Sorin Armeanu-Ebinger

Precision oncology is based on comprehensive molecular characterization of a patient's tumor. This is mostly realized by next‐generation sequencing panels or exome sequencing. Data on the value of genome sequencing from formalin‐fixed paraffin embedded (FFPE) material in a clinical setting is still scarce. In this pilot, we generated datasets of matched exome and genome sequencing of FFPE tumor samples from 15 cancer patients to benchmark quality metrics, clinical feasibility, and added value for a molecular tumor board. Despite the reduced sequencing depth, diagnostic detection of small nucleotide variations, copy number variations, and complex biomarkers was maintained in genome sequencing compared to exome sequencing with the exception of hard‐to‐sequence regions. Evaluation by the local molecular tumor board identified additional treatment recommendations with high priority in 20% (3/15) of patients and additional molecular markers to support existing treatment recommendations in another 20% (3/15) of patients. Our work underscores the diagnostic superiority of genome sequencing even for FFPE samples and therefore supports its integration into clinical practice.

Genomic events and their timing that grant a primary tumour the competence to disseminate remain poorly defined. We performed sequencing of 247 stage I/II primary cutaneous melanomas (CMs) and 60 matched metastases without intervening therapy from a prospectively followed registry cohort with a median followup of 92 months, integrating copy-number, mutational, protein and spatial-transcriptomic analyses. Relapse was not distinguished by oncogenic point mutations, which were largely shared between primaries and metastases, but by somatic copy-number alterations (SCNAs) and global chromosomal instability. We defined OncoCycle, a six-gene copy-number signature (amplification of CDK4 , MCL1 and CD276 ; biallelic loss of CDKN2A , CDKN2B and TP53BP1 ) that predicted relapse independently of established clinicopathological features in melanoma, and a pan-cancer analysis. In matched pairs, metastatic progression was driven by continued copy-number evolution and reduction in intra-tumoural heterogeneity, rather than by acquired point mutations, and OncoCycle alterations from primary tumours were preserved in metastasis seeding clones. Clonal reconstruction revealed both monoclonal and polyclonal metastasis seeding, and spatial transcriptomics resolved copy-number-defined metastatic subclones occupying and programming distinct immune and stromal niches. Thus, metastatic competence was primed early by focal SCNAs on a background of chromosomal instability, elaborated by continued copy-number evolution during dissemination and spatio-temporal interactions with the tumour-microenvironment.