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Large Genomic Profiling Study Sees Mutation-Rich Tumors From Many Cancer Types

NEW YORK (GenomeWeb) – Profiling mutations in a few hundred genes appears to be a promising method for identifying mutation-rich tumors that may respond to drugs that target the immune checkpoint pathway, according to a new research study led by Foundation Medicine.

Using their comprehensive genomic profiling (CGP) assay, researchers from Foundation Medicine and their collaborators targeted between roughly 200 and 400 cancer-related genes in tumors from nearly 102,300 individuals with a range of cancer types. As they reported online yesterday in Genome Medicine, the mutational burden identified in the tumors with CBP profiling appears to be on par with findings from broader exome sequencing analyses. Early results of the study were presented by the company at the American Society of Clinical Oncology annual meeting last June.

"Using this method, we find that many disease types have a substantial portion of patients with high [tumor mutational burden] who might benefit from immunotherapy," corresponding author Garrett Frampton, associate director of bioinformatics at Foundation Medicine, and his co-authors wrote.

For example, the team saw a jump in the mutational burden associated with tumors from older individuals and identified a subset of mutation-prone skin cancers that have alterations affecting the promoter of the mismatch repair gene PMS2.

The researchers began by using the company's FoundationOne assay to assess tumor mutations across 315 cancer-related genes in 29 tumors that had also been analyzed by matched tumor-normal exome sequencing.

In general, the number of mutations per million bases of targeted sequence lined up well in the CGP assays and exome-sequenced tumors, the team reported, though the correlation with exome-based mutations appeared to be more robust in tumors with an elevated mutational burden compared with those showing low or intermediate levels of mutation.

Similarly, the researchers found that mutations in the same set of 315 genes more or less lined up with mutations detected across the exome in more than 8,900 tumors profiled for the Cancer Genome Atlas project.

From there, the team turned its attention to 102,292 clinical tumor samples, focusing in on between 185 and more than 405 genes in 92,439 formalin-fixed, paraffin-embedded tumor samples from individuals ranging in age from less than a year to more than 89 years.

After sequencing the targeted exonic and intronic regions to an average depth of more than 500-fold coverage, the researchers considered the CGP-based mutation patterns. Their results suggest that the average mutational burden more than doubled in tumors from the elderly compared with those from pediatric cancer patients.

The team also detected mutational burden differences across cancer types, with rampant mutations observed in cancers such as melanoma or lung cancer, which are often due to mutagen exposure, compared with relatively muted mutational patterns in leukemia, lymphoma, and neuroblastoma.

The targeted sequence data also offered a glimpse at other alterations, such as microsatellite instability in the tumors, the researchers reported, along with insights into the genes and pathways that are most often mutated in tumors with enhanced overall mutational burden.

From these and other results, the authors argued that CGP "is an accurate, cost-effective, and clinically available tool for measuring [tumor mutational burden]." And with high mutational burden turning up in more than one in 10 tumors across 22 cancer types, they noted that the approach may uncover targetable neoantigens in tumors not normally considered for checkpoint blockade immunotherapy.

"These data should help to guide design of immunotherapy clinical trials across a broader range of indications," they wrote. "Currently, immunotherapies targeting CTLA-4, PD-1, and PD-L1 are approved in a small number of indications … We identified several novel disease types with high [tumor mutational burden] which may be good targets for immuno-oncology treatment development."