暗基因组合丰富了难以测序或不可能通过短读序列进行测序的基因。该 Alliance 组合由学术界的合作伙伴使用 Twist 机械片段化文库制备试剂盒、DNA 纯化磁珠、标准杂交 V2 试剂和其他试剂设计和验证。此外，经过优化，它可为使用 Twist 长读文库制备方案。仅供研究使用。Targets 389 genes (20 Mb) Built for the Long Read Protocol optimized for long fragment enrichment Panel optimized for high uniformity and sequencing efficiency

Cancer of unknown primary (CUP) is the 6th most common cause of cancer death in Australia.  CUP has a dismal prognosis with one and 5-year survival rates of 25% and 14%, respectively. Since cancer medicine is still largely based on identifying an anatomical location of the primary cancer, CUP significantly challenges the established care paradigms. Employing precision medicine by identifying mutations that guide targeted treatments can offer an alternative cancer agnostic approach to conventional site directed chemotherapies; however, CUP patients can still be disadvantaged in this regard as access to molecularly targeted therapies through clinical trials or registered government schemes is often restricted to specific cancer types. A strong rationale therefore exists to develop better diagnostic methods for CUP to help resolve the primary origin of a patient’s tumour. Our goal is to develop and rapidly deploy clinical genomics and precision medicine for CUP patients in Australia. The SUPER-NEXT study builds upon one of Australia’s longest running clinical genomics studies: the Solving Unknown Primary Cancer (SUPER) study. SUPER-NEXT is employing clinical whole genome and transcriptome (WGTS) sequencing to measure the increased sensitivity over panel-based approaches. In addition, the use of “liquid biopsies”, targeting circulating tumour DNA in patient blood, is being tested, potentially enabling non-invasive and more rapid genomic testing. In addition to finding potentially actionable mutations in CUP tumours we are employing WGTS data for the classification of tissue of origin (TOO). Although DNA and RNA methods have both been shown to be useful in this regard, they each have their deficiencies, especially in the most challenging CUP cases where a cancer has an atypical molecular profile. We are also exploring the potential utility of DNA methylation profiling, which has also been shown to be useful for TOO prediction in CUP. Importantly, DNA methylation is highly applicable to liquid biopsy, as recently shown in the development of multi-cancer early detection (MCED) tests. One of the biggest challenges of DNA methylation analysis for clinical samples is the amount of nucleic acid needed and that samples are often suboptimal quality. The recent development of methods for enzymatic conversion of unmethylated DNA then used for next-generation sequencing combined with a large capture panel promises to enable application of DNA methylation profiling to even relatively small clinical samples such as core biopsy or plasma DNA. In this talk I will therefore describe the application of the Twist Human Methylome Panel to challenging clinical samples from patients recruited to the SUPER-NEXT study with the view to potentially employing these methods for development of TOO assays and use in the clinic.

Like many genetic diagnostic laboratories past and current, the Victorian Clinical Genetics Service (VCGS), one of the first laboratories in Australian to be accredited for clinical genomic testing, used to employ a variety of different molecular tests and targeted sequencing panels to meet different demands for clinical genomic testing. However, with increased scale, and improvements in lab automation and capture chemistries, the cost of data generation has now dropped to a level where it is more efficient to use exome sequencing as the underlying platform for most clinical genomic applications. Here we will discuss our experience with transitioning from physical targeted panels to in-silico panels backed by exomes, and provide an outlook on emerging clinical genomic applications, including epigenomics and newborn screening.