An Approach to Solving the Complex Clinicogenomic Data Landscape in Precision Oncology: Learnings From the Design of WAYFIND-R, a Global Precision Oncology Registry.

Precision oncology, where patients are given therapies based on their genomic profile and disease trajectory, is rapidly evolving to become a pivotal part of cancer management, supported by regulatory approvals of biomarker-matched targeted therapies and cancer immunotherapies. However, next-generation sequencing (NGS)-based technologies have revealed an increasing number of molecular-based cancer subtypes with rare patient populations, leading to difficulties in executing/recruiting for traditional clinical trials. Therefore, approval of novel therapeutics based on traditional interventional studies may be difficult and time consuming, with delayed access to innovative therapies. Real-world data (RWD) that describe the patient journey in routine clinical practice can help elucidate the clinical utility of NGS-based genomic profiling, multidisciplinary case discussions, and targeted therapies. We describe key learnings from the setup of WAYFIND-R (NCT04529122), a first-of-its-kind global cancer registry collecting RWD from patients with solid tumors who have undergone NGS-based genomic profiling. The meaning of 'generalizability' and 'high quality' for RWD across different geographic areas was revisited, together with patient recruitment processes, and data sharing and privacy. Inspired by these learnings, WAYFIND-R's design will help physicians discuss patient treatment plans with their colleagues, improve understanding of the impact of treatment decisions/cancer care processes on patient outcomes, and provide a platform to support the design and conduct of further clinical/epidemiologic research. WAYFIND-R demonstrates user-friendly, electronic case report forms, standardized collection of molecular tumor board-based decisions, and a dashboard providing investigators with access to local cohort-level data and the ability to interact with colleagues or search the entire registry to find rare populations. Overall, WAYFIND-R will inform on best practice for NGS-based treatment decisions by clinicians, foster global collaborations between cancer centers and enable robust conclusions regarding outcome data to be drawn, improve understanding of disparities in patients' access to advanced diagnostics and therapies, and ultimately drive advances in precision oncology.

Gene-environment interactions and the complexity of human genetic diseases.

In the assessment of mortality and morbidity risk, the ability of family history and genetic test results to predict the age of occurrence, severity, and long-term prognosis of 'genetic' diseases is important. An increasing number of gene-gene and gene-environment interactions have been demonstrated in a number of monogenic Mendelian diseases. These interactions can significantly modify the clinical presentation (disease phenotype) of diseases previously regarded purely as 'genetic.' As a result, 'genetic' diseases can be positioned in a continuum between classic Mendelian and complex disease where the extremes, pure genetic or solely non-genetic, do not exist. The position of any given disease in this continuum is defined by three components: the major gene(s) contributing to the phenotype, the variability added by modifier genes and the significance of environmental factors influencing the phenotype. As the predictive value of genetic test results can be significantly influenced by additional genetic and environmental risk factors, a better understanding of these factors may influence the quantification of mortality and morbidity risk.

Promoter choice determines splice site selection in protocadherin alpha and gamma pre-mRNA splicing.

A family of mammalian protocadherin (Pcdh) proteins is encoded by three closely linked gene clusters (alpha, beta, and gamma). Multiple alpha and gamma Pcdh mRNAs are expressed in distinct patterns in the nervous system and are generated by alternative pre-mRNA splicing between different "variable" exons and three "constant" exons within each cluster. We show that each Pcdh variable exon is preceded by a promoter and that promoter choice determines which variable exon is included in a Pcdh mRNA. In addition, we provide evidence that alternative splicing of variable exons within a gene cluster occurs via a cis-splicing mechanism. However, virtually every variable exon can engage in trans-splicing with constant exons from another cluster, albeit at a far lower level.