Mutacijski status gena IGHV in stereotipnost B-celičnega receptorja pri slovenskih bolnikih s kronično limfocitno levkemijo

Milanović, Saša (avtor), Podgornik, Helena (mentor), Šućurović, Sandra (komentor)

Kronična limfocitna levkemija (KLL) predstavlja najpogostejšo obliko levkemije v zahodnem svetu. Med njene najpomembnejše napovedne dejavnike sodi mutacijski status gena IGHV. Predstavlja neodvisen dejavnik, ki ostaja med boleznijo nespremenjen. Določamo ga z metodami sekvenciranja. Omogoča nam razvrstitev bolnikov v 2 podskupini-mutirano (M-) ter nemutirano (ang. unmutated, U-) KLL. Za M-KLL je značilna manj kot 98% identičnost z zarodno progo, za U-KLL pa več kot 98% identičnost. M-KLL ima značilno ugodnejše klinične izide in klinični potek kot U-KLL. Mutacijski status IGHV je pomemben tudi za načrtovanje zdravljenja. Najnovejše smernice Evropskega konzorcija za izvajanje raziskav o KLL priporočajo ugotavljanje stereotipnosti B-celičnega receptorja (BCR), ki predstavlja obetaven napovedni dejavnik KLL. Analizirali smo rezultate bolnikov z naročeno preiskavo mutacijski status IGHV, ki so bili rutinsko obravnavani v Specializiranem hematološkem laboratoriju (SHL) v obdobju 2016–2022. Poleg mutacijskega statusa IGHV smo uporabili še spremljajoče podatke o spolu bolnikov, genih IGHV-D-J, stereotipnih BCR, mutacijskem statusu TP53. Zbrali smo podatke 434-ih bolnikov s KLL. Večino (64%) so predstavljali moški. Prevladoval je nemutiran status gena IGHV (60%). Najpogosteje prisotni geni IGHV so bili: IGHV1-69, IGHV4-34, IGHV3-23, IGHV1-2, IGHV3-30, IGHV3-48, IGHV3-21, IGHV3-7, IGHV4-39 in IGHV3-11. Vsi, z izjemo IGHV4-34, IGHV3-23 in IGHV3-7, ki so prevladovali pri bolnikih z M-KLL, so bili večinoma prisotni pri bolnikih z U-KLL. Podatki o stereotipnosti BCR so edini odstopali od navedb v literaturi. Odkrili smo jo pri 12% bolnikov, kar je manj od deleža (30–40%), navedenega v literaturi. Poleg tega smo le pri dveh bolnikih našli podtip KLL#8 in pri nobenem KLL#4, ki sta dva izmed štirih najpogostejših podtipov. Preostala dva (KLL#1 in KLL#2) sta prevladovala tudi v obravnavani populaciji. Večina bolnikov (več kot 80%) je imela nemutiran gen TP53. Napovedno neugodni nemutiran status IGHV in nepravilnosti TP53 so prevladovale pri moških, a razlika med spoloma ni bila statistično značilna. S to nalogo smo dobili prvi celovit vpogled v mutacijski status gena IGHV pri slovenskih bolnikih s KLL. Omogočila nam je, da smo glede na primerljivost rezultatov z literaturnimi navedbami ocenili, da je kakovost preiskave mutacijski status IGHV v SHL ustrezna. O posebnostih v populaciji, kljub določenim odstopanjem, ne moremo govoriti.

• Jezik: Slovenski jezik
• Ključne besede: kronična limfocitna levkemija, mutacijski status IGHV, stereotipnost B-celičnega receptorja, napovedni dejavnik, zdravljenje
• Vrsta gradiva: Magistrsko delo/naloga
• Organizacija: FFA - Fakulteta za farmacijo
• Leto izida: 2023
• PID: 20.500.12556/RUL-150476
• Datum objave v RUL: 19.09.2023

Sekundarni jezik

• Jezik: Angleški jezik
• Naslov: Mutational status of the IGHV gene and B-cell receptor stereotypy in Slovenian patients with chronic lymphocytic leukemia

Izvleček

Chronic lymphocytic leukemia (CLL) is the most common leukemia in the Western World. One of its most important prognostic factors is mutational status of the IGHV gene. It is an independent factor, which remains unchanged as the disease evolves. Method for its detection is sequencing. Based on mutational status of IGHV we split patients into 2 subgroups-mutated (M-) CLL with less than 98% identity with the germline and unmutated (U-) CLL with more than 98% identity. M-CLL has significantly better clinical outcomes and clinical course than U-CLL. Mutational status of IGHV is also important for treatment planning. The newest recommendations of European Research Initiative on CLL recommend assessment of B-cell receptor (BCR) stereotypy, which is a promising prognostic factor. We collected data of samples from patients with ordered IGHV gene mutational status analysis that were analyzed in the Specialized Haematology Laboratory (SHL) from 2016–2022. In addition to the mutational status of IGHV, we also obtained data of patients' gender, genes IGHV-D-J, BCR stereotypy, mutational status of the TP53 gene. We collected data of 434 patients with CLL. Majority of them (64%) were men. Most patients (60%) had unmutated status of IGHV gene. The most common IGHV genes were: IGHV1-69, IGHV4-34, IGHV3-23, IGHV1-2, IGHV3-30, IGHV3-48, IGHV3-21, IGHV3-7, IGHV4-39 and IGHV3-11. IGHV4-34, IGHV3-23 and IGHV3-7 were mostly present in patients with M-CLL, while others were more common for patients with U-CLL. The only data that differed from the literature was about BCR stereotypy. It was present in 12 % of patients, which is lower than 30–40% that is mentioned in the literature. Beside that we discovered only two patients with CLL#8 and none with CLL#4, which represent two of four most common subtypes. The other two (CLL#1 and CLL#2) also predominated in our population. Most patients (more than 80%) had unmutated TP53 gene. Bad prognosticators unmutated status of IGHV and TP53 aberrations, were mostly present in men but the difference between genders was not statistically significant. With this master's thesis we obtained the first comprehensive insight into the mutational status of the IGHV gene in Slovenian patients with CLL. It enabled us to assess the quality of the IGHV mutational status investigation in SHL as adequate, given the comparability of the results with literature references. We cannot talk about specifics in the population, despite certain deviations.

• Ključne besede: chronic lymphocytic leukemia, IGHV mutational status, B-cell receptor stereotypy, prognostic marker, treatment