Optimising tissue acquisition and the molecular testing pathway for patients with non-small cell lung cancer: A UK expert consensus statement.

Targeted therapy against actionable variants has revolutionised the treatment landscape for non-small cell lung cancer (NSCLC). Approximately half of NSCLC adenocarcinomas have an actionable variant, making molecular testing a critical component of the diagnostic process to personalise therapeutic options, optimise clinical outcomes and minimise toxicity. Recently, genomic testing in England has undergone major changes with the introduction of Genomic Laboratory Hubs, designed to consolidate and enhance existing laboratory provision and deliver genomic testing as outlined in the National Genomic Test Directory. Similar changes are ongoing in Scotland, Wales and Northern Ireland. However, multiple challenges exist with current tissue acquisition procedures and the molecular testing pathway in the UK, including quantity and quality of available tissue, adequacy rates, test availability among genomic laboratories, turnaround times, multidisciplinary team communication, and limited guidance and standardisation. The COVID-19 pandemic has added an extra layer of complexity. Herein, we summarise best practice recommendations, based on expert opinion, to overcome existing challenges in the UK. The least invasive biopsy technique should be undertaken with the aim of acquiring the greatest quality and quantity of tissue. Use of sedation should be considered to improve patient experience. Rapid on-site evaluation may also be useful to help guide adequate sampling, and liquid biopsy may be beneficial in some instances. Sample processing should be appropriate to facilitate biomarker testing, in particular, next-generation sequencing for comprehensive genomic information. Steps to optimise tissue utilisation and turnaround times, such as planning of tissue usage, limiting immunohistochemistry, tumour enrichment, and reflex testing at diagnosis, should be implemented. Guidelines for tissue acquisition and sample processing may help to improve sample adequacy to perform downstream testing. Communication among genomic laboratories will help to standardise test availability across England and local auditing could identify further areas for optimisation, including ways to improve turnaround times and adequacy rates.

Regulation of translation initiation by the yeast eIF4E binding proteins is required for the pseudohyphal response.

The eukaryotic translation initiation factor eIF4E is responsible for the recognition of the mRNA cap structure and, as such, plays a key role in the selection of mRNAs for translation. The interaction of eIF4E with the 'multi-adaptor' eIF4G (and thus recruitment of ribosomes to mRNA) can be regulated via competitive binding of 4E-binding proteins (4E-BPs). 4E-BPs have broad functions in cell growth, proliferation and development. We have found that disruption of the genes for either of the yeast 4E-BPs (Eap1p or Caf20p) leads to an inhibition of pseudohyphal growth in the resulting diploid yeast strain following nitrogen limitation. Specific 4E-binding domain mutations destroy the capacity of each 4E-BP gene to complement the non-pseudohyphal phenotype, suggesting that a translational function for the 4E-BPs is important for pseudohyphal growth. In addition, neither of the 4E-BP deletion strains is deficient in global or stress-regulated protein synthesis. However, our evidence reveals that the two 4E-BPs are functionally distinct with regard to pseudohyphal growth. Therefore, this work supports a model where the yeast 4E-BPs are acting on specific mRNAs to facilitate a defined proliferative response to environmental stress in yeast.