Fanconi anemia gene-associated germline predisposition in aplastic anemia and hematologic malignancies.

Whether Fanconi anemia (FA) heterozygotes are predisposed to bone marrow failure and hematologic neoplasm is a crucial but unsettled issue in cancer prevention and family consulting. We retrospectively analyzed rare possibly significant variations (PSVs) in the five most obligated FA genes, BRCA2, FANCA, FANCC, FANCD2, and FANCG, in 788 patients with aplastic anemia (AA) and hematologic malignancy. Sixty-eight variants were identified in 66 patients (8.38%). FANCA was the most frequently mutated gene (n = 29), followed by BRCA2 (n = 20). Compared with that of the ExAC East Asian dataset, the overall frequency of rare PSVs was higher in our cohort (P = 0.016). BRCA2 PSVs showed higher frequency in acute lymphocytic leukemia (P = 0.038), and FANCA PSVs were significantly enriched in AA and AML subgroups (P = 0.020; P = 0.008). FA-PSV-positive MDS/AML patients had a higher tumor mutation burden, higher rate of cytogenetic abnormalities, less epigenetic regulation, and fewer spliceosome gene mutations than those of FA-PSV-negative MDS/AML patients (P = 0.024, P = 0.029, P = 0.024, and P = 0.013). The overall PSV enrichment in our cohort suggests that heterozygous mutations of FA genes contribute to hematopoietic failure and leukemogenesis.

Targeted minor histocompatibility antigen typing to estimate graft-versus-host disease after allogeneic haematopoietic stem cell transplantation.

Graft-versus-host disease (GVHD) is a critical complication after allogeneic haematopoietic stem cell transplantation induced by genetic differences in donor-recipient pairs. Rigorous HLA matching has reduced GVHD, but severe GVHD still occurs. Minor histocompatibility antigens (mHAs) are another source of GVHD inducers. We designed a multi-mHA panel with 35 valid mHA loci and retrospectively analyzed 391 donor-recipient pairs with the anticipation of implementing mHA typing into clinical practice to optimize donor selection. Results showed the total mismatching in mHA loci in this panel, as well as mismatching in the GVH direction in unmatched-related recipients (UMRs) were 1.8 times and 1.3 times as those in matched-sibling recipients (MSRs) (p = 4.1e-4, p = 0.012, respectively). There was no significant association between mHA loci mismatching and grades II-IV acute GVHD (aGVHD), III-IV aGVHD, extensive chronic GVHD (cGVHD), or relapse in neither group. UMRs had an increased cumulative incidence of II-IV aGVHD (p = 0.002), but there was no statistical difference of the incidences in severe aGVHD or cGVHD (p = 0.093; p = 0.930). This is a preliminary study to explore GVHD risks brought by mHA loci mismatching in both unmatched-related recipients and matched-full-sibling recipients. Our results confirmed that stringent HLA matching is the key to reduce the risks for GVHD.