Abstract 5787: Identification of genomic alterations in lymphoepithelioma-like carcinoma by next-generation sequencing

Abstract Introduction: Lymphoepithelioma-like carcinoma (LELC) is a special pathological tumor exclusive to Asians and EBV infection. As LELC is rare, the genetic picture is not very clear. Our study aims to identify the genomic alterations (GAs) and novel potential predictive biomarkers for LELC by next-generation sequencing (NGS). Materials and Methods: A retrospective search was performed to retrieve the LELC samples from Queen Elizabeth Hospital (Hong Kong SAR, China). We identified 38 pathologically confirmed LELC patients with archived surgically resected samples. Of these, 22 tissue specimens had median or heavy deamination and thus did not meet the strict sequencing quality control criteria. Deep targeted sequencing was performed in 16 LELC tissues (12 stage I, 1 stage II, 2 stage III, and 1 stage IV), using a panel of 440 cancer-related genes. Results: We identified 52 mutations, including 45 missenses, 3 splice-sites, and 4 frameshifts. The 9 most frequently mutated genes were MUC6 (43.75%), MUC16 (18.75%), LRP1B (12.5%), FRG1 (12.5%), NSD1 (12.5%), KMT2C (12.5%), ATM (12.5%), KMT2D (12.5%), and MED12 (12.5%). Copy number variant (CNV) analysis identified 172 CNVs, including 163 gains, 5 amplifications, and 4 heterozygous deletions. Gene copy number gain was common (12.5%-18.75%) in chromosome 5p (FGF10, RICTOR, IL7R, ADAMTS16, SDHA, TERT), 6p (TNF, HIST1H1C, HIST1H1E), and 12p (KRAS, SLCO1B3, SLCO1B3, CCND2, FGF23, FGF6, KDM5A, RAD52, IKZF1). These GAs were associated with 8 pathways, including the cell cycle, TP53, NOTCH, PI3K/AKT/mTOR, RTK/RAS/RAF/MEK, TGF-β, β-catenin/WNT, and DNA remodeling pathways. The NGS-derived tumor mutational burden was 1.2 muts/Mb (range 0-7.1) and no tumor exhibited a microsatellite-high signature. For actionability analysis, five patients harbored deleterious or likely deleterious mutations in HRR genes (1 ARID1A, 2 ATM, 1 BRCA2, 1 RAD51C) and thus their tumors might respond to PARP inhibitors, especially two patients with biallelic loss. One patient had concomitant CDK4 and EGFR copy number gain, suggesting a necessity blockade of CDK4/6 and EGFR. Conclusion: Our data may provide insight for understanding the molecular basis underlying LELC and may help develop potential personalized targeted therapies for LELC patients. More than 31% of the LELC cases harbored at least one actionable GA, with five potential candidates for the treatment with FDA-approved drugs for other types of cancer, making the evaluation of these GAs as potential targets for LELC worth considering in future clinical trials. Given the limited treatment options in LELC patients, comprehensive genomic profiling of tumors by NGS has the potential to identify novel treatments for precision medicine in LELC management. Citation Format: William C. Cho, Ka-Po Tse, Kien-Thiam Tan, Wah Cheuk, James C. Chow, Ka M. Cheung, Shu-Jen Chen. Identification of genomic alterations in lymphoepithelioma-like carcinoma by next-generation sequencing [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 5787.