Equitable Access to Genomic Molecular Testing for Australian Cancer Patients: Insights from the Victorian Precision Oncology Summit.

The Victorian Precision Oncology Summit, convened in 2023, was a joint initiative between the Victorian Comprehensive Cancer Centre Alliance (VCCC Alliance) and the Monash Partners Comprehensive Cancer Consortium (MPCCC) and was proposed to guide a coordinated state-wide conversation about how the oncology sector can overcome some of the current obstacles in achieving equity of access to clinical cancer genomics for Victorian patients. Themes that emerged from discussion groups at the Summit include standardisation, centralisation, funding, education and communication and insights across those themes are outlined in this manuscript. The event served as a large consultation piece for the development of a broader precision oncology roadmap, which explores equitable access to molecular testing for Victorian patients, currently in development by the VCCC Alliance and MPCCC in collaboration with other key Victorian and national stakeholders. While this symposium was a Victorian initiative, it is felt that the insights garnered from this consultation piece will be of interest to consumer groups, clinicians, researchers, educators, policy makers and other key stakeholders in other states of Australia as well as in other countries implementing comprehensive genomic profiling within complex health systems.

Comparison of the catalytic parameters and reaction specificities of a phage and an archaeal flap endonuclease.

Flap endonucleases (FENs) catalyse the exonucleolytic hydrolysis of blunt-ended duplex DNA substrates and the endonucleolytic cleavage of 5'-bifurcated nucleic acids at the junction formed between single and double-stranded DNA. The specificity and catalytic parameters of FENs derived from T5 bacteriophage and Archaeoglobus fulgidus were studied with a range of single oligonucleotide DNA substrates. These substrates contained one or more hairpin turns and mimic duplex, 5'-overhanging duplex, pseudo-Y, nicked DNA, and flap structures. The FEN-catalysed reaction properties of nicked DNA and flap structures possessing an extrahelical 3'-nucleotide (nt) were also characterised. The phage enzyme produced multiple reaction products of differing length with all the substrates tested, except when the length of duplex DNA downstream of the reaction site was truncated. Only larger DNAs containing two duplex regions are effective substrates for the archaeal enzyme and undergo reaction at multiple sites when they lack a 3'-extrahelical nucleotide. However, a single product corresponding to reaction 1 nt into the double-stranded region occurred with A. fulgidus FEN when substrates possessed a 3'-extrahelical nt. Steady-state and pre-steady-state catalytic parameters reveal that the phage enzyme is rate-limited by product release with all the substrates tested. Single-turnover maximal rates of reaction are similar with most substrates. In contrast, turnover numbers for T5FEN decrease as the size of the DNA substrate is increased. Comparison of the catalytic parameters of the A. fulgidus FEN employing flap and double-flap substrates indicates that binding interactions with the 3'-extrahelical nucleotide stabilise the ground state FEN-DNA interaction, leading to stimulation of comparative reactions at DNA concentrations below saturation with the single flap substrate. Maximal multiple turnover rates of the archaeal enzyme with flap and double flap substrates are similar. A model is proposed to account for the varying specificities of the two enzymes with regard to cleavage patterns and substrate preferences.