London Calling 2026 Asia Pacific Collection

Li-Fraumeni syndrome (LFS) is a rare but highly penetrant hereditary cancer predisposition disorder classically caused by germline pathogenic variants in the TP53 tumour suppressor gene. Individuals with LFS face markedly elevated lifetime cancer risks and often develop early onset or multiple primary tumours across a wide spectrum. Despite this strong genotype–phenotype association, a substantial proportion of clinically suspected LFS cases remain unresolved following short read sequencing due to TP53 variants that may be mosaic, deep intronic, structural, or otherwise cryptic to conventional methods.

Here, we describe an ongoing study evaluating the potential of Oxford Nanopore Technologies long read whole genome sequencing (WGS) to increase diagnostic yield in this unresolved subset. We are performing long read WGS on blood samples from a cohort of 290 individuals from the International Sarcoma Kindred Study with strong clinical suspicion of LFS but negative prior short read testing. Long read sequencing enables comprehensive detection of structural variation, complex rearrangements, repeat expansions, and difficult to resolve genomic regions that may harbour previously undetectable alterations or pathogenic mechanisms relevant to an LFS like phenotype.

In parallel, a subset of 50 matched samples from this cohort will undergo true multi omic analysis. By sequencing genomic DNA and cDNA on a single Nanopore flow cell, this integrated approach allows simultaneous interrogation of genomic sequence, transcript structure, and epigenetic signatures from the same sample. This design aims to determine whether transcriptomic or epigenomic signals, such as allele specific expression, aberrant splicing, or dysregulated p53 related pathways, can provide diagnostic insight in cases where genome level analysis remains inconclusive.

Together, this work will evaluate the utility of long read WGS and integrated multi omic sequencing for improving diagnostic yield in hereditary cancer syndromes, with the goal of resolving currently unexplained LFS like presentations that lack identifiable TP53 mutations using standard testing.

Oxford Nanopore sequencing provides a flexible solution for generating multi-omics data on a single platform. Here, we present Oxford Nanopore-only workflows established in our lab for genome assembly and integrated multi-omics research. Using optimised DNA extraction protocols, we routinely obtain ultra-long reads with N50 values exceeding 150 kb from optimised samples such as fibrous plants and small invertebrates, enabling highly contiguous, gap-free genome assemblies that resolve complex repetitive regions. For challenging silica-dried specimens, we implemented dedicated extraction and library preparation strategies to improve DNA integrity and compatibility with Oxford Nanopore sequencing. Building on this genomic foundation, we applied Oxford Nanopore-based workflows for full-length transcriptome sequencing and developed epigenomic workflows, including our SMAC-seq implementation, enabling single-molecule profiling of transcript boundaries, isoforms, chromatin accessibility, and DNA methylation. These workflows provide practical solutions for studying genome structure and multi-omics regulation across diverse biological systems.

Homologous recombination deficiency (HRD) affects breast, ovarian, pancreas and prostate cancers. Patients with HRD tumours can respond to poly ADP-ribose polymerase (PARP) inhibitors and platinum-based therapies. HRD results in a variety of single base, insertion and deletion and large structural variants (SVs) that serve as biomarkers for detection. However, these mutations can occur years prior to diagnosis and might not reflect the true HRD status of the tumour and its response to therapy. We hypothesize that we can detect features of HRD through single base, large SV and methylation signatures that provide a comprehensive set of HRD features, representative of current HRD status and predict treatment response. We compared the performance of mSigDetectHRD with WGS of the tumours as ground truth, to build a cost-effective test using adaptive sampling. Mutations accumulate non-uniformly throughout the genome and we hypothesize that we can target regions of higher signature activity to obtain better detection. In addition, using multiple features of HRD we can distinguish BRCA1 and BRCA2 loss that can have clinical importance for familial genetic testing. Last, by training our classifier on public methylation data from cancer genomes, we developed a HRD methylation signature that corresponds with genomic features of HRD and predict patients™ response to platinum-based therapies. We envision our approach to develop multi-omic diagnostic tests, based on adaptive sampling, to be able to address clinical challenges in predicting treatment responses and provide an unprecedented depth of information for cancer diagnosis in the future.

Preimplantation genetic testing for monogenic disorders (PGT-M) plays a critical role in preventing the transmission of inherited genetic conditions. Conventional PGT-M approaches depend on comprehensive familial haplotype information, which restricts their application in cases involving incomplete pedigrees, de novo mutations, or complex genetic variants. Although long-read sequencing offers potential solutions in such scenarios, its cost has limited widespread clinical adoption. Nanopore adaptive sampling presents a targeted and cost-effective alternative by enabling the enrichment of specific genomic regions. In this study, we implemented nanopore adaptive sequencing using peripheral blood samples from 1,376 couples, achieving a technical success rate of 98.9% (1,361/1,376). The method demonstrated high accuracy in identifying pathogenic mutations and supported robust haplotype-based linkage analysis. Subsequent successful embryo transfers and concordant prenatal diagnostic results in selected families further confirmed its clinical reliability. Compared to traditional short-read next-generation sequencing, nanopore adaptive sampling emerges as a promising and economically efficient strategy for PGT-M, particularly for cases with limited family genetic data or de novo variants. These findings support its broader integration into routine reproductive genetics practice.