Genetska variabilnost in dolžina telomerov kot označevalca odziva na zdravljenje raka dojk z obsevanjem

Trstenjak, Ana (avtor), Trebušak Podkrajšek, Katarina (mentor), Goričar, Katja (komentor)

Duktalni karcinom in situ (DCIS) je neinvazivna oblika raka dojk, ki ga pogosto odkrijejo v okviru presejalnih programov. Čeprav imajo bolniki dobro prognozo, je med njimi velika variabilnost glede izidov zdravljenja, pri nekaterih lahko napreduje tudi v invaziven rak dojk. Del standardnega zdravljenja po ohranitveni operaciji dojk je tudi obsevanje. Odgovor na zdravljenje z obsevanjem je pri vsakem posamezniku drugačen in je odvisen tudi od številnih molekularnih dejavnikov. Eden od novejših potencialnih bioloških označevalcev odgovora na obsevanje je tudi dolžina telomerov. Telomeri ščitijo konce kromosomov pred krajšanjem in vzdržujejo genomsko stabilnost. Namen magistrske naloge je bil določiti dinamiko spreminjana dolžine telomerov v levkocitih pri bolnicah z DCIS, zdravljenih z obsevanjem, in oceniti povezavo genetskih dejavnikov z dolžino telomerov v levkocitih. Zanimal nas je tudi vpliv dolžine telomerov in genetskih dejavnikov na pojav neželenih učinkov po obsevanju. V longitudinalno raziskavo smo vključili 89 bolnic. Genomsko DNA bolnic z DCIS smo izolirali iz vzorcev polne venske krvi, odvzetih pred zdravljenjem z obsevanjem, takoj po obsevanju in 6 mesecev po obsevanju. S qPCR (kvantitativna verižna reakcija s polimerazo) smo nato določili dolžino telomerov v teh treh časovnih točkah in s kompetitivnim alelno specifičnim PCR določili prisotnost izbranih polimorfizmov v genu telomerazne reverzne transkriptaze (TERT). Rezultati naše raziskave kažejo, da se dolžina telomerov pri bolnicah z DCIS takoj po zdravljenju zviša in se v šestih mesecih po obsevanju pri dobri polovici spet zniža. Zato telomeri predstavljajo potencialni biološki označevalec odgovora na obsevanje. Dokazali smo tudi statistično značilno povezavo med nosilkami vsaj enega polimorfnega alela T TERT rs2736098 z daljšimi telomeri v levkocitih pred zdravljenjem z obsevanjem. Na pojav neželenih učinkov obsevanja so vplivale lastnosti bolnic, povezave polimorfizmov z neželenimi učinki pa nismo uspeli dokazati. Dolžina telomerov takoj po obsevanju je bila statistično značilno povezana s pojavom neželenih učinkov na srcu 6 mesecev po zdravljenju z obsevanjem. Naši rezultati pomembno pripomorejo k opredelitvi telomerov kot novih bioloških označevalcev, s katerimi bi lahko pripomogli k izboljšanju kakovosti življenja bolnic z DCIS in predstavljajo pomembno izhodišče za nadaljnje raziskave.

• Jezik: Slovenski jezik
• Ključne besede: duktalni karcinom in situ, obsevanje, relativna dolžina telomerov, TERT, kvantitativna verižna reakcija s polimerazo v realnem času
• Vrsta gradiva: Magistrsko delo/naloga
• Organizacija: FFA - Fakulteta za farmacijo
• Leto izida: 2023
• PID: 20.500.12556/RUL-147148
• Datum objave v RUL: 24.06.2023

Sekundarni jezik

• Jezik: Angleški jezik
• Naslov: Genetic variability and telomere length as markers of response to radiotherapy in breast cancer

Izvleček

Ductal carcinoma in situ (DCIS) is a non-invasive form of breast cancer that is often detected through screening programs. While patients generally have a good prognosis, treatment outcomes can vary greatly, with some cases progressing to invasive breast cancer. Radiation is a part of the standard treatment after breast-conserving surgery. Individual responses to radiation therapy differ and are possibly influenced by various molecular factors. Telomere length is also one of the potential biomarkers of predicting radiation response. Telomeres protect chromosome ends from shortening and maintain genomic stability. This master’s thesis aimed to explore the dynamics of the leukocyte telomere length of DCIS patients undergoing radiation treatment, as well as assess the association of genetic factors with leukocyte telomere length. We also investigated the impact of telomere length and genetic factors on the occurrence of adverse events following radiation. In this longitudinal study, 89 DCIS patients were included. Genomic DNA was extracted from whole blood samples obtained before radiation treatment, immediately after and six months after radiation. Quantitative PCR was then used to determine the leukocyte telomere length. The presence of selected polymorphisms in the TERT gene was determined by competitive allele specific PCR. Our results demonstrate that telomere length in patients with DCIS increases immediately after radiation and decreases again within six months. This finding suggests that telomere length could serve as a potential biomarker of radiation response. We also identified a statistically significant association between carriers of at least one TERT rs2736098 polymorphic T allele, with longer telomeres in leukocytes before radiation. The occurrence of adverse events following radiation was influenced by patients’ clinical characteristics. However, we did not find evidence supporting an association between studied polymorphisms and adverse events of radiation. Telomere length immediately after radiation treatment was associated with the occurrence of adverse cardiac events six months after radiation. Our results significantly contribute to establishing of telomeres as a new biomarker that could help improve the quality of life for DCIS patients and provide an important foundation for further research.

• Ključne besede: ductal carcinoma in situ, radiation, relative telomere length, TERT, quantitative polymerase chain reaction