The Molecular Investigation of Familial Leukaemia
Abstract
Acute myeloid leukaemia (AML) and myelodysplastic syndrome (MDS) are clonal
disorders of haematopoiesis which culminate in bone marrow failure. In rare cases,
families demonstrate an autosomal dominant predisposition to these disorders,
associated with germline mutations in the haematopoietic transcription factors RUNX1,
CEBPA, GATA2 and ETV6. This thesis investigates the molecular profiling of tumours from
multiple families with different germline mutations, examining longitudinal patterns of
disease evolution and identifying novel candidate germline lesions.
Studies initially focused on the comprehensive characterisation of AML associated with
germline CEBPA mutations. In-depth molecular profiling was performed to detail both
the genetic events initiating leukaemia and the clinical progression of disease across
multiple families. Integrated whole-exome (WES) and deep sequencing analysis revealed
the presentation of entirely new leukaemic episodes initiating disease recurrence. This
represents a unique model of disease progression in AML and clinical data support this
hypothesis by demonstrating continued sensitivity to secondary therapies, with some
patients experiencing several episodes of AML recurrence over decades.
Convergence of tumour profiles was demonstrated across relatives from two families
with different germline CEBPA mutations. To further explore this phenomenon, tumours
from multiple siblings within a RUNX1-mutated family were investigated with WES.
Three of the four siblings presented in an identical manner, all developing high risk MDS
or secondary AML at 5 years of age. The molecular disease profiles were remarkable, as
these 3 siblings all demonstrated somatic mutations causing upregulation of JAK-STAT
signalling. This pattern of intra-familial disease convergence has not previously been
reported in haematopoietic or solid familial tumours and highlights the importance of
host genetic factors in governing somatic mutation acquisition.
The final chapter of this thesis describes the investigation of novel germline lesions
including partial allelic deletions of RUNX1 and atypical CEBPA and GATA2 mutations,
with clinical manifestations varying significantly within these families. Novel genetic
candidates are also discussed, highlighting the need for further work to demonstrate
recurrence of these lesions.
To conclude, this work reveals novel insights into the heterogeneous entity of familial
leukaemia. By revealing unique patterns of disease evolution and intra-familial tumour
convergence, these studies highlight the distinct properties of germline mutations in
governing the biology of familial leukaemia. Further work is required to characterise the
somatic and constitutional molecular landscape and determine the precise mechanisms
governing disease latency, penetrance and phenotype.
Authors
Tawana, KiranCollections
- Theses [4209]