmi in izražanjem MMP9 ter vpliv serumske koncentracije MMP9 na preživetje in napredovanje MM. Metode: V prvi del naše raziskave, kjer smo določali tveganje za nastanek MM, smo vključili 236 bolnikov in 161 zdravih krvodajalcev. Z alelno specifičnim PCR (KASPAR) smo določili deset polimorfizmov v treh genih MMP: MMP2 rs243865, rs243849 and rs7201, MMP9 rs17576, rs17577, rs2250889 in rs20544, ter MMP14 rs1042703, rs1042704 in rs743257. V drugem delu smo pri 199 bolnikih z MM preverjali pomen polimorfizmov MMP kot prognostičnih bioloških označevalcev. V tretjem delu raziskave smo pri 110 bolnikih določili izražanje MMP9 v serumu. Za statistično analizo smo uporabili aditivni in dominatni genetski model. Povezavo polimorfizmov s tveganjem za MM smo predstavili z razmerjem obetov (OR) in intervalom zaupanja (95% CI) izračunanimi z metodo logistične regresije. Vpliv serumske koncentracije MMP9 na preživetje in povezave s polimorfizmi MMP9 smo preverili z neparametričnimi testi, logistično in Coxovo regresijsko metodo. Rezultati: Nosilci vsaj enega polimorfnega alela MMP2 rs243865 so imeli manjše tveganje za nastanek MM (OR = 0,66, 95% CI = 0,44&#8210;1,00; P = 0,050). Povezava je bila še bolj značilna pri bolnikih izpostavljenih azbestu, med katerimi so nosilci vsaj enega polimorfnega alela imeli pomembno manjše tveganje za MM (OR = 0,55, 95% CI = 0,35&#8210;0,86; P = 0,009). Nosilci vsaj enega polimorfnega alela MMP9 rs2250889 so imeli krajši čas do napredovanja bolezni (6,07 vs. 10,03 mesecev, HR = 2,45, 95% CI = 1,45-4,14, p = 0,001) in krajše celokupno preživetje (9,23 vs. 19,2 mesecev, HR = 2,39, 95%CI = 1,37-4,18, p = 0,002). Nasprotno so imeli nosilci vsaj enega polimorfnega alela MMP9 rs20544 daljši čas do napredovanja bolezni (10,93 vs. 9,40 mesecev, HR 0,57 95%CI = 0,38-0,86 p = 0,007) in daljše celokupno preživetje (20,67 vs. 13,50 mesecev, HR 0,56 95%CI = 0,37-0,85, p = 0,007). Srednja serumska koncentracija MMP je bila pred zdravljenjem 706,7 (499,6-1224,9) ng/ml, po zdravljenju 440,5 (255,9-685,2) ng/ml in ob napredovanju bolezni 502,8 (307,2-851,4) ng/ml. Po kemoterapiji je bila razlika srednjih vrednosti MMP9 -286.3 (-607.3 do -70.2) ng/ml (P<0,001) za 87 bolnkov (79,8%). Tudi ob napredovanju bolezni je imelo 47 (65,3%) bolnikov nižjo serumsko koncentracijo MMP9, kot pred zdravljenjem. Srednja vrednost spremembe je bila 163,7 (-466,6 to 108,6) ng/ml (P = 0,001). Bolniki s slabšim stanjem zmogljivosti so imeli pred pričetkom zdravljenja višjo serumsko koncentracijo MMP9 kot ostali bolniki (P = 0,010). S koncentracijo serumskega MMP9 pred zdravljenjem je bil povezan samo MMP9 rs17576 (P=0,041). Zaključki: Polimorfizem MMP2 rs243865 ima lahko zaščitno vlogo pred razvojem malignega mezotelioma (MM). Dva izmed preiskovanih polimorfizmov, MMP9 rs2250889 in MMP9 rs20544 sta povezana s preživetjem bolnikov z MM in bi lahko služila kot prognostična označevalca. Srednja serumska vrednost MMP9 se je razlikovala pred in po koncu zdravljenja MM, vendar razlika ni bila statistično pomembna. Serumska koncentracija MMP9 in značilni polimorfizmi MMP bi lahko doprinesli k boljši napovedni vrednosti sestavljenih bioloških označevalcev pri MM.

• Language: Slovenian
• Keywords: maligni mezoteliom, matriksne metaloproteinaze, genski polimorfizmi
• Work type: Doctoral dissertation
• Organization: MF - Faculty of Medicine
• Year: 2019
• PID: 20.500.12556/RUL-108349
• COBISS.SI-ID: 300870144
• Publication date in RUL: 29.06.2019

Secondary language

• Language: English
• Title: The influence of selected polymorphisms in matrix metalloproteinases on response to treatment and disease progression in patients with mesothelioma

Abstract

Background: Malignant mesothelioma (MM) is a rare disease with a relatively short overall survival (OS). Metalloproteinases (MMPs) have a vast biological effect on tumor progression, invasion, metastasis formation, and apoptosis. MMP expression was previously associated with survival in MPM. Our aim was to evaluate if genetic variability of MMP genes could serve as a risk assessment and as a prognostic biomarker in MM. We further set out to evaluate MMP9 expression as a potential prognostic biomarker. Methods: In the first part of the study 236 patients and 161 healthy blood donors were included to assess ther risk for MM. Fluorescence-based competitive allele-specific assay (KASPar) was used to genotype ten polymorphisms of selected MMPs: MMP2 rs243865, rs243849 and rs7201, MMP9 rs17576, rs17577, rs2250889 and rs20544, and MMP14 rs1042703, rs1042704 and rs743257. In the second part of the study 199 patients were included to evaluate these polymorphism as prognostic biomarkers. The additive and dominant genetic models were used in statistical analyses. The association of genetic polymorphism with MM risk were examined by logistic regression to calculate odds ratios (ORs) and their 95% confidence intervals (CIs). The influence on survival as well as the role of serum MMP9 and MMP9 polymorphisms in treatment response was determined using nonparametric tests, logistic and Cox regression. Results: Carriers of at least one polymorphic MMP2 rs243865 allele tended to have a decreased risk for MM (OR = 0.66, 95% CI = 0.44&#8210;1.00; P = 0.050). This association was more pronounced in patients with known asbestos exposure. Among them, at least one polymorphic allele had significantly lower MM risk (OR = 0.55, 95% CI = 0.35&#8210;0.86; P = 0.009). Carriers of polymorphic MMP9 rs2250889 allele had shorter time to progression (TTP) (6.07 vs. 10.03 months, HR = 2.45, 95% CI = 1.45-4.14, p = 0.001) and overall survival (OS) (9.23 vs. 19.2 months, HR = 2.39, 95% CI = 1.37-4.18, p = 0.002). In contrast, carriers of at least one polymorphic MMP9 rs20544 allele had longer TTP (10.93 vs. 9.40 months, HR 0.57 95% CI = 0.38-0.86 p = 0.007) and OS (20.67 vs. 13.50 months, HR 0.56 95%CI = 0.37-0.85, p = 0.007). Median serum MMP9 was 706.7 (499.6-1224.9) ng/ml before treatment, 440.5 (255.9-685.2) ng/ml after chemotherapy and 502.8 (307.2-851.4) ng/ml at disease progression. After chemotherapy, 87 (79.8%) patients had lower serum MMP9, with the median change of -286.3 (-607.3 to -70.2) ng/ml (P<0.001). At disease progression, 47 (65.3%) patients had lower serum MMP9 compared to pre-treatment values, median change was -163.7 (-466.6 to 108.6) ng/ml (P = 0.001). Patients with higher ECOG performance score had higher serum MMP9 before treatment (P = 0.010), compared to other patients. Among investigated polymorphisms, only rs17576 was associated with serum MMP9 levels before treatment (P = 0.041). Conclusions: The MMP2 rs243865 polymorphism may have a protective role in malignant mesothelioma development. Median serum MMP9 levels differed significantly before and after treatment of MM but failed to reach significance as a standalone biomarker. Some of the investigated MMP SNPs were associated with survival of MM patients and could be used as potential prognostic biomarkers. MMP9 concentration and polymorphisms should be further tested as composite biomarkers.

• Keywords: malignant mesothelioma, matrix metalloproteinases