Primarily due to recent advances of detection techniques, microchimerism (the proportion of minor variant population is below 1%) has recently gained increasing attention in the field of transplantation. Availability of polymorphic markers, such as deletion insertion or single nucleotide polymorphisms along with a vast array of high sensitivity detection techniques, allow the accurate detection of small quantities of donor- or recipient-related materials. This diagnostic information can improve monitoring of allograft injuries in solid organ transplantations (SOT) as well as facilitate early detection of relapse in allogeneic hematopoietic stem cell transplantation (allo-HSCT). In the present review, genetic marker and detection platform options applicable for microchimerism detection are discussed. Furthermore, current results of relevant clinical studies in the context of microchimerism and SOT or allo-HSCT respectively are also summarized.

We retrospectively analyzed the prognostic impact of Proteasome subunit beta type 1 rs12717 polymorphism in 211 consecutively diagnosed multiple myeloma cases. Patients carrying the variant G allele showed significantly shorter progression free survival. In proteasomes of individuals with G/G genotype we found significantly reduced protease activity and lower inhibitory capacity of bortezomib on the caspase-and trypsin-like activity. 4Abstract Background: Proteasome subunit beta type 1 (PSMB1) rs12717 polymorphism, an SNP with unknown functional effect, was recently reported to influence response to bortezomib based therapy in follicular lymphoma. Patients and Methods: We retrospectively analyzed the prognostic impact of this polymorphism in 211 consecutively diagnosed multiple myeloma cases, and performed in vitro experiments to look into its functional consequences. Results: On univariate analysis patients carrying the variant G allele showed significantly shorter progression free survival (PFS) with a pattern suggestive of a gene dose effect (PFS 26.4, 22.3,and 16.4 months in C/C, C/G, and G/G patients, respectively, p=0.002). On multivariate analysis, carrying the G/G genotype was a significant independent risk factor for relapse (HR 2.29, p<0.001) with a similar trend in C/G carriers (HR 1.33, p=0.097) when compared to the major allele carrier C/C cohort. Our subsequent in vitro analyses demonstrated significantly reduced protease activity in proteasomes of individuals with G/G genotype compared to that of C/C carriers, despite the fact that the PSMB1 expression and the proteasome assembly remained unaltered. Bortezomib exhibited a lower inhibitory capacity on the caspase-and trypsin-like activity of proteasomes from G/G individuals. Conclusion: Our results show that carriership of PSMB1 rs12717 minor allele is predictive for suboptimal response with bortezomib treatment, which could be explained by less active proteasomes which are less sensitive to bortezomib, and myeloma cells consequently relying on other escape mechanism to cope with the abundance of misfolded proteins.

Monitoring measurable residual disease (MRD) in acute myeloid leukemia (AML) plays an important role in predicting relapse and outcome. The applicability of the leukemia-initiating nucleophosmin1 (NPM1) gene mutations in MRD detection is well-established, while that of isocitrate dehydrogenase1/2 (IDH1/2) mutations are matter of debate. The aim of this study was to investigate the stability of NPM1 and IDH1/2 mutations at diagnosis and relapse retrospectively in 916 adult AML patients. The prognostic value of MRD was evaluated by droplet digital PCR on the DNA level in a selected subgroup of patients in remission. NPM1 re-emerged at relapse in 91% (72/79), while IDH1/2 in 87% (20/23) of mutation-positive cases at diagnosis. NPM1 mutation did not develop at relapse, on the contrary novel IDH1/2 mutations occurred in 3% (3/93) of previously mutation-negative cases. NPM1 MRD-positivity after induction (n = 116) proved to be an independent, adverse risk factor (MRDpos 24-month OS: 39.3±6.2% versus MRDneg: 58.5±7.5%, p = 0.029; HR: 2.16; 95%CI: 1.25–3.74, p = 0.006). In the favorable subgroup of mutated NPM1 without fms-like tyrosine kinase 3 internal tandem duplication (FLT3-ITD) or with low allelic ratio, NPM1 MRD provides a valuable prognostic biomarker (NPM1 MRDpos versus MRDneg 24-month OS: 42.9±6.7% versus 66.7±8.6%; p = 0.01). IDH1/2 MRD-positivity after induction (n = 62) was also associated with poor survival (MRDpos 24-month OS: 41.3±9.2% versus MRDneg: 62.5±9.0%, p = 0.003; HR 2.81 95%CI 1.09–7.23, p = 0.032). While NPM1 variant allele frequency decreased below 2.5% in remission in all patients, IDH1/2 mutations (typically IDH2 R140Q) persisted in 24% of cases. Our results support that NPM1 MRD even at DNA level is a reliable prognostic factor, while IDH1/2 mutations may represent pre-leukemic, founder or subclonal drivers.

Fibroblast growth factor receptor 1 oncogene partner N-terminal like gene (FOPNL) rs72773978 polymorphism was identified as an adverse prognostic factor in multiple myeloma (MM). We aimed to investigate the associations of rs72773978 with clinical characteristics and treatment outcome in 373 Hungarian MM patients. In our cohort, FOPNL polymorphism showed differential prognostic effect that depended on the treatment applied. Among patients treated with non-proteasome inhibitor (PI)-based therapy, carriership of the minor allele was significantly associated with adverse overall survival (p=.022). In contrast, the adverse effect was overcome by the application of PI-containing treatment (p=.048). Multivariate analyses revealed the independent adverse effect of rs72773978 on survival in the non-PI-treated group (p=.045), but not in PI treatment (OS: p=.093). We confirmed the adverse prognostic effect of rs72773978 associated with non-PI-based treatment regimens. Our results point to the importance of genotypic prognostic information associated with complex clinical background MM.