Exploration of the rare variant germline genomic architecture of sarcoma
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ICR Authors
Authors
Garrett, A
Document Type
Thesis or Dissertation
Date
2024-09-20
Date Accepted
Abstract
Sarcoma is a rare cancer occurring in tissues of mesenchymal origin, constituting ~1% of cancer diagnoses and comprising >70 subtypes. On account of its low frequency, sarcoma susceptibility studies to-date have had limited power for new susceptibility gene identification. This thesis presents analyses relating to genetic susceptibility to sarcoma.
I performed case-control gene-burden analyses integrating data from six sarcoma case datasets and four control datasets, which I organised into four analysis “pillars”. I initially focussed on 91 established cancer susceptibility genes, followed by exome-wide analyses with two variant filtering “tiers” (Tier 1: loss-of-function variants and Tier 2: loss-of-function and protein-altering variants). I combined the results from three analysis pillars (comprising 3,569 cases and 21,788 controls in total) through random effects meta-analysis. Despite being better-powered than previous studies, with ~80% to detect a hypothetical novel sarcoma susceptibility with odds ratio of ≥5 down to a population frequency of deleterious variants of ≥0.17%, no statistically-significant novel gene-sarcoma risk associations were identified. However, association signal for TP53, a well-established sarcoma susceptibility gene, was “reidentified” in the cancer susceptibility gene analyses and subsets of the exome-wide Tier 2 analyses.
The identification through clinical testing of pathogenic variants in established cancer susceptibility genes can enable implementation of enhanced screening, risk-reduction interventions and identification of other “at-risk” relatives through familial cascade testing. There is thus substantial potential clinical value in extending the repertoire of cancer susceptibility genes. However, no novel sarcoma susceptibility genes were identified through these analyses. The size of the analysis and accordant power therefore imply that pathogenic variants in hereto undiscovered sarcoma susceptibility genes are likely associated with small effect size and/or occur at low frequency and/or association is limited to specific rare subtypes, meaning their clinical utility may arguably be quite limited.
Citation
2024
DOI
Source Title
Publisher
Institute of Cancer Research (University Of London)
ISSN
eISSN
Collections
Research Team
Translational Genetics