Tumor mutational burden (TMB) status, a biomarker for multiple myeloma (MM) treatment, may be significantly inflated for Black patients compared with white patients, according to a study published in npj Precision Oncology.
High TMB status is a U.S. Food and Drug Administration approved biomarker for treatment with PD-1 inhibition. According to the authors, “The most accurate TMB estimate requires patient-paired germline sequencing to filter out non-somatic variants. However, since patient germline DNAs (e.g. peripheral blood) are not routinely collected in clinic for germline analysis, TMB is often calculated from tumor-only sequencing relying on public germline variant databases to filter out non-somatic polymorphisms.”
To assess potential racial bias deriving from the use of public databases, the investigators compared TMB estimates from germline exome sequencing data to estimates calculated using data from the 1000 Genomes Project and Exome Aggregation Consortium. Genomic sequencing data was collected from 701 patients with newly diagnosed MM enrolled in the Multiple Myeloma Research Foundation CoMMpassSM study, including 126 (18%) self-reported Black patients and 575 (82%) self-reported white patients.
TMB estimates using patient germline sequencing data were comparable Black and white patients (mean TMB, 6.09 vs. 5.47, respectively). However, when non-somatic filtering was conducted based on public databases, overall TMB estimates were significantly higher for all patients. In addition, TMB estimates for Black patients were significantly inflated compared to white patients.
“Clinicians who rely on TMB calculated from tumor-only sequencing as a biomarker for patient selection to receive ICIs need to be aware of the potential for inflated TMB values, especially in patients who are under-represented in the public genetic variant databases,” wrote the authors in conclusion.