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ID naloge: 136 Letnik: 2003 Predmet: genetika
VPLIV POLIMORFIZMA GENA ZA CITOKROM P450 2C9 (CYP2C9) NA OGROŽENOST ZA RAKA ŠIROKEGA CREVESA PRI SLOVENCIH
Avtor: Andreja Klevišar
Mentor: doc. dr. Vita Dolžan
Somentor: prof. dr. Metka Ravnik Glavac
Izhodišce: Citokrom P450 2C9 (CYP2C9) je encim, ki je vpleten v aktivacijo telesu tujih snovi, med drugim tudi prekancerogenov, ki jih v telo vnesemo s hrano. Pri tej aktivaciji nastanejo elektrofilni produkti, ki lahko poškodujejo molekule DNK. Kopicenje poškodb na DNK pa vodi v postopen prehod od normalne sluznice crevesa, preko hiperplazije do razvoja raka.
Namen: Gen CYP2C9 je polimorfen, saj obstaja vec razlicic tega gena med katerimi so pri beli rasi najpogostejši aleli CYP2C9*1, *2 in *3. CYP2C9*1 predstavlja normalen alel, CYP2C9*2 in *3 pa polimorfna alela z zmanjšano sposobnostjo aktivacije telesu tujih snovi in manjšim nastajanjem elektrofilnih produktov. Primerjali smo frekvence alelov in možnih genotipov CYP2C9 pri bolnikih z rakom širokega crevesa in zdravih kontrolah, da bi preverili: (1) kakšna je pogostnost polimorfnih alelov in genotipov CYP2C9 pri bolnikih z rakom in jo primerjali s podatki za zdravo slovensko populacijo, (2) ali obstaja razlika v pogostnosti genotipov med sporadicno in družinsko obliko raka, (3) ali se vpliv genskega polimorfizma CYP2C9 na tveganje za nastanek raka razlikuje glede na spol, (4) ali se razporeditev genotipov CYP2C9 razlikuje glede na lokacijo in histološke znacilnosti tumorja, (5) kakšna je pogostnost polimorfnih genotipov CYP2C9 pri slovenskih bolnikih z rakom širokega crevesa v primerjavi s tujimi populacijami.
Hipoteza: V tej nalogi smo želeli preveriti domnevo, da je pri osebah, ki so homozigoti za alel CYP2C9*1, zaradi hitrejše zmožnosti aktivacije prekancerogenov, tveganje za nastanek raka širokega crevesa vecje.
Metode: Polimorfizem gena CYP2C9 smo analizirali z metodo genotipizacije. Ta temelji na pomnoževanju dela genomske DNK z verižno reakcijo s polimerazo in na cepitvi pomnoženega odseka z ustreznim encimom. V analizo smo vkljucili vzorce DNK 142 bolnikov z rakom širokega crevesa. Pridobljene podatke smo primerjali z že znanimi podatki o polimorfizmu gena CYP2C9 v zdravi slovenski populaciji in v tujih populacijah. Rezultate smo statisticno ovrednotili z uporabo testa hi-kvadrat.
Rezultati: S primerjavo frekvenc alelov CYP2C9 pri bolnikih z rakom širokega crevesa in pri zdravih kontrolah smo ugotovili, da med skupinama ni bilo velikih razlik (?2 = 0.25, m=2, p > 0.05). Podobno med skupinama ni bilo velikih razlik v deležih posameznih genotipov. V primerjavi s kontrolami nismo ugotovili razlik v deležih posameznih genotipov pri sporadicni (?2 = 0.59, m = 2, p > 0.05) in družinski (?2 = 1.51, m = 2, p > 0.05) obliki raka. Tudi razlike med skupinama bolnikov in bolnic niso bile statisticno znacilne (?2 = 4.56, m = 2, p > 0.05). Pri bolnikih z rakom v primerjavi s kontrolami nismo ugotovili razlik v deležih posameznih genotipov glede na lokacijo, stopnjo diferenciacije in razširjenost tumorja. Pogostnost genotipa CYP2C9*1/*1 je bila v razlicnih populacijah pri bolnikih z rakom približno enaka, pri zdravih pa se je razlikovala.
Zakljucki: Iz omenjenih rezultatov smo zakljucili, da polimorfizem gena CYP2C9 v slovenski populaciji ne predstavlja dejavnika tveganja za nastanek raka širokega crevesa. Polimorfizem CYP2C9 tudi ni bil povezan z razlicnim tveganjem za nastanek raka glede na sporadicno oziroma družinsko obliko raka, spol, lokacijo ali histološke znacilnosti tumorja. Glede na naše rezultate in frekvence genotipa *1/*1 pri bolnikih z rakom in kontrolah iz razlicnih populacij smo sklepali, da imajo drugi genetski dejavniki ali dejavniki okolja vecji vpliv na tveganje za raka širokega crevesa kot genetski polimorfizem CYP2C9.
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[Abstract / English version]
VPLIV POLIMORFIZMA GENA ZA CITOKROM P450 2C9 (CYP2C9) NA OGROŽENOST ZA RAKA ŠIROKEGA CREVESA PRI SLOVENCIH
Author: Andreja Klevišar
Mentor: doc. dr. Vita Dolžan
Co-mentor: prof. dr. Metka Ravnik Glavac
Background: CYP2C9 enzyme is involved in the metabolic activation of various xenobiotics, including dietary precarcinogens. Most of these substances are activated into electrofilic products that can form DNA adducts. If these adducts are not succesfully repaired the transformation of normal epithelium to hyperplasia and then to colorectal cancer (CRC) can occur.
Aims: CYP2C9 gene is polymorphic. Several allelic variants exist but CYP2C9*1, *2 and *3 are the most common in Caucasian populations. The functional wild-type allele is classified as CYP2C9*1 and two alleles coding for impaired metabolic capacity are classified as CYP2C9*2 and *3. CYP2C9 allele and genotype frequencies were determined among CRC patients and compared to data obtained from healthy controls to investigate: (1) if CYP2C9 allele and genotype frequencies differ between Slovenian CRC patients and healthy controls, (2) if sporadic and familial CRC form differ in CYP2C9 genotype frequencies distribution, (3) if CYP2C9 polymorphism has a gender-specific influence on colorectal cancer risk, (4) if CYP2C9 genotype frequencies distribution depends on the location or histologic characteristics of the tumor, (5) if the frequencies of CYP2C9 genotypes in Slovenian CRC patients differ from other studied populations.
Hypothesis: In this sudy we wanted to test the following hypothesis: Individuals homozygous for the wild-type CYP2C9*1 allele assumed to have high activating capacity for precarcinogens are at increased risk for developing colorectal cancer.
Methods: CYP2C9 polymorphism was analysed by a genotyping technique based on polymerase chain reaction (PCR) followed by restriction analysis. DNA samples from 142 patients with CRC were included in this study. The genotype data was compared with the data available for 129 Slovenian healthy controls and with the data from other studied populations. The ?2 test was used for the statistical analysis.
Results: No significant differences in CYP2C9 allele frequencies were observed among CRC patients and healthy controls (?2 = 0.25, m=2, p > 0.05). Similarly no significant differences in genotype frequencies distribution were observed either when all CRC patients or when only sporadic (?2 = 0.59, m = 2, p > 0.05) or familial (?2 = 1.51, m = 2, p > 0.05) CRC forms where compared to healthy controls. CYP2C9 polymorphism had no gender-specific influence on colorectal cancer risk (?2 = 4.56, m = 2, p > 0.05). CYP2C9 genotype frequencies distribution did not depend on the location or histologic characteristics of the tumor. CYP2C9*1/*1 frequency in Slovenian CRC patients was similar to frequencies observed in CRC patients from other populations studied. Suprisingly differences in CYP2C9*1/*1 frequency were observed between normal controls from different populations.
Conclusions: Our results suggest that CYP2C9 polymorphism does not represent a risk factor for the development of colorectal cancer in Slovenian population. CYP2C9 polymorphism is not related to increased risk for familial or sporadic form of CRC, gender, location and histologic characteristics of the tumor. Our results and the similarity of CYP2C9*1/*1 frequencis to CRC patients from different populations suggest that other genetic or environmental factors have higher influence on the colorectal cancer risk than CYP2C9 polymorphism itself.
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