Maladaptive Somatic Rescue in FLT3 Mutations of Suspected Germline Nature

Somatic genetic rescue (SGR) is a very rare process in which the occurrence of a somatic genetic event offsets the consequences of a germline (GL) mutation resulting in genetic mosaicism and, in some cases, in a milder disease phenotype 1. Acquired somatic mutations may be adaptive by countering the negative effects of the primary mutation ( e.g., improving hematopoiesis) or maladaptive by overcorrecting the initial impairment causing a different, possibly opposite, disease phenotype ( e.g., leading to the development of a myeloid malignancy) 2. Exemplary cases of the latter scenario are mainly represented by severe congenital neutropenia (SCN) cases developing AML as consequence of somatic CSF3R mutations 3 and, sporadically, by adaptive SGR in the context of germline GATA2 and secondary acquisition of somatic GATA2 mutation, counterbalancing the germline effect 4. Although SGR has been functionally demonstrated in these two above mentioned cases, given the molecular heterogeneity of myeloid neoplasia (MN) and the rarity of such genetic events, one can suspect that, in various clinical contexts, any mutation in any gene could be the SG rescuer. During our clinical experience, we encountered a case of a 57yo. woman with newly diagnosed aplastic anemia (AA) who was found to harbor a rare germline FLT3R311W mutation (VAF 50%; predicted to be a loss-of-function/hypomorphic alteration; Fig1) who subsequently evolved to MDS with monosomy 7. Coexisting somatic hits included non RUNT-homology domain, RUNX1P398L mutation (VAF 19%). Ultimately, the patient progressed to AML with emergence of a FLT3D825V (VAF 14%) and a NRASG13D (24%) lesions. In this case carrying GL FLT3 variant, biallelic somatic FLT3 mutation may represent maladaptive SGR. Therefore, we reviewed NGS sequencing results of 5,308 patients with MN and found three other suspected cases harboring GL variants in FLT3 gene, which inspired further investigations. In total we identified 3 additional cases (total of 4/5308 screened patients and among 248 somatic FLT3 mutations. Interestingly, the other case GL FLT3A680T occurred in a patient with AA (35yo.) who subsequently progressed to MDS and AML and acquired somatic NPM1L258fs, PTPN11 A72V, WT1 A365fs and most importantly, a somatic CSF3RL619S . The latter may represent an illustrative case of SGR, in analogy to AML developing in the context of SCN. In addition, 2 other cases with MDS or MDS/MPN were identified both presenting with cytopenia. A 53yo. w