Abstract 3964: HLA typing and its association with TMB in a pan-cancer Chinese cohort study
Authors: Ran Shu, Li Bian, Ying Yang, Jian Shen, Xiaoyu Tuo, Yanxi Li, Shiyue Liu, Feilong Zhao, Ding Zhang, Zhe Yang
Journal: Cancer Research (2025)

Background: Previous studies have linked HLA-I heterozygosity to immunotherapy efficacy. Given that tumor mutational burden (TMB) is a well-established biomarker for immunotherapy, this study explores the relationships among HLA-I heterozygosity, HLA-I subtypes, and TMB. Methods: Whole exome sequencing (WES) was performed on all samples. HLA-I typing was identified using HLAscan and clustered with HLAClustRView. Mutation analysis was performed with Maftools. Results: We analyzed 810 patients, covering over 20 tumor types, with 163 in the any-homozygous group and 647 in the all-heterozygous group. No significant differences were observed between groups in age, gender, or MSI status. HLA-I subtype landscape revealed a predominance of A02 and A11 for HLA-A, B15 and B40 for HLA-B, and C03 and C01 for HLA-C. Approximately 50% of patients exhibited heterozygosity for both HLA-B and HLA-C loci, while none were heterozygous across all three loci. Utilizing the similarity distances of HLA-I gene subtypes, we categorized patients into six distinct clusters. Each cluster displayed a preference for specific tumor types, and for particular HLA-I gene subtypes. All-heterozygous patient proportion was notably higher in clusters #6, #2, and #3, and lower in cluster 4. Gene mutation analysis revealed significant enrichment of ADSS1, USP8, and MYOCD in cluster 3, as well as MUC22 in cluster 6, whereas the other clusters did not demonstrate significant mutation enrichment. HLA clusters also demonstrates a potential association with TMB (p = 0.069), where cluster 6 exhibited significantly lower TMB than the other clusters. TMB was slightly lower in the all-heterozygous group (p = 0.13). Stratified by cancer type, TMB was generally higher in the all-heterozygous group, particularly in liver cancer (p = 0.005), but lower in gastric cancer (p = 0.027). In gastric cancer, the any-homozygous group (n = 39) exhibited a higher proportion of MSI-H patients (p = 0.024), suggesting that MSI-H may contribute to TMB discrepancies. This finding also posits that HLA homozygosity may promote MSI-H occurrence. Comparative analysis of gene mutations revealed significant enrichment of 41 genes, including CSF2RB, NUP210L, and NUP214, in the any-homozygous group, with enrichment analysis linking these genes to reproductive system development, lipid localization, and HIV infection. In liver cancer, the any-homozygous (n = 14) and All-heterozygous groups (n = 70) showed no significant differences in age, sex, or MSI status. However, MUC16 and EPPK1 mutations were significantly enriched in the all-heterozygous group, while DSPP mutations were notably enriched in the Any-homozygous group (p = 0.034). Conclusion: This study illustrated HLA-I subtypes in a large Chinese pan-cancer cohort, identifying six clusters. HLA heterozygosity and clusters were associated with TMB, suggesting potential for HLA-based personalized therapy development. Citation Format: Ran Shu, Li Bian, Ying Yang, Jian Shen, Xiaoyu Tuo, Yanxi Li, Shiyue Liu, Feilong Zhao, Ding Zhang, Zhe Yang. HLA typing and its association with TMB in a pan-cancer Chinese cohort study [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2025; Part 1 (Regular Abstracts); 2025 Apr 25-30; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2025;85(8_Suppl_1):Abstract nr 3964.