Disease evolution and outcomes in familial AML with germline CEBPA mutations

Abstract

Key Points• Germ-line CEBPA mutations are highly penetrant, causing early-onset de novo AML associated with favorable survival outcomes.• Familial CEBPA-mutated AML displays a unique model of disease progression, with recurrence caused by novel, independent leukemic episodes.In-depth molecular investigation of familial leukemia has been limited by the rarity of recognized cases. This study examines the genetic events initiating leukemia and details the clinical progression of disease across multiple families harboring germ-line CEBPA mutations. Clinical data were collected from 10 CEBPA-mutated families, representing 24 members with acute myeloid leukemia (AML). Whole-exome (WES) and deep sequencing were performed to genetically profile tumors and define patterns of clonal evolution. Germline CEBPA mutations clustered within the N-terminal and were highly penetrant, with AML presenting at a median age of 24.5 years (range, 1.75-46 years). In all diagnostic tumors tested (n 5 18), double CEBPA mutations (CEBPAdm) were detected, with acquired (somatic) mutations preferentially targeting the C-terminal. Somatic CEBPA mutations were unstable throughout the disease course, with different mutations identified at recurrence. Deep sequencing of diagnostic and relapse paired samples confirmed that relapse-associated CEBPA mutations were absent at diagnosis, suggesting recurrence was triggered by novel, independent clones. Integrated WES and deep sequencing subsequently revealed an entirely new complement of mutations at relapse, verifying the presentation of a de novo leukemic episode. The cumulative incidence of relapse in familial AML was 56% at 10 years (n 5 11), and 3 patients experienced ‡3 disease episodes over a period of 17 to 20 years. Durable responses to secondary therapies were observed, with prolonged median survival after relapse (8 years) and long-term overall survival (10-year overall survival, 67%). Our data reveal that familial CEBPA-mutated AML exhibits a unique model of disease progression, associated with favorable long-term outcomes. (Blood. 2015;126(10)

Myeloid Neoplasm With Germline Predisposition: A 2016 Update for Pathologists

“…Recent clinical data from 10 affected families reported a median age for the diagnosis of AML of 24.5 years (range, 1.75-46 years). 11 In contrast, the median age at diagnosis for sporadic AML is 65 years. Morphologically, AML with mutated CEBPA often presents as AML with minimal differentiation or AML without maturation associated with normal karyotype (Figure 1, A).…”

“…Families with germline CEBPA mutation inherit an N-terminal frameshift or nonsense mutation that predisposes to acquiring a somatic C-terminal CEBPA mutation on the other allele. 4,11 Clinical features and family history can provide useful clues in identifying patients with germline CEBPA mutations, which are inherited in an autosomal dominant fashion and are highly penetrant. The age of onset for AML with germline CEBPA mutations is younger than that for sporadic AML.…”

“…[2][3][4][5][6][7][8][9][10][11][12][13] Studies of large series of normal-karyotype AML have reported a frequency of CEBPA mutation of 8% to 13% 4,8,14 ; among these, 7% to 11% have germline CEBPA mutations. 4,8 The majority of the AML patients have 2 CEBPA mutations with both N-terminal frameshift mutation and C-terminal inframe mutation on different alleles.…”

Familiáris myelodysplasiás szindróma és akut myeloid leukaemia klinikai és genetikai háttere

“…Érdekes megfigyelés, hogy egyes esetekben a betegség relapsusakor nem ugyanazon szomatikus mutációt hordozó klón jelenik meg újra, hanem egy új, a korábbi vizsgálatok idejé-ben még nem kimutatható klón. Ezek alapján az is felmerül, hogy a visszatérő betegség nem is hagyományos értelemben vett relapsus, hanem egy második de novo AML [18].…”

Acute myeloid leukemia in the era of precision medicine: recent advances in diagnostic classification and risk stratification

“…AML with biallelic mutant CEBPA occurs in individuals who have an initial germline monoallelic mutation in CEBPA, followed by a subsequent acquired, somatic mutation in the second CEBPA allele. This AML entity may occur sporadically or in familial form, with the first family harboring a germline CEBPA mutation and showing autosomal dominant of AML reported in 2004 103 . The germline CEBPA mutation typically occurs in the Nterminal region of the gene, while the somatic, acquired mutation occurs in the C-terminal region.…”