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Tumor mutational burden assessment and standardized bioinformatics approach using custom NGS panels in clinical routine. | LitMetric

AI Article Synopsis

  • Scientists found that tumors with a lot of mutations (high TMB) respond better to a special cancer treatment called pembrolizumab.
  • They created a new way to measure TMB using their own tests and compared it to another test called FoundationOne®.
  • Their new method showed different results, and they think their TMB measurement can be adjusted for different types of tests and tumor samples.

Article Abstract

Background: High tumor mutational burden (TMB) was reported to predict the efficacy of immune checkpoint inhibitors (ICIs). Pembrolizumab, an anti-PD-1, received FDA-approval for the treatment of unresectable/metastatic tumors with high TMB as determined by the FoundationOne®CDx test. It remains to be determined how TMB can also be calculated using other tests.

Results: FFPE/frozen tumor samples from various origins were sequenced in the frame of the Institut Curie (IC) Molecular Tumor Board using an in-house next-generation sequencing (NGS) panel. A TMB calculation method was developed at IC (IC algorithm) and compared to the FoundationOne® (FO) algorithm. Using IC algorithm, an optimal 10% variant allele frequency (VAF) cut-off was established for TMB evaluation on FFPE samples, compared to 5% on frozen samples. The median TMB score for MSS/POLE WT tumors was 8.8 mut/Mb versus 45 mut/Mb for MSI/POLE-mutated tumors. When focusing on MSS/POLE WT tumor samples, the highest median TMB scores were observed in lymphoma, lung, endometrial, and cervical cancers. After biological manual curation of these cases, 21% of them could be reclassified as MSI/POLE tumors and considered as "true TMB high." Higher TMB values were obtained using FO algorithm on FFPE samples compared to IC algorithm (40 mut/Mb [10-3927] versus 8.2 mut/Mb [2.5-897], p < 0.001).

Conclusions: We herein propose a TMB calculation method and a bioinformatics tool that is customizable to different NGS panels and sample types. We were not able to retrieve TMB values from FO algorithm using our own algorithm and NGS panel.

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Source
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC10880437PMC
http://dx.doi.org/10.1186/s12915-024-01839-8DOI Listing

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