A study published in the prestigious journal Nature Communications –led by the Centro Nacional de Analisis Genómico (CNAG-CRG), located at the Barcelona Science Park (PCB), and the  German Cancer Research Center (DKFZ)– revealed a high degree of heterogeneity in how cancer genome sequencing is done at different institutions across the globe. The results of this work –carried out within the framework of the International Cancer Genome Consortium (ICGC)– lay the foundation for the coming era of cancer genomics by creating guidelines and providing new tools for achieving higher quality data, for better diagnosis and precision medicine.

The study  (doi:10.1038/ncomms10001) is the result of an effort to create reliable standards to obtain accurate results in the detection of somatic mutations, which are a hallmark of cancer genomes. Somatic mutations are genetic alterations spontaneously acquired by a cell that can be passed to the progeny of the mutated cell in the course of cell division and tumor growth. Somatic mutations differ from germline variants, which are inherited from parents to children.

The project, involving 83 researchers from 78 research institutions, identified big differences in procedures and quality of cancer genome sequencing between sequencing centers. This led to dramatic discrepancies in the number and types of gene mutations detected when using the same cancer genome sequences for analysis.

Out of >1,000 confirmed somatic single-base mutations in the cancer genome analyzed, only 40% were unanimously identified by all participating teams. Small insertions or deletions in the DNA sequence were even more challenging – only a single somatic insertion/deletion mutation out of 337 was identified in all centers (0.3%). As a consequence, the consortium has established a reference mutation dataset to assess analytical procedures. The ‘gold-set’ reference database has helped the ICGC community to improve procedures for identifying more true somatic mutations in cancer genomes while making fewer false positive calls.

As whole genome sequencing of cancer genomes is increasingly being used as a clinical tool, full understanding of the variables affecting sequencing analysis output quality is required. The key points to consider and the necessary tools for improvement are provided here. “The findings of our study have far-reaching implications for cancer genome analysis. We have found many inconsistencies in both the sequencing of cancer genomes and the data analysis at different sites. We are making our findings available to the scientific and diagnostic community so that they can improve their systems and generate more standardized and consistent results,” says Ivo Gut, senior author of the publication and director of the CNAG-CRG.

David Jones, a Senior Scientist at the DKFZ who co-led the study, commented that “as the latest technological advances in cancer genome analysis become more widely available to support personalized cancer medicine, it is vitally important that rigorous quality testing is applied to ensure accuracy and consistency of results. We hope that our study can provide a framework for this process, to help researchers in providing the best possible analysis of patients’ samples”.