Medicine (RMH) - Research Publications

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End date: 2024 × Start date: 2021 × Type: Preprint ×

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    A tumor focused approach to resolving the etiology of DNA mismatch repair deficient tumors classified as suspected Lynch syndrome.
    Walker, R ; Mahmood, K ; Joo, JE ; Clendenning, M ; Georgeson, P ; Como, J ; Joseland, S ; Preston, SG ; Antill, Y ; Austin, R ; Boussioutas, A ; Bowman, M ; Burke, J ; Campbell, A ; Daneshvar, S ; Edwards, E ; Gleeson, M ; Goodwin, A ; Harris, MT ; Henderson, A ; Higgins, M ; Hopper, JL ; Hutchinson, RA ; Ip, E ; Isbister, J ; Kasem, K ; Marfan, H ; Milnes, D ; Ng, A ; Nichols, C ; O'Connell, S ; Pachter, N ; Pope, BJ ; Poplawski, N ; Ragunathan, A ; Smyth, C ; Spigelman, A ; Storey, K ; Susman, R ; Taylor, JA ; Warwick, L ; Wilding, M ; Williams, R ; Win, AK ; Walsh, MD ; Macrae, FA ; Jenkins, MA ; Rosty, C ; Winship, IM ; Buchanan, DD ; Family Cancer Clinics of Australia, ( 2023-03-01)
    Routine screening of tumors for DNA mismatch repair (MMR) deficiency (dMMR) in colorectal (CRC), endometrial (EC) and sebaceous skin (SST) tumors leads to a significant proportion of unresolved cases classified as suspected Lynch syndrome (SLS). SLS cases (n=135) were recruited from Family Cancer Clinics across Australia and New Zealand. Targeted panel sequencing was performed on tumor (n=137; 80xCRCs, 33xECs and 24xSSTs) and matched blood-derived DNA to assess for microsatellite instability status, tumor mutation burden, COSMIC tumor mutational signatures and to identify germline and somatic MMR gene variants. MMR immunohistochemistry (IHC) and MLH1 promoter methylation were repeated. In total, 86.9% of the 137 SLS tumors could be resolved into established subtypes. For 22.6% of these resolved SLS cases, primary MLH1 epimutations (2.2%) as well as previously undetected germline MMR pathogenic variants (1.5%), tumor MLH1 methylation (13.1%) or false positive dMMR IHC (5.8%) results were identified. Double somatic MMR gene mutations were the major cause of dMMR identified across each tumor type (73.9% of resolved cases, 64.2% overall, 70% of CRC, 45.5% of ECs and 70.8% of SSTs). The unresolved SLS tumors (13.1%) comprised tumors with only a single somatic (7.3%) or no somatic (5.8%) MMR gene mutations. A tumor-focused testing approach reclassified 86.9% of SLS into Lynch syndrome, sporadic dMMR or MMR-proficient cases. These findings support the incorporation of tumor sequencing and alternate MLH1 methylation assays into clinical diagnostics to reduce the number of SLS patients and provide more appropriate surveillance and screening recommendations.
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    Vaccination is Australia's most important COVID-19 public health action, even though herd immunity is unlikely
    McBryde, E ; Meehan, M ; Sziklay, J ; Adekunle, A ; Kuddus, A ; Ogunlade, S ; Jayasundara, P ; Ragonnet, R ; Trauer, J ; Cope, R ( 2021)
    The Australian National Cabinet four-step plan to transition to post-pandemic re-opening begins with vaccination to achieve herd protection and protection of the health system against a surge in COVID-19 cases. Assuming a pre-vaccination reproduction number for the Delta variant of 5, we show that for the current Mixed program of vaccinating over 60s with AstraZeneca and 16-60s with Pfizer we would not achieve herd immunity. We would need to cover 85% of the population (including many 5-16 year-olds to achieve herd immunity). At lower reproduction number of 3 and our current Mixed strategy, we can achieve herd immunity without vaccinating 5-15 year olds. This will be achieved at a 60% coverage pursuing a strategy targetting high transmitters or 70% coverage using a strategy targetting the vulnerable first. A reproduction number of 7 precludes achieving herd immunity, however vaccination is able to prevent 75% of deaths compared with no vaccination. We also examine the impact of vaccination on death in the event that herd immunity is not achieved. Direct effects of vaccination on reducing death are very good for both Pfizer and AstraZeneca vaccines. However we estimate that the Mixed or Pfizer program performs better than the AstraZeneca program. Furthermore, vaccination levels below the herd immunity threshold can lead to substantial (albeit incomplete) indirect protection for both vaccinated and unvaccinated populations. Given the potential for not reaching herd immunity, we need to consider what level of severe disease and death is acceptable, balanced against the consequences of ongoing aggressive control strategies.