Genetske spremembe akvaporina 1 kot dejavniki tveganja za nastanek malignega mezotelioma in označevalec odgovora na zdravljenje s cisplatinom

Šenk, Barbara (author), Franko, Alenka (mentor), Kovač, Viljem (comentor)

POVZETEK 1. UVOD Maligni mezoteliom (MM) je zelo agresiven rak, ki je povezan z izpostavljenostjo azbestu, in ima slabo napoved. Pri MM so v tumorskem tkivu zasledili povečano izražanje transmembranskega beljakovinskega vodnega kanalčka akvaporina 1 (AQP1). Menijo, da bi njegovo izražanje lahko vplivalo na napoved poteka bolezni. Polimorfizme gena za AQP so že povezovali s preživetjem pri raku pljuč, debelega črevesa, dojke, možganov, jeter, prostate, ledvic, materničnega vratu, sečnega mehurja, žrela, krvnih celic, žolčevoda in drugimi, medtem ko vpliva genetske variabilnosti AQP na tveganje za nastanek MM, kot tudi na odgovor in stranske učinke pri zdravljenju s cisplatinom ter na preživetje do sedaj še niso raziskovali. Kljub številnim raziskavam do sedaj še ni klinično uporabnih specifičnih tumorskih označevalcev tveganja za nastanek in odgovor na zdravljenje pri MM. Simptomi MM se pogosto pojavljajo le v poznih fazah, zato so lahko novi označevalci za zgodnejšo diagnozo MM in za določitev odgovora na zdravljenje obetavna priložnost za te bolnike. 2. NAMEN DELA IN HIPOTEZE Namen naše študije je bil raziskati vpliv genetskih polimorfizmov AQP1 na tveganje za nastanek MM in na odgovor na zdravljenje, ki temelji na cisplatinu. V doktorski nalogi smo preverili tri hipoteze: da izbrani polimorfizmi v genu AQP1 vplivajo na tveganje za nastanek MM, da vplivajo na pojav stranskih učinkov pri zdravljenju s cisplatinom ter da vplivajo na napredovanje bolezni in celokupno preživetje. 3. PREISKOVANCI IN METODE Raziskava primerov s kontrolami je zajela 231 bolnikov z MM, zdravljenih na Onkološkem inštitutu v Ljubljani, in kontrolne preiskovance, to je 316 zdravih krvodajalcev iz Zavoda za transfuzijsko medicino v Ljubljani. S postopki genotipizacije smo vsem preiskovancem določili genotipe za tri polimorfizme AQP1 (rs28362731, rs1049305 in rs1476597). V statistični analizi smo uporabili logistično in Coxovo regresijo. Mediano preživetja smo določili s Kaplan-Meierjevo metodo. 4. REZULTATI Razporeditev preiskovanih genotipov je bila pri AQP1 rs28362731 in AQP1 rs1049305 v skladu s Hardy-Weinbergovim ravnovesjem; pri AQP1 rs1476597 pa ni bila skladna ne pri bolnikih kot tudi ne pri zdravih kontrolah, zato smo ta polimorfizem izključili iz nadaljnje statistične analize. Polimorfizem AQP1 rs1049305 je statistično značilno vplival na tveganje za MM v dominantnem modelu, prilagojeno na spol in starost (RO = 0,60, 95 % IZ = 0,37?0,96, Padj = 0,033). Ta polimorfizem je v dominantnem modelu statistično značilno vplival tudi na nastanek anemije (neprilagojeno: RO = 0,49, 95 % IZ = 0,27?0,90, P = 0,021; prilagojeno na CRP: RO = 0,52, 95 % IZ = 0,27?0,99, P = 0,046) in levkopenije (RO = 2,09, 95 % IZ = 1,00?4,35, P = 0,049). V aditivnem modelu je bil ta polimorfizem povezan tudi z nastankom trombocitopenije (RO = 3,06, 95 % IZ = 1,01?9,28, P = 0,048) in alopecije (RO = 2,92, 95 % IZ = 1.00?8.46, P = 0.049). AQP1 rs28362731 je bil statistično značilno povezan s trombocitopenijo (neprilagojeno: RO = 3,73, 95 % IZ = 1,00?13,84, P = 0,049; prilagojeno na bolečino: RO = 4,63, 95 % IZ = 1,13?19,05, P = 0,034) v aditivnem modelu. 5. RAZPRAVA IN ZAKLJUČKI Naša raziskava prinaša nove ugotovitve o povezavah med genetsko variabilnostjo AQP1 in tveganjem za nastanek MM, ki do sedaj še niso bile raziskane. V tej raziskavi smo ugotovili, da genetska variabilnost AQP1 lahko vpliva na tveganje za nastanek MM in na pojav stranskih učinkov, kot so anemija, levkopenija, trombocitopenija in alopecija, pri zdravljenju s cisplatinom v kombinaciji z gemcitabinom ali s pemetreksedom. Nova dognanja bi lahko doprinesla k izboljšanju napovedi stranskih učinkov, povezanih z zdravljenjem pri MM.

• Language: Slovenian
• Keywords: maligni mezoteliom, AQP1, polimorfizem, cisplatin
• Work type: Doctoral dissertation
• Organization: MF - Faculty of Medicine
• Year: 2020
• PID: 20.500.12556/RUL-116043
• COBISS.SI-ID: 3516539
• Publication date in RUL: 09.05.2020

Secondary language

• Language: English
• Title: Genetic changes in aquaporin 1 as risk factors for malignant mesothelioma and a marker of response to cisplatin treatment

Abstract

ABSTRACT 1. INTRODUCTION Malignant mesothelioma (MM) is a highly aggressive cancer that is associated with asbestos exposure and has poor prognosis. In MM, increased expression of aquaporin 1 transmembrane protein water channel (AQP1) was observed in tumour tissue. It is believed that its expression could influence the prognosis of the disease. AQP gene polymorphisms have already been linked to survival in lung, colon, breast, brain, liver, prostate, kidney, cervix, bladder, pharynx, blood cells, bile ducts cancer and other cancers, whereas the influence of AQP genetic variability on the risk of developing MM as well as on the response and side effects of cisplatin treatment and on the survival have not been investigated yet. Despite numerous studies, there are no clinically applicable specific tumour markers of the risk of developing and responding to MM therapy to this date. MM symptoms often occur only in late stages, so new markers for early diagnosis of MM and markers for determining response to treatment may be a promising opportunity for these patients. 2. AIM AND HYPOTHESES The aim of our study was to investigate the influence of AQP1 genetic polymorphisms on the risk of developing MM and response to cisplatin-based treatment. In the doctoral thesis we tested three hypotheses, namely that selected polymorphisms in the AQP1 gene influence the risk of MM formation, the occurrence of side effects in cisplatin treatment, and affect disease progression and overall survival. 3. SUBJECTS AND METHODS The case-control study included 231 MM patients treated at the Institute of Oncology Ljubljana and the control subjects, i.e. 316 healthy blood donors from the Ljubljana Institute for Transfusion Medicine. Genotyping procedures determined the genotype for all AQP1 polymorphisms (rs28362731, rs1049305 and rs1476597) for all subjects. Logistic and Cox regression were used in the statistical analysis. The median survival was determined by the Kaplan-Meier method. 4. RESULTS The distribution of the examined genotypes was consistent with Hardy-Weinberg equilibrium for AQP1 rs28362731 and AQP1 rs1049305, and was not consistent in patients as well as in healthy controls for AQP1 rs1476597, so we excluded this polymorphism from further statistical analysis. AQP1 rs1049305 polymorphism was significantly associated with the risk of MM in the dominant model adjusted for gender and age (OR = 0.60, 95% CI = 0.37㐀0.96, Padj = 0.033). This polymorphism was also associated with anaemia in dominant model (unadjusted: OR = 0.49, 95% CI = 0.27㐀0.90, P = 0.021; adjusted for CRP: OR = 0.52, 95% CI = 0.27㐀0.99, P = 0.046) and leukopenia (OR = 2.09, 95% CI = 1.00㐀4.35, P = 0.049). In additive model this polymorphism was also significantly associated with thrombocytopenia (OR = 3.06, 95% CI = 1.01㐀9.28, P = 0.048) and alopecia (OR = 2.92, 95% CI = 1.00㐀8.46, P = 0.049). AQP1 rs28362731 was significantly associated with thrombocytopenia (unadjusted: OR = 3.73, 95% CI = 1.00㐀13.84, P = 0.049; adjusted for pain: OR = 4.63, 95% CI = 1.13㐀19.05, P = 0.034) in additive model. 5. DISCUSSION AND CONCLUSIONS Our study provides new findings on the associations between AQP1 genetic variability and the risk of developing MM that have not been investigated to this date. This study found that AQP1 genetic variability may influence the risk of MM and the occurrence of side effects such as anaemia, leukopenia, thrombocytopenia and alopecia in patients treated with cisplatin in combination with gemcitabine or pemetrexed. New findings could help improve the prognosis of side effects associated with the treatment of MM.

• Keywords: malignant mesothelioma, AQP1, polymorphism, cisplatin