Investigating rare pathogenic mutations of the extended Fanconi Anaemia DNA repair pathway in Acute Myeloid Leukaemia (AML)
Date
2017
Authors
Maung, Kyaw Ze Ya
Editors
Advisors
D’Andrea, Richard
Gray, James
Gray, James
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Abstract
a significant association of BRCA1/2 variants with Down syndrome and trisomy 21 was also
observed (P=0.045).
The mutation data were also cross-referenced to the disease databases for FA and breast cancer
to determine known disease-causing mutations (D-C mutations). In the adult AML, a significant
enrichment was observed for D-C mutations affecting the 19 FANC genes compared to the allfemale
healthy control cohort [P=0.018; Odds ratio=3.3 (1.3-8.6)]. Similarly, an overrepresentation
of D-C mutations affecting 16 of the FANC genes was observed in the adult
AML cohort, compared to that reported in a separate published study of large healthy
populations [P=0.002; odds ratio=3.4 (1.7-7.0)]. The mutation data was also compared against
cancer and disease databases to determine the presence of disease-causing (D-C) mutations in
all 58 genes, and to identify other disease-associated (D-A) variants. This analysis revealed a
number of mutations that were present in multiple disease samples, while being absent, or
present at low frequency, in the control cohorts.
Gene expression profiling was performed for a small set of adult AML (n=57) using microarray.
This analysis, comparing gene expression in mutant versus non-mutant AML, revealed
differences in gene expression pattern associated with presence of rare variants affecting
functional gene subgroups within the FA/BRCA-HRR network. Examination of the individual
differentially-expressed genes, and gene set enrichment analysis (GSEA), suggested that there
may be potential differences in leukaemic cell of origin for AML carrying rare variants affecting
the different functional subgroups of the extended FA/BRCA-HRR network. GSEA also
suggested potential up-regulation of gene-sets associated with base excision repair and
homologous recombination repair, as well as replicative stress, in samples carrying rare variants
affecting the genes encoding the FA core & ID2 proteins. It is speculated that this may be
indicative of increased basal replicative stress and DNA damage in the samples carrying these
rare variants, with compensatory up-regulation of these repair pathways.
Based on the data presented it is hypothesised that rare germline variants affecting the genes in
the FA/BRCA-HRR network result in subtle changes to the effectiveness of the FA DNA repair
pathway in HSC, with a resultant modest increased pre-disposition to AML. An important
question raised by this study relates to the cellular phenotype associated with rare, heterozygous
deleterious variants affecting genes in the FA/BRCA-HRR network, and the FANC genes in
particular. To investigate this further clonal cell lines were generated from a non-cancer cell
line (MCF10A) carrying heterozygous or bi-allelic damaging mutations in FANCL. Changes to
DNA repair capacity have been shown in cells with FANCL heterozygous mutations to be
statistically different to the wild type cells.
School/Discipline
Adelaide Medical School
Dissertation Note
Thesis (Ph.D.) -- University of Adelaide, Adelaide Medical School, 2017
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