The prevalence of HLA‐I LOH in Chinese pan‐cancer patients and genomic features of patients harboring HLA‐I LOH

Abstract

HLA‐I LOH may facilitate immune evasion. However, large population studies on the prevalence of HLA‐I LOH across different cancer types and in relation to mutational profiles are lacking, in particular, in the Chinese population. In this study, analysis was performed in 1504 advanced pan‐cancer patients and 134 early‐stage non‐small‐cell lung cancer patients using a 1021‐gene panel. The consistency between the 1021‐gene panel and whole‐exome sequencing was evaluated in 45 samples, where concordant results were obtained in 95.6% (43/45) of the samples. Analytical results revealed that the prevalence of HLA‐I LOH in tumor tissue presents considerable differences across cancer types. HLA‐I LOH was relevant to genomic instability, reflected in higher tumor mutation burden level. HLA‐I LOH occurs more frequently in MSS samples than in MSI‐H samples. The alteration frequencies of p53 pathway, RTK/RAS pathway, Notch pathway, Hippo pathway, and Nrf2 pathway in HLA‐I LOH group were significantly higher than that in HLA‐I stable group (p < .0001, p < .0001, p = .032, p = .013, p = .003, respectively). In DNA damage response pathways, alterations in the checkpoint factor pathway and Fanconi anemia pathway are enriched in HLA‐I LOH group (p < .0001, p = .023, respectively). Besides, HLA‐I LOH was accompanied by higher mutation rates of several tumor suppressors, including TP53 and LRP1B. These results may shed light on follow‐up tumor immunology research.

Integrated investigation of the prognostic role of HLA LOH in advanced lung cancer patients with immunotherapy

“…(Figures 1B,C and Supplementary Table S1). The frequency of HLA LOH in lung adenocarcinomas (LUAD) was lower than in lung squamous cell carcinomas (LUSC) (Figure 1D), which was consistent with previous studies (Zhao et al, 2021).…”

“…Compared with LUAD, the frequency of HLA LOH in LUSC was higher, which suggested that HLA LOH may have different effects on the efficacy of ICIs in LUAD and LUSC ( Zhao et al, 2021 ). Therefore, the predictive effect of HLA LOH on immunotherapy in NSCLC with different pathological classifications was further analyzed.…”

“…Compared with LUAD, the frequency of HLA LOH in LUSC was higher, which suggested that HLA LOH may have different effects on the efficacy of ICIs in LUAD and LUSC (Zhao et al, 2021).…”

Immune Subtypes in LUAD Identify Novel Tumor Microenvironment Profiles With Prognostic and Therapeutic Implications

“…Recently, anti-tumor immunity of LUAD patients (15)(16)(17), tumor immunogenicity (5, 6, 10-12, 16, 18-20), and tumor immune microenvironment (TME) (7,11,14,18,19,21) are also reported to modulate the therapeutic impact of ICIs. Several biomarkers, including tumor mutational burden (TMB) (11), blood tumor mutational burden (bTMB) (22), human leukocyte antigens (HLA) loss-of-heterozygosity (LOH) status (20), and murine double minute 2/4 (MDM2/ MDM4) amplification (23), which could affect the adaptive immune response to the tumors, have been widely studied to be associated with the efficacy of ICI therapy in LUAD patients.…”

“…Moreover, the proportion of the C3 inflammatory IS (179 patients, 39.2%) was the most common IS observed in the TCGA LUAD cohort, whereas C1 was particularly dominant in LUSC (273 patients, 57.1%). Other ISs were less commonly encountered in the TCGA NSCLC cohort, such as the C1 Wound healing (83 patients, 18.2%), C4 Lymphocyte depleted(20…”