Family with a germline mutation in the LYST gene
In Family3 both brothers displayed a germline missense single-nucleotide
mutation in the LYST gene, translating in p.R3398Q (Table 2).
This variant is currently annotated as VUS and the functional
consequences are unknown. Both siblings developed AML and somatic
mutational analysis of their leukemic samples identified pathogenic
variants. Brother ID5 harbored truncating pathogenic indels inASXL1 (p.R417*) and in RAD50 (p.N934Ifs*6), a likely
pathogenic truncating indel in TET2 (p.L1721Ffs*24) and a VUS inIGFN1 (p.D2249G). Brother ID6 harbored the second most common
somatic pathogenic variant in IDH2 , p.R172K, with VAF=36.9%
(Table 3).
In order to reconstruct the genomic evolution of the disease in patient
ID5, we exploited NGS analysis performed in our Institute on BM
aspirates for clinical monitoring using the commercially available
Oncomine Myeloid Research Assay. As shown in Figure 1A, there was
partial response to treatment post-induction with disappearance of cells
bearing TET2 p.L1721Ffs*24 and U2AF1 p.S34F variants, but
there were no effects on the blasts harboring ASXL1 p.R417* andTET2 p.D77Tfs*18 mutations. The patient underwent CR post-allo
TMB, however, unfortunately, he relapsed very rapidly with re-expansion
of the same AML clone detected pre-transplant and appearance of a new
mutation in TP53 , p.C141Y, that reached a VAF around 90%. The
patient succumbed of disease less than 8 months after relapse.