Here we present the pathology workflow of the Mutographs project, a 7-year, multicancer genomics initiative led by the Sanger Institute and funded by Cancer Research UK. Mutographs aims to elucidate global differences in cancer incidence through whole-genome sequencing and mutational signature analysis of selected cancers with unexplained variation of incidence rate worldwide. The Protocol was developed by the International Agency for Research on Cancer, where pathology assessment and paired tumor-blood DNA extraction were performed. We provide details for handling frozen cancer tissues for multistep pathology evaluation and quality control, tumor-enrichment methods (such as macrodissecion and laser-capture microdissection) for certain tumor types, and manual and automated DNA extraction. This Protocol has achieved an overall success rate of 88% in providing high-quality DNA for whole-genome sequencing, aiding in the decision to exclude low-quality or noneligible tissues. This Protocol provides a reproducible, fully integrated pathology-molecular pipeline in challenging conditions to ensure high-quality DNA and reliable data interpretation at an unprecedented multinational scale and could be considered a model for high-quality tissue processing in international genomics initiatives. It is based on routine practice of pathology and requires practical experience of processing frozen tissues and morphological assessment of frozen tissues by digital pathology.
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