| Abstract | Nasljedni sindromi raka čine raznovrsne skupine genetskih sindroma koje karakterizira rani razvoj histogenetski različitih neoplazmi koje se pojavljuju u nekoliko članova obitelji. Iako su mnogi rijetki, oni čine 3-10 % svih zloćudnih bolesti. Cilj ovoga istraživanja bio je utvrditi raspodjelu patogenih ili vjerojatno patogenih varijanti u nekoliko penetrantnih gena visokog rizika kao što su BRCA1 i BRCA2, PALB2, TP53, PTEN, STK11, CDH1 te genima za popravak krivo sparenih baza (MLH1, MSH2, MSH6 i PMS2) i njihov utjecaj na terapijske odluke u liječenju raka dojke. Provedena je retrospektivna neintervencijska studija na Klinici za onkologiju Kliničkog bolničkog centra Zagreb u razdoblju od 1. veljače 2019. godine do 31. siječnja 2020. godine. U navedenom je razdoblju od godine dana u genetičkom savjetovalištu proces savjetovanja prošla 161 osoba, a multigenskim panelom za nasljedni rak koji uključuje 113 gena, genetički je testirana 101 osoba. Patogene varijante otkrivene su u 6 pacijentica (54,55 %) s karcinomom dojke testiranih tijekom neoadjuvantnog liječenja, među kojima je 4 (36,36 %) imalo patogenu varijantu BRCA1 gena, 1 pacijentica (9,09 %) BRCA2 gena, a 1 pacijentica (9,09 %) patogenu varijantu ATM gena. Sve bolesnice s BRCA mutacijama bile su podvrgnute radikalnoj mastektomiji. Također, u pacijentica s metastatskim rakom dojke opažene su patogene varijante gena BRCA1, CHEK2 i AIP (12,50 %) te vjerojatno patogene varijante u genima TP53, CHEK2, BRIP1, BRCA1 i PALB2 (20,83 %). Pacijenticama s BRCA i PALB2 patogenom varijantom odobren je talazoparib, PARP-inhibitor, kao terapija metastatske bolesti. Ostale značajnije patogene varijante uočene su u genima HNF1A, AIP, ATM, MSH6, BRIP1, BARD1, FANCI. Zaključno, ovo istraživanje ukazuje na važnost genetičkog testiranja za nasljedni rak dojke radi pravilnog odabira terapijskih opcija i potrebe za uključivanjem više gena relevantnih za rak dojke s obzirom na njihovu prisutnost kod velikog broja bolesnica. |
| Abstract (english) | Hereditary cancer syndromes are consisted of a diverse group of genetic syndromes that characterize early development of different histogenetic neoplasms that occur in several family members. Although many of them are rare, they make up to 3-10 % of all malignancies. The aim of this study was to determine the distribution of pathogenic and likely pathogenic variants in several high- and moderate-penetrance genes such as BRCA1 and BRCA2, PALB2, TP53, PTEN, STK11, CDH1 and mismatch repair genes (MLH1, MSH2, MSH6, PMS2) and their impact on therapeutic decisions in the treatment of breast cancer. Retrospective non-interventional study was conducted in the Department of Oncology in University Hospital Center Zagreb during the period from February 1, 2019 until January 31, 2020. During this one year period, genetic counseling was attended by 161 clients and multi-gene panel testing including 113 genes was performed on 101 participants. Pathogenic variants were found in 6 breast cancer patients (54.55 %) during neoadjuvant treatment, 4 of them (36.36 %) in BRCA1, 1 (9.09 %) in BRCA2 and 1 (9.09 %) in ATM. All patients with BRCA mutations were subjected to radical mastectomy. Also, patients with metastatic disease of breast cancer had pathogenic variants in BRCA1, CHEK2 and AIP genes (12.50 %) and likely pathogenic variants in TP53, CHEK2, BRIP1, BRCA1 and PALB2 (20.83 %). Based on these genetic test results, women with BRCA and PALB2 likely pathogenic variants were assigned to receive talazoparib, PARP inhibitor, as a treatment option for metastatic disease. Other significant pathogenic and likely pathogenic variants were detected in HNF1A, AIP, ATM, MSH6, BRIP1, BARD1 and FANCI. In conclusion, this study shows the importance of genetic testing for hereditary breast cancer in order to properly select therapeutic options and the need of including more genes relevant to breast cancer in testing. |
