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Identifying genetic susceptibilities underlying familial haematological malignancies in a Tasmanian family resource


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Blackburn, NB 2015 , 'Identifying genetic susceptibilities underlying familial haematological malignancies in a Tasmanian family resource', PhD thesis, University of Tasmania.

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Haematological malignancies (cancers of the haematopoietic and lymphoid tissues)
are collectively one of the most frequently diagnosed cancers in Australia. Family
history is one of the strongest risk factors for disease. Evidence for this derives from
large population-based studies that have identified an increased risk of haematological
malignancies in first degree relatives of cases, as well as studies of individual families
where analyses have identified genes where family specific germline mutations
predispose to these malignancies. Despite intensive research into the genetic
predisposition to these cancers, the known genes account for only a small portion of
the overall inherited component of haematological malignancies, leaving a significant
gap in our understanding of the genetic basis of disease. Earlier studies used candidate
gene approaches or sparse sets of genome wide markers to identify predisposition
genes. Such approaches have a limited capacity for disease gene identification. Now,
application of innovative technologies, such as next generation sequencing, to familial
datasets with multiple cases of haematological malignancies presents an ideal
opportunity to identify new predisposing germline mutations and other genetic factors
contributing to disease development.
The aim of this study was to identify the genetic architecture of disease susceptibility
in large families affected by multiple subtypes of haematological malignancies. This
study takes advantage of a collection of extended Tasmanian haematological
malignancy pedigrees comprising 48 families, as well as 84 additional Tasmanian
haematological malignancy cases with no known family history of disease. This
resource is particularly valuable due to the recognised stability and relative genetic
homogeneity of the island population of Tasmania.
Next generation sequencing approaches were employed to identify novel, rare and
shared predisposing mutations in affected family members. This was achieved
through a combination of whole exome and whole genome sequencing in five
prioritised families. Genome and exome alignment and variant calling were conducted
using BWA and SAMtools. High-quality single nucleotide and small insertion /
deletion variants identified were then annotated with information from public data
sources using ANNOVAR. Variants were filtered to focus in on rare variants (with
population frequency estimates of 1% or less) using frequencies in Caucasian
population data from the 1000 Genomes Project and the UK10K consortia dataset. A
large number of rare shared genetic mutations were identified between related
haematological malignancy cases in these families. A tiered prioritisation strategy was
developed and employed to identify the top preferred candidates for further followup.
This strategy incorporated variant-based prioritisation, using in silico predictions
of variant effect, and gene-based prioritisation using known gene biology. For genebased
prioritisation a literature curated network analysis tool (Ingenuity Pathway
Analysis) and an ontology-based tool (Phevor) as well as publically available tissue
expression profiles of the mutated genes were used. Genes prioritised for further
follow-up include examples such as TNFSF9, TDP2, MMP8, and NOTCH1. These
genes have not been previously implicated in the familial risk for haematological
malignancies, although some have previously established roles in malignancy. For
example, TNFSF9 is a gene with clear connections to both T-cell and B-cell biology
and there is evidence from a mouse knockout model that disruption to this gene can
contribute to malignancy development.
A subsequent aim of this study was to explore the role of telomere biology in familial
haematological malignancies. Telomere biology has a well-characterised role in
cancer development. Disruption of key telomere biology genes has been shown to
lead to a spectrum of syndromes of which haematological malignancies are a feature
such as dyskeratosis congentia and aplastic anaemia. To examine whether disrupted
telomere biology was detectable in haematological malignancies, an analysis of
telomere length was conducted using a PCR-based assay measuring across the
familial resource, non-familial cases and population controls. Telomere length was
analysed as a quantitative trait using variance components modelling, adjusting for
age, sex and importantly kinship. The key finding from this analysis was that telomere
length was highly heritable at 62.5% (P=4.7×10-5) indicating a strong genetic effect
driving variation in telomere length and that both familial and non-familial
haematological malignancy cases had shorter telomeres (P=2.2×10-4 and 2.2×10-5
respectively). These results indicate that telomere length contributes broadly to
haematological malignancies. Genetic variation in some of the known telomere
biology genes was examined, however the underlying genetic contribution to the
observed shortened telomere length remains to be determined.
This thesis describes the genetic analysis of a rare resource, providing evidence for
several novel genes with possible roles in the development of haematological
malignancies. As expected next generation sequencing of these families has further
highlighted the multigenic contribution to risk in this complex disease.

Item Type: Thesis - PhD
Authors/Creators:Blackburn, NB
Keywords: Haematological malignancies, Genomics, Cancer, Tasmania, Bioinformatics, Familial cancer
Copyright Information:

Copyright 2015 The Author

Additional Information:

Appendix 5 .1 is a published paper. The citation is: Blackburn, N. B., Charlesworth, J. C., Marthick, J. R., Tegg, E. M., Marsden, K. A., Srikanth, V., Blangero, J., Lowenthal, R. M., Foote, S. J., Dickinson, J. L., A retrospective examination of mean relative telomere length in the Tasmanian familial hematological malignancies study, Oncology reports 33(1) (2015), 25-32 10.3892/or.2014.3568

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