Analiza povezanosti polimorfizama gena za BCL2, TP53, FCGR3A, FCGR2A i ATG16L1 sa kliničkim karakteristikama, tokom i ishodom lečenja bolesnika sa difuznim B limfomom velikih ćelija

Abstract

Uvod: Novi genetički markeri u DLBCL su značajni za unapređenje pognostičko/prediktivnih markera i obezbeđivanje novih terapijskih pristupa. Procenjivali smo povezanost ATG16L1 rs2241880, TP53 rs1042522, BCL2 rs2279115, FCGR2A rs180274 i FCGR3A rs396991 sa kliničkim karakteristikama, tokom i ishodom DLBCL. Metode: Studija obuhvata 130 bolesnika sa DLBCL koji su tretirani R-CHOP protokolom (od toga, 44 bolesnika su podvrgnuti transplantaciji matičnih ćelija a 55 radioterapiji). Genotipizacija je izvedena pomoću TaqMan eseja za alelsku diskriminaciju Real time PCR metodom. Rezultati: Genotipovi su povezani sa kliničkim stadijumom (TP53 CG+CC vs GG p=0,06), ekstranodalnom bolešću [(ATG16L1 AG vs AA p=0,07; AG vs GG p=0,04); (BCL2 CC+CA vs AA, p=0,02; CC vs CA+AA, p=0,17); FCGR3A VV vs FF,p=0,004; FF vs FV+VV,p=0,04; FF+FV vs VV,p=0,02)], prognostičkim skorovima (NCCN IPI: HH vs HR+RR, p = 0,004; aaIPI: HH vs HR+RR, p = 0,04), LMR (ATG16L1 AA vs AG+GG, p=0,004; AA vs GG, p=0,023) i NLR (ATG16L1 AA vs AG+GG, p=0,05; AA vs GG, p=0,004). Analizirani genotipovi nisu uticali na odgovor na terapiju, relaps, komplikacije povezane sa terapijom, OS i PFS. Bolesnici sa ATG16L1 AA imali su veću stopu preživljavanja od nosilaca GG genotipa (p=0,04). Kada su bili podvrgnuti radioterapiji, bolesnici sa ATG16L1 alelom A (p=0,05) ili AA genotipom (p=0,03) imali su bolje OS. Zaključak: Rezultati pokazuju povezanost TP53 rs1042522 sa kliničkim stadijumom, ATG16L1 rs2241880 sa ekstranodalnom bolešću, LMR i NLR, BCL2 rs2279115 i FCGR3A rs396991 sa ekstranodalnom bolešću i FCGR2A rs180274 sa prognostičkim skorovima. Uticaj genotipova ATG16L1 na OS kod bolesnika koji su podvrgnuti radioterapiji, ukazuje na značaj pojedinačnih SNP-a u pojedinim podgrupama DLBCL.

Background: Novel genetic markers in DLBCL are important for improving prognostic/predictive markers and providing new therapeutic approaches. We evaluated the association of ATG16L1 rs2241880, TP53 rs1042522, BCL2 rs2279115, FCGR2A rs180274 and FCGR3A rs396991 with clinical characteristics, and course of DLBCL. Methods:The study included 130 DLBCL patients treated with the R-CHOP (Of these, 44 patients were subjected to stem cell transplantation and 55 to radiotherapy ). Genotyping was performed by TaqMan genotyping assays for Real time PCR. Results: Genotypes were associated with clinical stage (TP53 CG+CC vs GG p = 0.06), extranodal disease [(ATG16L1 AG vs AA p=0.07; AG vs GG p = 0.04); (BCL2 CC+CA vs АА, p=0,02; CC vs CA+АА, p=0,17); (FCGR3A VV vs FF,p=0,004; FF vs FV+VV,p=0,04; FF+FV vs VV,p=0,02)], prognostic scores (NCCN IPI: FGCR2A HH vs HR+RR, p =0,004; ааIPI: FCGR2A HH vs HR+RR, p = 0,04), LMR (ATG16L1 AA vs AG+GG, p = 0.052; AA vs GG, p = 0.054) and NLR (ATG16L1 AA vs AG+GG, p = 0.033; AA vs GG, p = 0.003). Analyzed genotypes didn‘t impact response to therapy, relapse, therapy-related complications, OS and RFS. Patients with ATG16L1 AA had higher survival rate than GG carriers (p = 0.04). When subjected to radiotherapy, patients with ATG16L1 A allele (p = 0.05) or AA genotype (p = 0.03) had superior OS. Conclusion: Results demonstrated the association of TP53 rs1042522 with clinical stage, ATG16L1 rs2241880 with extranodal disease, LMR and NLR, BCL2 rs2279115 and FCGR3A rs396991 with extranodal disease and FCGR2A rs180274 with prognostic scores. The impact of ATG16L1 genotypes on OS in patients subjected to radiotherapy, indicates significance of individual single nucleotide polymorphisms (SNPs) in particular subgroups of DLBCL.