Preleukemic and second-hit mutational events in an acute myeloid leukemia patient with a novel germline RUNX1 mutation

• Published in: Biomarker research Vol. 6; no. 1; pp. 16 - 7
• Main Authors: Ng, Isaac Ks, Lee, Joanne, Ng, Christopher, Kosmo, Bustamin, Chiu, Lily, Seah, Elaine, Mok, Michelle Meng Huang, Tan, Karen, Osato, Motomi, Chng, Wee-Joo, Yan, Benedict, Tan, Lip Kun
• Format: Journal Article
• Language: English
• Published: England BioMed Central Ltd 11.05.2018; BioMed Central; BMC
• Subjects: Acute myeloid Leukaemia; Analysis; Cancer; Case Report; Chemotherapy; Familial platelet disorder; Genetic aspects; Genetic transcription; Methyltransferases; RUNX1; Stem cell transplant; Stem cells; Transplantation; Acute myeloid Leukaemia; Stem cell transplant; Familial platelet disorder; RUNX1
• ISSN: 2050-7771; 2050-7771
• DOI: 10.1186/s40364-018-0130-2

Germline mutations in the transcription factor give rise to a rare autosomal dominant genetic condition classified under the entity: Familial Platelet Disorders with predisposition to Acute Myeloid Leukaemia (FPD/AML). While several studies have identified a myriad of germline RUNX1 mutations implicated in this disorder, second-hit mutational events are necessary for patients with hereditary thrombocytopenia to develop full-blown AML. The molecular picture behind this process remains unclear. We describe a patient of Malay descent with an unreported 7-bp germline frameshift deletion, who developed second-hit mutations that could have brought about the leukaemic transformation from a pre-leukaemic state. These mutations were charted through the course of the treatment and stem cell transplant, showing a clear correlation between her clinical presentation and the mutations present. The patient was a 27-year-old Malay woman who presented with AML on the background of hereditary thrombocytopenia affecting her father and 3 brothers. Initial molecular testing revealed the same novel mutation in all 5 individuals. The patient received standard induction, consolidation chemotherapy, and a haploidentical stem cell transplant from her mother with normal profile. Comprehensive genomic analyses were performed at diagnosis, post-chemotherapy and post-transplant. A total of 8 mutations ( , , , , , 2 and ) were identified in the pre-induction sample, of which 5 remained ( , , , and 1 out of 2 ) in the post-treatment sample and none were present post-transplant. In brief, the 3 mutations which were lost along with the leukemic cells at complete morphological remission were most likely acquired leukemic driver mutations that were responsible for the AML transformation from a pre-leukemic germline -mutated state. On the contrary, the 5 mutations that persisted post-treatment, including the germline mutation, were likely to be part of the preleukemic clone. Further studies are necessary to assess the prevalence of these preleukemic and secondary mutations in the larger FPD/AML patient cohort and establish their prognostic significance. Given the molecular heterogeneity of FPD/AML and other AML subtypes, a better understanding of mutational classes and their involvement in AML pathogenesis can improve risk stratification of patients for more effective and targeted therapy.