Sir Peter MacCallum Department of Oncology - Research Publications

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Author: Bowtell, David × Author: Garsed, Dale × End date: 2019 × Start date: 2018 ×

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    Going to extremes: determinants of extraordinary response and survival in patients with cancer
    Saner, FAM ; Herschtal, A ; Nelson, BH ; deFazio, A ; Goode, EL ; Ramus, SJ ; Pandey, A ; Beach, JA ; Fereday, S ; Berchuck, A ; Lheureux, S ; Pearce, CL ; Pharoah, PD ; Pike, MC ; Garsed, DW ; Bowtell, DDL (NATURE PUBLISHING GROUP, 2019-06)
    Research into factors affecting treatment response or survival in patients with cancer frequently involves cohorts that span the most common range of clinical outcomes, as such patients are most readily available for study. However, attention has turned to highly unusual patients who have exceptionally favourable or atypically poor responses to treatment and/or overall survival, with the expectation that patients at the extremes may provide insights that could ultimately improve the outcome of individuals with more typical disease trajectories. While clinicians can often recount surprising patients whose clinical journey was very unusual, given known clinical characteristics and prognostic indicators, there is a lack of consensus among researchers on how best to define exceptional patients, and little has been proposed for the optimal design of studies to identify factors that dictate unusual outcome. In this Opinion article, we review different approaches to identifying exceptional patients with cancer and possible study designs to investigate extraordinary clinical outcomes. We discuss pitfalls with finding these rare patients, including challenges associated with accrual of patients across different treatment centres and time periods. We describe recent molecular and immunological factors that have been identified as contributing to unusual patient outcome and make recommendations for future studies on these intriguing patients.
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    Genomic Analysis Using Regularized Regression in High-Grade Serous Ovarian Cancer
    Natanzon, Y ; Earp, M ; Cunningham, JM ; Kalli, KR ; Wang, C ; Armasu, SM ; Larson, MC ; Bowtell, DDL ; Garsed, DW ; Fridley, BL ; Winham, SJ ; Goode, EL (SAGE PUBLICATIONS LTD, 2018-02-01)
    High-grade serous ovarian cancer (HGSOC) is a complex disease in which initiation and progression have been associated with copy number alterations, epigenetic processes, and, to a lesser extent, germline variation. We hypothesized that, when summarized at the gene level, tumor methylation and germline genetic variation, alone or in combination, influence tumor gene expression in HGSOC. We used Elastic Net (ENET) penalized regression method to evaluate these associations and adjust for somatic copy number in 3 independent data sets comprising tumors from more than 470 patients. Penalized regression models of germline variation, with or without methylation, did not reveal a role in HGSOC gene expression. However, we observed significant association between regional methylation and expression of 5 genes (WDPCP, KRT6C, BRCA2, EFCAB13, and ZNF283). CpGs retained in ENET model for BRCA2 and ZNF283 appeared enriched in several regulatory elements, suggesting that regularized regression may provide a novel utility for integrative genomic analysis.