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Peer-reviewedCC BY-NC-NDBMC cancer

Integrated genomic analysis of tumor mutational burden reveals heterogeneous immunotherapy outcomes in head and neck cancer.

  • Yan Chen1
  • Tiantian Han2,3
  • Xiaotong Xi2,3
  • Dongsheng Chen2,3
  • Qin Zhang2,3
  • Xing Zhang4,5
  • Zixiong Lei6
6 affiliations
  1. 1Department of Oncology, Xijing Hospital of Air Force Medical University, Xi'an, 710032, China.
  2. 2State Key Laboratory of Neurology and Oncology Drug Development, Jiangsu Simcere Diagnostics Co., Ltd, Nanjing, 210042, China.
  3. 3Department of Medicine, Nanjing Simcere Medical Laboratory Science Co., Ltd, Nanjing, 210042, China.
  4. 4State Key Laboratory of Neurology and Oncology Drug Development, Jiangsu Simcere Diagnostics Co., Ltd, Nanjing, 210042, China. [email protected].
  5. 5Department of Medicine, Nanjing Simcere Medical Laboratory Science Co., Ltd, Nanjing, 210042, China. [email protected].
  6. 6The Third Affiliated Hospital of Southern Medical University, Guangzhou, 510630, China. [email protected].
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Abstract

Background

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.Methods

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.Results

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.Conclusions

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.

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Cite

BibTeXRIS
BibTeX
@article{chen2026integrated,
  title = {{Integrated genomic analysis of tumor mutational burden reveals heterogeneous immunotherapy outcomes in head and neck cancer.}},
  author = {Yan Chen and Tiantian Han and Xiaotong Xi and Dongsheng Chen and Qin Zhang and Xing Zhang and Zixiong Lei},
  journal = {BMC cancer},
  year = {2026},
  month = aug,
  doi = {10.1186/s12885-026-16012-3},
  url = {https://europepmc.org/article/MED/43009817},
  note = {CC BY-NC-ND},
}
RIS
TY  - JOUR
TI  - Integrated genomic analysis of tumor mutational burden reveals heterogeneous immunotherapy outcomes in head and neck cancer.
AU  - Yan Chen
AU  - Tiantian Han
AU  - Xiaotong Xi
AU  - Dongsheng Chen
AU  - Qin Zhang
AU  - Xing Zhang
AU  - Zixiong Lei
PY  - 2026
DA  - 2026/08/12
JO  - BMC cancer
DO  - 10.1186/s12885-026-16012-3
UR  - https://europepmc.org/article/MED/43009817
AB  - Background  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.Methods  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.Results  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.Conclusions  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.
SN  - 1471-2407
ER  -