Proučevanje vpliva motenj v presnovi galaktoze in laktazne persistence na razvoj raka jajčnikov : doktorska disertacija

Prodan Žitnik, Irena (author), Lukač-Bajalo, Jana (mentor)

Galaktozemije so vrojene presnovne motnje, ki nastanejo kot posledica okvar treh od štirih encimov, ki sodelujejo pri presnovi galaktoze (GALK, GALT ali GALE). Zaradi motene presnove se galaktoza in njeni presnovki v tkivih kopičijo in toksično delujejo na celice, najbolj na celice očesnih leč, jajčnikov in možganske celice. Najpogostejše so okvare GALT, ki se pojavljajo v dveh oblikah - klasični in Duarte 2 galaktozemiji. Za prvo je značilno popolno, za drugo pa delno pomanjkanje aktivnosti encima. Najpogostejši mutaciji, ki povzročata klasično galaktozemijo sta Q188R in K285N, za Duarte 2 galaktozemijo pa so značilne mutacije N314D, IVS4-27G>C, IVS5+62G>A, IVS5-24G>A in -119_-116delGTCA. Rak jajčnikov je šesta najpogostejša vrsta raka pri ženskah. Čeprav ni najpogostejši ginekološki rak, povzroča največjo smrtnost. Vzroki za nastanek raka jajčnikov še niso popolnoma pojasnjeni, verjetno gre za kombinacijo genetskih in okoljskih vplivov. Ugotovljeno je bilo, da nastanek raka jajčnikov lahko povzročijo snovi, ki toksično delujejo na oocite, zato je možno, da imajo tak učinek tudi galaktoza in njeni metaboliti, ki se kopičijo pri moteni presnovi galaktoze. Posamezniki, ki pogosto uživajo mleko in mlečne izdelke ter tisti, ki imajo v odrasli dobi ohranjeno visoko aktivnost laktaze, so kronično izpostavljeni večjim količinam galaktoze, zato bi tudi ta dva dejavnika lahko prispevala k tveganju za nastanek raka jajčnikov. Vpliv znižane aktivnosti GALT in GALE, pogostega uživanja mleka in mlečnih izdelkov ter laktazne persistence na razvoj raka jajčnikov smo proučevali pri 60 bolnicah z rakom jajčnikov in 79 zdravih preiskovankah. V obeh skupinah smo določili povprečno aktivnost GALT in GALE ter pogostost glavnih mutacij v genu za GALT in polimorfizma C/T-13910 v bližini gena za LPH. Pri preiskovankah z znižano aktivnostjo GALT ali GALE smo z DNA sekvenčno analizo iskali morebitne še neodkrite mutacije v obeh genih. Pogostost uživanja mleka in mlečnih izdelkov smo ugotavljali z vprašalnikom. Povprečni aktivnosti GALT in GALE sta bili v skupini bolnic statistično značilno nižji, kot v kontrolni skupini. Pogostosti mutacij v genu za GALT in polimorfizma C/T-13910 v bližini gena za LPH se med skupinama niso razlikovale. V genu za GALT nismo odkrili novih mutacij. V genu za GALE smo odkrili eno mutacijo v 5' UTR (g.404C>T), 4 intronske mutacije (IVS4+168C>A, IVS4+186G>C, IVS6+118C>G in IVS10+13G>A), 4 mutacije, ki spremenijo aminokislinsko zaporedje v encimu (A84S, A89S, A254T in S312N) in dve mutaciji v 3'UTR (g.5034G>A in g.5185-5187insTAA). Odkrite mutacije bi lahko bile vzrok za ugotovljene znižane aktivnosti GALE. Bolnice z rakom jajčnikom so statistično značilno pogosteje uživale polnomastno mleko, kot preiskovanke v kontrolni skupini. Tveganje za razvoj raka jajčnikov povečujejo okvare GALT in GALE ter pogosto uživanje polnomastnega mleka, še posebej v skupini oseb z ohranjeno visoko aktivnostjo laktaze v odrasli dobi.

• Language: Slovenian
• Keywords: galaktoza, presnovne motnje, encimska aktivnost, medicinska genetika, mutacije, mleko, mlečni izdelki, laktoza, alaktazija
• Work type: Dissertation
• Typology: 2.08 - Doctoral Dissertation
• Organization: FFA - Faculty of Pharmacy
• Place of publishing: Ljubljana
• Publisher: [I. Prodan Žitnik]
• Year: 2009
• Number of pages: 154 str.
• PID: 20.500.12556/RUL-127051
• UDC: 616-008.9(043.3)
• COBISS.SI-ID: 2711665
• Publication date in RUL: 14.05.2021

Secondary language

• Language: English
• Title: Study of impaired galactose metabolism and lactase persistance in relation to ovarian cancer risk

Abstract

Galactosemia is an inborn error of metabolism, caused by the deficiency of three of four enzymes involved in galactose metabolism (GALK, GALT or GALE). Impaired breakdown of galactose results in accumulation of galactose and its metabolites in the tissues, which has harmful effects on different cell types, especially on lens, ovarian and brain cells. The most common error of galactose metabolism is GALT deficiency. Two forms of GALT deficiency galactosemia exist: classical and Duarte 2 galactosemia, first with complete and second with partial loss of enzyme activity. The most common classical galactosemia mutations are Q188R and K285N. Mutations N314D, IVS4-27G>C, IVS5+62G>A, IVS5-24G>A and -119_-116delGTCA are characteristic for Duarte 2 galactosemia. Ovarian cancer is the sixth most common type of cancer in women. It has the highest mortality rate among gynecological cancers. The causes for ovarian cancer have not yet been completely identified. It is probably caused by a combination of genetic and environmental factors. Studies have shown that the substances, toxic to oocytes, can induce ovarian cancer. It is therefore possible that galactose and its metabolites have the same effect. Individuals who frequently consume milk and milk products and those with high lactase activity in the adult age are chronically exposed to high concentrations of galactose and could be at a higher risk for developing ovarian cancer. We investigated the influence of low GALT and GALE activity, milk consumption and lactase status on ovarian cancer risk in 60 patients with ovarian cancer and 79 healthy women. We determined the mean GALT and GALE activities, the frequencies of the most common GALT gene mutations and the frequency of polymorphism C/T-13910 in both groups. We used DNA sequencing to search for new mutations in GALT and GALE gene in individuals with low activity of these enzymes. Milk and milk product consumption was assessed using a questionnaire. The mean GALT and GALE activities were significantly lower in the group of patients with ovarian cancer compared to the control group, while the frequencies of GALT gene mutations and C/T-13910 polymorphism did not differ significantly between the two groups. No new mutations were discovered in the GALT gene. In the GALE gene, we discovered one mutation in 5' UTR (g.404C>T), 4 intron mutations (IVS4+168C>A, IVS4+186G>C, IVS6+118C>G and IVS10+13G>A), 4 mutations that affect amino acid sequence of the enzyme (A84S, A89S, A254T and S312N) and two mutations in 3'UTR (g.5034G>A and g.5185-5187insTAA). These mutations could be the reason for low GALE activity. Consumption of whole milk was significantly higher in ovarian cancer group, than in control group. The risk for ovarian cancer is increased by impairment of GALT and GALE and by consumption of whole milk, especially in individuals with high lactase activity in the adult age.