Page 352 - Haematologica Vol. 109 - July 2024

CASE REPORT
bryologically derived from the yolk sac and aorta-gona- do-mesonephros. The timing of the hematologic malignancy diagnosis, nearly always during the year after GCT diagnosis and sometimes simultaneously, argues against secondary leukemia. Clues for a common clone are the presence of hematologic malignant cells in the yolk sac component of the GCT,5 and the description of shared karyotype alterations, such as an isochromosome i(12p)6 which was observed in the present case and typically occurs in GCT, but never in de novo hematological malignancies.1 Our data also support a common origin since the three patient’s tumors carried a rare TP53 somatic variant and PTEN LOH, as previously described in similar situations.7,8 Together, they may play a critical role in pathogenesis and sarcoma differentiation. If TP53 inactivation is frequent in cancer, splice variants are far less common than missense variants.9 No germline TP53 alteration was found in this patient, although this variant has been reported in a hereditary syndrome. In addition, some of the 13 shared somatic variants detected, including TP53
and CDK12 splice site mutations, are considered putative driver mutations, which induce genomic instability and de- fective DNA repair, rendering tumor cells prone to further genetic alterations promoting tumor progression. Altogether, our molecular analysis confirmed the common origin of the three cancers and identified additional drivers that may contribute to the unusual switch to sarcoma phenotype. The extraordinary clinical outcome described here can po- tentially be explained by the combination of (i) an aggressive polychemotherapy regimen, (ii) the anti-tumor effect of the allogenic HSCT and subsequent DLI, and (iii) a neoanti- gen-specific T-cell response, for which the direct causality with clinical outcome could not be tested because of un- availability of viable tumor material. Debulking of AML/GCT was initially obtained with a chemotherapy regimen com- bining compounds targeting AML (cytarabine, mitoxantrone TD, etoposide) and GCT (etoposide and cisplatin), that may deserve further investigation in other patients with this rare entity. A beneficial role of allogenic HSCT and DLI, which
AB
Figure 2. Molecular analysis of the patient’s tumors. (A) Phylogenetic tree based on shared and private exomic mutations in dif- ferent tumors from the patient. Putative driver events are marked in boxes. (B) Violin plots of variant allele frequency (VAF) of mutations in tumors. Red - TP53 driver mutation. Green - common mutations. GCT: germ cell tumor; AML: acute megakaryocyt- ic leukemia; SARC: sarcoma.
Figure 3. Interferon-γ ELISPOT assay showing recognition of peptide pools 6 and 12, and of the interleukin 36G16-24 peptide com- mon to the two pools. Displayed number above the spot is per 200,000 peripheral blood mononulcear cells. DMSO: dimethyl sulfoxide; IL: interleukin; SEB: Staphylococcal enterotoxin B.
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