Profiles of Germline Predisposition Gene Variants in Hematologic Disorders and Its Impact on Prognosis of Allogeneic Hematopoietic Stem Cell Transplantation

Some studies have demonstrated that germline predisposition plays a certain role in both myeloid and lymphoid malignancies as well as bone marrow failure. In current study, germline predisposition gene variants in the patients with hematologic disorders are investigated systemically and the impact of pathogenic genetic variants on prognosis of allogeneic hematopoietic stem cell transplantation (allo-HSCT) is analyzed.

Between March 2018 and March 2022, 352 patients with hematologic disorders who received allo-HSCT and detection of germline predisposition gene variants in our hospital were included. Blood samples were collected from patients, parents and other potential related donors before transplant. More than 700 germline predisposition genes associated with hematologic and immunologic diseases were detected by next-generation sequencing and analyzed according to American College of Medical Genetics and Genomics guidelines. Class I genetic variants were defined as pathogenic and class II genetic variants were defined as likely pathogenic. The impact of germline predisposition gene variants on the prognosis of allo-HSCT was evaluated. The median age was 18 (1-71) years old. The diagnosis included B-acute lymphoblastic leukemia (B-ALL, n=156, 44.3%), T-acute lymphoblastic leukemia/lymphoma (T-ALL/LBL, n=40, 11.4%), acute myeloid leukemia (AML, n=97, 27.6%), myelodysplastic syndrome (MDS, n=13, 3.7%), chronic myeloid leukemia (n=1, 0.3%), non-Hodgkin lymphoma (NHL, n=31, 8.0%), multiple myeloma (n=1, 0.3%), blastic plasmacytoid dendritic cell neoplasm (n=1, 0.3%), and severe aplastic anemia (SAA, n=12, 3.4%). Transplant types included matched related (n=31, 8.8%), unrelated (n=68, 19.3%) and haploidentical (n=253, 71.9%). In our previous studies, the overall survival (OS) of allo-HSCT among above 3 kinds of transplants were similar in both hematologic malignancies and SAA.

Overall, 299 patients (84.9%) were found with class I germline variants. The most frequent 25 genetic variants were SERPINE1, TNFAIP3, BTLA, EP300, MLH1, CYP2C19, NCF2, YARS2, STK11, MPEG1, F7, KIT, HIF1A, ATM, ADAMTS13, TP53, BRCA2, DPYD, ITGA2, TET2, THBD, CD36, FANCA, GALT, and NUDT15. In B-ALL, the most frequent 15 genetic variants were SERPINE1, EP300, CYP2C19, MLH1, TNFAIP3, YARS2, BTLA, HIF1A, NCF2, F7, KIT, MPEG1, STK11, TP53, and DNASE1. In T-ALL/LBL, the most frequent 15 genetic variants (more than 5% frequency) were SERPINE1, ATM, ATP7B, F7, GALT, HIF1A, KIT, NCF2, NUDT15, TNFAIP3, BRCA2, BTLA, CARD14, CYP2C19, and CYP3A4. In AML, the most frequent 15 genetic variants were BTLA, MLH1, SERPINE1, NCF2, ADAMTS13, ATM, KIT, MPEG1, STK11, TET2, YAER2, DNMT3A, EP300, F7, and TP53. Univariate Cox analysis showed that CD36 and UGT1A1 germline variants were associated with an increased risk of all-cause death after allo-HSCT. Twelve patients (3.4%) carried CD36 germline variants (class I), including B-ALL (n=5), AML (n=2), NHL (n=2), T-ALL (n=1), and SAA (n=2). Missense mutation and frame shift deletion were the main mutation types, accounting for 42% and 33% and were heterozygous. The patients with CD36 germline variants had a poor prognosis after HSCT with higher relapse rate (mutant vs. wild-type as 46.1% vs. 24.2%, p=0.062) and much lower OS (mutant vs. wild-type as 40.2% vs. 74.3%, p=0.0026). Seven of 12 patients (58.3%) with CD36 germline variants died (relapse 4, infection 2, multiple organ failure (MOF) 1) after transplant. Seven patients (2.0%) carried UGT1A1 germline variants (class I), including AML (n=4), MDS (n=2), and B-ALL (n=1). All mutations were missense mutations and heterozygous. The risk of death after allo-HSCT in patients with UGT1A1 germline variants was significantly higher than that with wild-type (HR: 2.8 (95% CI: 1.1- 6.8), p=0.026). The OS of the patientswith UGT1A1 germline variants was significantly lower than that with wild-type (17.1% vs. 65.8%, p=0.026%). Five of 7 patients (71.4%) with UGT1A1 germline variants died (relapse 2, graft-versus-host disease and infections 2, MOF 1) post-transplant.

Our preliminary results have shown the profiles of germline predisposition gene variants in the patients with hematologic disorders and the most frequent genetic variants in B-ALL, T-ALL/LBL and AML. In present study, the patients with CD36 or UGT1A1germlinevariantshave poor prognosis after allo-HSCT. In the future, the mechanism needs to be further investigated.

No relevant conflicts of interest to declare.