The prevalence of HLA LOH in Chinese pan-cancer patients and its correlation with genomic alterations.

e14521 Background: Human leukocyte antigen (HLA) molecules are essential components involved in tumor antigen presentation. Loss of heterozygosity in HLA (HLA LOH) may facilitate tumor immune evasion. However, the large population study of HLALOH in Chinese pan-cancer patients remains to be explored. Methods: In this study, analysis were performed in 1504 advanced patients across 12 cancer types and 134 early-stage NSCLC patientsusing a 1021-gene panel. HLA LOH were analysis using LOHHLA algorithm. The consistency between target sequencing by 1021-gene panel and whole-exome sequencing (WES) was evaluated in 45 samples. Results: In 45 samples processed with both approaches, 95.6% (43/45) obtained concordant results. Among the 1638 patients, 24 were excluded due to homozygosity at all three HLA-Iloci. The prevalence of HLALOH in advanced patients presented considerable differences among cancer typeswith an average incidence of 45.6% (676/1482), ranging from 12.2% (prostate adenocarcinoma) to 68.0% (cervical squamous cell carcinoma). In NSCLC patients, there was an enrichment of HLALOH in both early-stage (I-IIIa) LUSC (24/88 [27.3%] of LUAD vs. 26/42 [61.9%] of LUSC, p<0.001) and advanced (IIIb-IV) LUSC. In 43.3% (293/676) patients harboring HLALOH, LOH co-occurred in HLA-A, B, and C. Consistent with previous studies, the occurrence of HLALOH was relevant to an elevated TMB level(median TMB 6.72 vs. 5.76, p<0.0001). In addition, the TMB level of patients with LOH at all three HLA-I loci was higher than those with LOH at only one HLA-I locus (median TMB 7.68 vs. 6.72, p=0.027).However, despite that MSI-H patients presented the highest incidence of TMB-H (TMB≥10.56), the incidence of HLALOH decreased in these patients. Alterations of multiple signaling pathways are enriched in HLALOH patients, including CPF (checkpoint factor) pathway, FA (Fanconi anemia) pathway, p53 pathway, RTK/RAS pathway, Notch pathway, Hippo pathway and Nrf2 pathway(p<0.0001, p=0.023, p<0.0001, p<0.0001, p=0.032, p=0.013, p=0.003, respectively, Table).Several oncogenes, such as TP53 and LRP1B, had higher alteration frequencies in the HLALOH group(p<0.001 for TP53,p<0.05 for LRP1B, Table 1). Conclusions: The 1021-gene panel could be applied for HLALOH analysis, provided that the relevant regions are well captured. The prevalence of HLALOH in Chinese cancer patients presents considerable differences across cancer types. Besides, the occurrence of HLA LOH was accompanied by higher alteration frequencies in several oncogenes and oncogenic signaling pathways. These insights may provide valuable information for clinical practice and follow-up research.[Table: see text]