Pojavnost mutacije gena BRAF u displastičnom nevusu i melanomu in situ

Prkačin, Ivana (2019) Pojavnost mutacije gena BRAF u displastičnom nevusu i melanomu in situ. PhD thesis, Sveučilište u Zagrebu.

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Abstract

Mutations in the BRAF gene are common in melanomas and represent an early oncogenic event at their occurrence. The idea of this study is that the BRAF mutation analysis in samples of dysplastic nevi and melanoma in situ may help enlighten the unclear role of dysplastic nevi as precursor melanoma lesions.The objectives of the study were to determine and compare the frequency of BRAF gene mutations in dysplastic nevi and melanomas in situ and determine whether there is a correlation between the presence of BRAF gene mutations and various anamnestic, clinical and pathohistological variables. A total of 175 patients, i.e. 106 patients with dysplastic nevi, 41 patients with melanoma in situ and 28 patients with lentigo maligna melanoma, were included in the study. DNA has been extracted from tissue samples of all patients embedded in paraffin and analyzed using the competitive allele-specific TaqMan polymerase chain reaction in real time, all in order to determine the presence of BRAF V600E and V600K mutations.The obtained mutation data were compared with anamnestic, clinical and pathohistological data using appropriate statistical methods. Out of a total of 175 patients, BRAF mutation was found in 87 patients (49.7%): 68 (38.9%) patients with V600E and 20 (11.4%) patients with V600K. There was no statistically significant difference in the presence of BRAF mutation in patients with dysplastic nevi (58.5% of mutated) and those with melanoma in situ (60.9% of mutated) (p=0,371). In patients with dysplastic nevi, V600E mutation was significantly more common (89% of patients with mutation), while the V600K mutation was more common in patients with melanoma in situ (52% of patients with mutation). There was a statistically significant connection between the presence of BRAF mutations, tumor localization and the age of the patient (p=0,0001). Patients with mutation were younger than patients without mutations. No statistically significant connection between the presence of BRAF mutation and sex (p=0,104), tumor size (p=0,404), or previous melanoma diagnosis (p=0,856) has been found. The results of this study imply that BRAF mutations in dysplastic nevi have an important, but in itself insuffitient, role in triggering malignant transformation and onset of melanoma. In this respect, this research is a contribution to a better understanding of the etiopathogenesis of melanoma and the role of dysplastic nevi as precursor lesions.

Abstract in Croatian

Mutacije u genu BRAF su česte u melanomima i predstavljaju rani onkogeni događaj u njihovom nastanku. Ideja ovog istraživanja je da analiza BRAF mutacija u uzorcima displastičnih nevusa i melanoma in situ može pomoći u rasvjetljavanju zasad nejasne uloge displastičnih nevusa kao mogućih prekursorskih lezija melanoma. Ciljevi istraživanja bili su odrediti i međusobno usporediti učestalost mutacija gena BRAF u displastičnim nevusima i melanomima in situ te odrediti postoji li povezanost između prisutnosti mutacija gena BRAF i različitih anamnestičkih, kliničkih i patohistoloških varijabli. U istraživanje je bilo uključeno ukupno 175 bolesnika, 106 bolesnika s displastičnim nevusima, 41 bolesnik s melanomom in situ i 28 bolesnika s lentigo maligna melanomom. Svim bolesnicima je izdvojena DNA iz uzoraka tkiva uklopljenog u parafin i analizirana metodom kompetitivne alel-specifične TaqMan lančane reakcije polimerazom u stvarnom vremenu kako bi se odredila prisutnost BRAF V600E i V600K mutacija. Dobiveni podatci o mutacijama uspoređeni su s anamnestičkim, kliničkim i patohistološkim podacima primjenom odgovarajućih statističkih metoda. Od ukupno 175 bolesnika, u njih 87 (49,7%) je nađena BRAF mutacija: u 68 (38,9%) bolesnika V600E, a u 20 (11,4%) bolesnika V600K. Nije nađena statistički značajna razlika u prisutnosti BRAF mutacije između bolesnika s displastičnim nevusima (58,5% mutiranih) i onih s melanomom in situ (60,9% mutiranih) (p=0,371). U bolesnika s displastičnim nevusima značajno češća je bila V600E mutacija (89% bolesnika s mutacijom) dok je kod bolesnika s melanomom in situ češća bila V600K mutacija (52% bolesnika s mutacijom). Nađena je statistički značajna povezanost prisutnosti BRAF mutacija sa lokalizacijom tumora i dobi bolesnika (p=0,0001). Bolesnici s mutacijom su bili mlađi od bolesnika bez mutacije. Nije nađena statistički značajna povezanost prisutnosti BRAF mutacija sa spolom (p=0,104), veličinom tumora (p=0,404), ni prethodnom dijagnozom melanoma (p=0,856). Rezultati ovog istraživanja govore u prilog uloge BRAF mutacije u displastičnom nevusu kao važnog, ali samog po sebi nedovoljnog onkogenog pokretača u nastanku melanoma. U tom smislu ovo istraživanje predstavlja doprinos boljem razumijevanju etiopatogeneze melanoma i uloge displastičnih nevusa kao mogućih prekursorskih lezija.

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