Sledování genetických faktorů ovlivňujících riziko vzniku a průběh karcinomů kolorekta a pankreatu

• Název práce v češtině: Sledování genetických faktorů ovlivňujících riziko vzniku a průběh karcinomů kolorekta a pankreatu
• Název v anglickém jazyce: Study of genetic factors modifying the risk of onset and progression of colorectal and pancreatic cancer
• Klíčová slova: karcinom, pankreas, tlusté střevo, biotransformace, transport léčiv
• Klíčová slova anglicky: carcinoma, pancreas, colon, biotransformation, drug transport
• Akademický rok vypsání: 2011/2012
• Typ práce: disertační práce
• Jazyk práce: čeština
• Ústav: externí pracoviště (11-00099)
• Vedoucí / školitel: doc. RNDr. Pavel Souček, CSc.
• Řešitel: skrytý - zadáno a potvrzeno stud. odd.
• Datum přihlášení: 06.02.2012
• Datum zadání: 06.02.2012
• Datum potvrzení stud. oddělením: 06.02.2012
• Datum a čas obhajoby: 23.05.2012 13:45
• Místo konání obhajoby: Děkanát 3. LF UK
• Datum odevzdání elektronické podoby: 06.02.2012
• Datum proběhlé obhajoby: 23.05.2012
• Předmět: Obhajoba dizertační práce (B90002)
• Oponenti: prof. RNDr. Lenka Skálová, Ph.D.

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Úvod: Cílem této práce bylo sledování genetických faktorů ovlivňujících riziko vzniku a průběh karcinomů kolorekta a pankreatu. První část se zabývá etiologickými faktory, a to vlivem polymorfismů v biotransformačních enzymech a genetických alterací v genu CHEK2 na vznik těchto malignit. V druhé části jsou analyzovány geny transportu cytostatik jako případné prognostické a prediktivní markery odpovědi na onkologickou léčbu. Materiály a metody: Polymorfismy a další genetické alterace byly zjišťovány pomocí real-time PCR, alel-specifické PCR a PCR-RFLP metody v DNA získané z krve pacientů. Byla hodnocena frekvence polymorfismů a posuzován jejich význam s ohledem na dostupná epidemiologická data. Exprese genů byly stanoveny metodou qPCR v párových vzorcích tkání nádoru a okolního parenchymu. Výsledky: Pro většinu námi sledovaných polymorfismů se nepodařilo prokázat vztah mezi jejich přítomností a rizikem vzniku obou těchto malignit. Variantní alela CYP2A13*7, byla nalezena u 7 z 265 hodnocených zdravých kontrol, ale nebyla nalezena u žádného pacienta s karcinomem pankreatu. Výskyt variantní alely GSTP1-Val a genotypu GSTT1-null byl naopak spojen se zvýšeným rizikem vzniku karcinomu pankreatu (OR=2,38; 95% CI=1,17- 4,83). V souboru pacientů s kolorektálním karcinomem byl genotyp GSTT1-null v kombinaci s GSTM1-null genotypem spojen s mírně zvýšeným rizikem (OR=1,58; 95% CI=1,01- 2,47) a samotná delece GSTM1 zvyšovala riziko kolorektálního karcinomu po zohlednění ostatních sledovaných faktorů (OR=1,30; 95% CI=1,01-1,68). Porovnáním exprese všech 49 členů lidské nadrodiny ABC transportérů u vzorků nádoru pankreatu s okolní nenádorovou tkání pankreatu jsme zjistili, že 11 genů bylo statisticky významně upregulováno a 4 downregulovány (p<0,05) v tkáni adenokarcinomu. Zjištěná zvýšená exprese ABCB2, ABCB3, ABCB4, ABCC1, ABCC5 v nádorové tkáni je ve shodě s jejich dříve prokázaným fenotypem mnohočetné lékové rezistence. Downregulace ABCA3 (p=0,002), ABCA5 (p=0,010), ABCC6 (p<0,001) a ABCC7 (p=0,016) ve tkáni karcinomu pankreatu zatím nebyla publikována. Závěry: Naše výsledky ukazují, že polymorfismy v genech kódující biotransformační enzymy mohou ovlivňovat riziko vzniku maligního onemocnění slinivky břišní a tlustého střeva v české populaci. Výsledky pilotní studie zaměřené na expresi ABC transportérů ve tkáni karcinomu pankreatu prokázaly významné rozdíly v hladinách transkriptů těchto membránových enzymů, které jsou klíčové pro transport cytostatik ven z nádorových buněk. Pro potvrzení těchto výsledků jsou však nutné ověřující analýzy na větších souborech pacientů.

Předběžná náplň práce v anglickém jazyce

Introduction: The aim of this study was to evaluate the role of genetic and lifestyle factors in the risk of onset and progression of colorectal and pancreatic cancer. The first part deals with the etiological factors and the importance of polymorphisms in biotransformation enzymes and genetic alterations in the gene CHEK2 in the origin of these malignancies. In the second part, the ABC transporter genes were analyzed as potential prognostic and predictive markers of a treatment’s outcome. Materials and methods: The polymorphisms and other genetic alterations were detected using real-time PCR, allelespecific PCR and PCR-RFLP methods in DNA which was extracted from the blood of patients. The frequency of polymorphisms was evaluated and their importance was assessed with regard to the available epidemiological data. Gene expressions were determined by qPCR in paired samples of tumor tissue and adjacent non-tumorous parenchyma. Results: A majority of the observed polymorphisms failed to show a relationship between their presence and the risk of any of these malignancies. CYP2A13 variant allele*7 coding inactive enzyme was found in 7 of 265 controls and in none of 235 pancreatic carcinoma patients. In contrast, GSTP1-codon 105 Val variant allele and GSTT1-null genotype were associated with an elevated pancreatic cancer risk (OR=1.38; 95%CI=0.96-1.97 and OR=1.56; 95%CI=0.93-2.61, respectively). A combination of GSTT1-null and GSTP1-codon 105 Val variants further increased the risk of pancreatic cancer (OR=2.50; 95%CI=1.20-5.20). In the group of patients with colorectal cancer, the GSTT1-null genotype in combination with the GSTM1-null genotype was associated with a slightly increased risk (OR=1.58, 95% CI=1.01-2.47) and the actual deletion of GSTM1 increased the risk of colorectal cancer after adjusting for other observed factors (OR=1.30, 95% CI=1.01-1.68). By comparing the expression levels of all 49 members of the human ABC transporters in pancreatic tumor samples with nonmalignant pancreatic tissue, we found that 11 genes were significantly upregulated and 4 genes downregulated (p<0.05) in adenocarcinoma tissue. The observed increased expression of ABCB2, ABCB3, ABCB4, ABCC1, ABCC5 in tumor tissue is consistent with their previously demonstrated multidrug resistance phenotype. Downregulation of ABCA3 (p=0.002), ABCA5 (p=0.010), ABCC6 (p<0.001) and ABCC7 (p=0.016) in pancreatic cancer tissue has not yet been published. Conclusions: Our results indicate that polymorphisms in genes coding for biotransformation enzymes may influence the risk of malignant disease of the pancreas and colon in the Czech population. The results of the pilot study on the expressions of ABC transporters in pancreatic cancer tissues showed signifiant differences in transcript levels of these membrane proteins that are crucial for the transport of chemotherapeutic agents outside of tumor cells. However, analyses on larger sets of patients are necessary to verify and confirm these results.