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Detecting Somatic Genetic Alterations in Tumor Specimens by Exon Capture and Massively Parallel Sequencing
Published on: October 18, 2013
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Estimating tumor mutational burden across multiple cancer types using whole-exome sequencing
Chuang Zhou1, Song Chen2, Fei Xu3
1Department of Hepatobiliary Pancreatic Surgery, the First Affiliated Hospital of Zhengzhou University, Zhengzhou, China.
Annals of Translational Medicine
|November 4, 2021
Summary
Tumor mutational burden (TMB) shows promise in immune checkpoint inhibitor (ICI) therapy, but thresholds vary by cancer type. TMB may predict ICI benefit in colorectal cancer but not all cancers in Chinese patients.
Area of Science:
- Oncology
- Genomics
- Immunotherapy
Background:
- Tumor mutational burden (TMB) is a key biomarker for immune checkpoint inhibitor (ICI) therapy effectiveness.
- Whole-exome sequencing (WES) is the gold standard for TMB, but targeted panels are more common due to cost and complexity.
- Establishing appropriate TMB thresholds for different cancers remains a challenge.
Purpose of the Study:
- To investigate the utility of whole-exome sequencing-derived tumor mutational burden (TMB) as a predictive biomarker for immune checkpoint inhibitor (ICI) therapy across diverse cancer types.
- To evaluate the impact of different TMB stratification methods (fixed threshold vs. tertile) on survival outcomes in patients receiving ICI therapy.
- To determine if TMB can reliably predict ICI treatment benefit in a Chinese patient cohort.
Main Methods:
- Whole-exome sequencing (WES) was performed on tumor and matched blood samples from 309 patients receiving ICI therapy across five cancer types.
- Somatic mutations were identified to calculate TMB, defined as nonsynonymous mutations per megabase (Mb) of tumor exome.
- Patients were categorized into TMB-high and TMB-low groups using a fixed threshold (10 mutations/Mb) and the top tertile within each cancer type for survival analysis.
Main Results:
- WES-derived TMB varied significantly across cancer types, with colorectal cancer (CRC) showing the highest median TMB (4.64 mutations/Mb).
- In CRC, high TMB was significantly associated with improved survival regardless of the threshold method used.
- In hepatocellular carcinoma, the 10 mutations/Mb threshold was more advantageous than the top tertile. No significant survival differences were observed for nervous system tumors, cholangiocarcinoma, or gastric cancer between high and low TMB groups.
Conclusions:
- The optimal TMB threshold for predicting ICI therapy response differs across cancer types.
- TMB is not a universal predictor of ICI benefit in the studied Chinese patient population.
- TMB may serve as a valuable biomarker for predicting clinical benefit from ICI therapy specifically in colorectal cancer patients.
