Dvacet let molekulární analýzy genů BRCA1 a BRCA2 v MOÚ – aktuální vývoj v klasifikaci nálezů


Autoři: Eva Machackova 1;  Kathleen Claes 2;  Miroslava Mikova 1;  Jana Házová 1;  Eva Hrabincová Sťahlová 1;  Petra Vasickova 1;  Martin Trbusek 3;  Marie Navrátilová 1;  Marek Svoboda 1;  Lenka Foretová 1
Působiště autorů: Department of Cancer Epidemiology and Genetics, Masaryk Memorial Cancer Institute, Brno 1;  Center for Medical Genetics, Ghent University Hospital, Ghent, Belgium 2;  Department of Internal Medicine Haematology and Oncology, University Hospital Brno 3
Vyšlo v časopise: Klin Onkol 2019; 32(Supplementum2): 51-71
Kategorie: Původní práce
doi: 10.14735/amko2019S51

Souhrn

Východiska: Patogenní mutace v genech BRCA1 a BRCA2 jsou majoritní příčinou dědičné dominantní predispozice ke vzniku nádoru prsu a vaječníku. Interpretace molekulárně-genetických nálezů vždy závisí na dostupných informacích v době uzavření laboratorní zprávy. Cílem této studie byla revize klasifikace všech výsledků testování BRCA genů v Masarykově onkologickém ústavu (MOÚ).

Soubor pacientů a metody: Pacienti ze 7 400 rodin s podezřením na dědičnou predispozici ke vzniku nádorů prsu a/nebo vaječníků byli v MOÚ vyšetřeni v období let 1999 až první poloviny 2018. Vyšetření genů BRCA bylo vždy indikováno klinickým genetikem. V průběhu 20 let laboratorní praxe byly použity různé metody – počínaje vyšetřením cíleným na detekci zkrácené délky proteinu a heteroduplexní analýzu přes vysokorozlišovací analýzu křivek tání a Sangerovo sekvenování až po masivní paralelní sekvenování.

Výsledky: Mutační analýza vedla k odhalení dědičné predispozice k nádoru prsu/ovaria u 20,5 % rodin. Vysoce riziková zárodečná mutace byla detekována u 1 021 rodin v genu BRCA1 a u 497 rodin v genu BRCA2. Bylo zachyceno široké spektrum patogenních a pravděpodobně patogenních unikátních mutací v obou genech – 124 různých mutací v genu BRCA1 a 123 různých mutací v genu BRCA2. Jako benigní nebo pravděpodobně benigní bylo klasifikováno 96 unikátních variant v genu BRCA1 a 126 variant v genu BRCA2. Zbývajících 82 vzácných unikátních variant zůstalo klasifikováno jako „nejasného významu“, především z důvodu ojedinělého výskytu a nedostatku podkladů pro jejich zařazení do ostatních skupin. Výsledky jsou shrnuty v tabulkách dle typu mutace/varianty vč. podkladů pro jejich klasifikaci.

Závěr: Co nejpřesnější klinická klasifikace variant identifikovaných v BRCA genech má dopad na genetické poradenství a následnou klinickou péči. V této studii uvádíme přehled frekvencí BRCA mutací detekovaných v našem regionu, retrospektivní hodnocení a případně reklasifikaci u některých dříve reportovaných variant ve světle nedávných zjištění.

Děkujeme laborantkám MOÚ, které se podílely na laboratorních analýzách: Hana Pavlů, Jitka Kuklová, Veronika Kosinová, Zuzana Jurášková, Marcela Macků. Děkujeme lékařům ostatních genetických pracovišť v České republice, kteří se podíleli na indikaci pacientů vyšetřovaných v MOÚ: Ústav biologie a lékařské genetiky 2. LF UK a FN Motol v Praze; Klinika lékařské genetiky Thomayerovy nemocnice v Praze; Klinika lékařské genetiky FN Hradec Králové; Klinika lékařské genetiky FN Olomouc; Klinika lékařské genetiky FN Ostrava; Oddělení lékařské genetiky FN Brno; Klinika klinické genetiky Nemocnice České Budějovice, Klinika klinické genetiky Masarykovy nemocnice Ústí nad Labem; a další genetičtí poradci z různých oblastí České republiky.

Tato práce byla podpořena MZ ČR – DRO (MOÚ, 00209805) a granty NV15-28830A, NV15-27695A.

Autoři deklarují, že v souvislosti s předmětem studie nemají žádné komerční zájmy.

Redakční rada potvrzuje, že rukopis práce splnil ICMJE kritéria pro publikace zasílané do biomedicínských časopisů.

Obdrženo: 27. 2. 2019

Přijato: 18. 4. 2019

Klíčová slova:

nádor prsu – nádor ovaria – gen BRCA1 – gen BRCA2 – zárodečné mutace


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