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Jinglong Wang
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P60 - Tumor Biology and Systems Biology - Basic and Translational Science - Immune Bio (ID 198)
- Event: WCLC 2020
- Type: Posters
- Track: Tumor Biology and Systems Biology - Basic and Translational Science
- Presentations: 1
- Moderators:
- Coordinates: 1/28/2021, 00:00 - 00:00, ePoster Hall
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P60.04 - The Association of Patient HLA Class I Genotype and Genomic Alterations of Non-Small Cell Lung Cancer (ID 1720)
00:00 - 00:00 | Presenting Author(s): Jinglong Wang
- Abstract
Introduction
Cancer immunotherapy, especially immune checkpoint inhibitors (ICIs), has provided a remarkable antitumor effect in non‐small cell lung cancer (NSCLC), but only a limited number of patients can derive durable benefit. The human leukocyte antigen class I (HLA-I) genotype has been linked with differential immune responses to infectious diseases, and previous studies have demonstrated that heterozygosity at the highly polymorphic HLA-I loci determines ICI response as heterozygous HLA-I genotypes facilitate presentation of a more diverse set of tumor antigens to T cells. However, the distribution of heterozygous HLA-I genotypes and its relationship with genomic alterations and tumor mutational burden (TMB) remain elusive.
Methods
Formalin-fixed, paraffin-embedded (FFPE) tumor samples were collected from 4659 Chinese patients with NSCLC and subjected to a clinical-grade next-generation sequencing (NGS)-based 450 gene panel test from December 2017 to January 2019. Genomic alterations were assessed by next-generation sequencing assay with a mean coverage of 1000X, including single base substitution, short and long insertion/deletions, copy number variations, gene fusions and rearrangements and tumor mutational burden (TMB) values were calculated. HLA-I genotyping was assessed by 450 gene panel and patients were considered fully heterozygous at HLA-I if they had six different HLA-I alleles.
Results
Heterozygous HLA-I genotypes were detected in 77.7% of patients with NSCLC, while 22.3% patients harboring homozygous HLA-I genotypes including 13.4% HLA-A, 5.9% HLA-B and 10.4% HLA-C. There was no statistical difference in baseline characteristics between the heterozygous and homozygous HLA-I genotypes groups except histological type. Compared with patients with homozygous HLA-I genotypes, those with heterozygosity at HLA-I locus were associated with a significantly lower tumor mutational burden (TMB) (4.6 vs. 4.3 muts/Mb, p=0.009) and 22.4% of them were classified as TMB-H (TMB ≥ 10 muts/Mb). The profiling of genomic alteration varied between patients with heterozygosity or homozygosity at HLA-I locus. Alterations of ALK, RET, NOTCH2 and NOTCH4 occurred more frequently in heterozygous HLA-I genotypes group while alterations of ATR, BTK, HDAC9 and RUNX1 occurred more frequently in homozygous HLA-I genotypes group. Previous reports indicated that HLA-B44 supertype might be favorable predictor of the response of ICIs. HLA-B44 supertype occurred in 34.5% of patients in our cohort, most common in squamous cell lung cancer (40.4%), followed by lung adenocarcinoma (33.5%) and other type NSCLC (36.6%). In addition, EGFR and MDM2 alterations were significantly less common in patients with HLA-B44 supertype (B44 (+)) compared to the B44 (-) patients (p=0.004 & p=0.011, respectively).
Conclusion
Heterozygosity at HLA-I loci was found in 77.7 % of Chinese patients with NSCLC and 17.4% of NSCLC patients who were heterozygous at each class I locus and whose tumors had high mutation burden were identified in our cohort. Patients with B44 superfamily alleles were found in 34.5% of patients in our cohort and were associated with lower frequency of EGFR and MDM2 alterations.
