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Integrated genomic analysis of tumor mutational burden reveals heterogeneous immunotherapy outcomes in head and neck cancer
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DOI：10.1186/s12885-026-16012-3.png)
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Abstract
En 中文
Head and neck cancer (HNC) is a highly heterogeneous malignancy. Immune checkpoint inhibitors have transformed the treatment landscape of head and neck cancer; however, substantial heterogeneity in clinical outcomes remains. Tumor mutational burden (TMB) is widely reported in clinical sequencing assays; however, its standalone value in guiding the use of immune checkpoint inhibitors (ICIs) remains inconsistent, and its interpretation alongside co-occurring genomic alterations is not well defined in routine practice. We retrospectively analyzed 389 Chinese patients with HNC using a 551-gene targeted sequencing panel and validated key findings in the MSKCC ICI-treated cohort. Tumor mutational burden (TMB), copy number variation (CNV), tumor fusion burden (TFB), and germline variants were comprehensively profiled to identify molecular determinants of immunotherapy efficacy. TMB-high (TMB-H, ≥ 10 mut/Mb) tumors accounted for 23% of cases and were enriched for mutations in TP53, NOTCH1, and PIK3CA, whereas TMB-low (TMB-L) tumors showed frequent CNVs, including CCND1, EGFR, and FGFR1 amplifications and CDKN2A loss. In the MSKCC cohort, integrating TMB with the mutation status of PIK3CA, TP53, NOTCH1, and FAT1 provided improved stratification of immunotherapy outcomes compared with TMB alone, highlighting the importance of genomic context when interpreting mutation burden. Additionally, higher tumor fusion burden (TFB) correlated with distinct chemosensitivity patterns, and germline variants in DNA repair genes were associated with increased somatic mutation accumulation. These findings demonstrate that immunotherapy outcomes in head and neck cancer are strongly influenced by the genomic context of tumor mutational burden. Integrated genomic analysis provides a biologically grounded framework for understanding heterogeneity in genomic-guided cancer treatment.
Keywords:
Head and neck cancer
Tumor mutational burden
Tumor fusion burden
Genomic instability
Germline variants
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