- 5,233 例 NSCLC 的 447 基因 NGS：MTAP 纯合缺失 5.6%，在从不/轻度吸烟者肺腺癌及伴 ALK 融合或 EGFR 突变者中更常见。
- 105 例对照 IHC：严格质控并排除肿瘤含量 ≤30% 的 NGS 结果后，一致率 97.3%；约 13% 的“缺失”病例 IHC 呈异质性染色。
- 不一致病例：非二倍体基因组致 NGS 误判 1 例；NGS 拷贝中性但 IHC 完全缺失 1 例——低肿瘤含量或亚克隆事件时 IHC 更敏感。
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摘要
甲硫腺苷磷酸化酶（MTAP）是由位于染色体 9p21 的 MTAP 基因编码的一种酶。MTAP 失活会造成一种代谢脆弱性，对靶向治疗具有意义。MTAP 缺失可在蛋白或 DNA 水平检测，但针对非小细胞肺癌（NSCLC）中这一事件的临床检测方法的特征描述仍很有限。我们回顾性分析了一个机构内 5,233 例具有 447 基因二代测序（NGS）数据（含 MTAP 编码序列全覆盖）的 NSCLC 队列，考察 MTAP 基因缺失的临床病理及基因组学相关因素。在其中 105 例的子集中，评估了 NGS 检出的 MTAP 缺失与免疫组化（IHC）MTAP 表达之间的相关性。NGS 在 5.6% 的 NSCLC 中检出 MTAP 纯合缺失；该缺失在从不吸烟/轻度吸烟患者的肺腺癌（34.8%），以及伴 ALK 融合（8.2%）或 EGFR 突变（45.9%）的病例中显著更常见。约 13% 的 MTAP“缺失”病例 IHC 呈异质性染色模式。在严格质控（包括识别出 1 例 3′ 端 MTAP 部分缺失）并排除肿瘤含量 ≤30% 肿瘤的 NGS 结果后，NGS 与 IHC 检测 NSCLC 中 MTAP 缺陷的一致率为 97.3%。其余 2 例不一致病例中，1 例为非二倍体基因组、存在多种拷贝状态，导致 NGS 判读错误；另 1 例 NGS 结果为拷贝中性，而 IHC 显示蛋白表达完全缺失。因此，在无测序改变的情况下观察到 MTAP 蛋白缺失的病例 <1%。MTAP 基因缺失似乎在具有某些分子驱动改变的 NSCLC 中富集。NGS 与 IHC 检测 NSCLC 中 MTAP 缺失可表现出极佳的一致性，而在肿瘤含量低或存在亚克隆事件时，IHC 显示出更高的敏感性。
- 447-gene NGS in 5,233 NSCLC: homozygous MTAP deletion in 5.6%, enriched in never/light-smoker adenocarcinomas and with ALK fusions or EGFR mutations.
- In 105 cases with IHC: 97.3% concordance after careful QC and excluding NGS from tumours with ≤30% tumour content; ~13% of “loss” cases showed heterogeneous IHC staining.
- Discordant cases: one non-diploid genome misinterpreted by NGS; one copy-neutral NGS with complete IHC loss — IHC more sensitive with low tumour content or subclonal events.
Scope: PubMed abstract only. The article is subscription-only (Unpaywall: closed); the publisher page showed only the abstract to this site, so full text, figures and tables were not collected.
Abstract
Methylthioadenosine phosphorylase (MTAP) is an enzyme encoded by MTAP gene on chromosome 9p21. MTAP inactivation introduces a metabolic vulnerability with implications for targeted therapy. MTAP loss may be detected at the protein or DNA level, but characterization of clinical assays for detection of this event in non-small cell lung carcinoma (NSCLC) is limited. Clinicopathologic and genomic correlates of MTAP gene deletion were examined via retrospective review of an institutional cohort of 5,233 NSCLC cases with available next generation sequencing (NGS) data for 447 genes, including full coverage of the MTAP coding sequence. A subset of 105 cases were examined to assess the correlation between MTAP deletion by NGS and MTAP expression by immunohistochemistry (IHC). Homozygous deletion of MTAP was detected in 5.6% of NSCLC by NGS and was significantly more common in lung adenocarcinomas from patients with never/light smoking history (34.8%), and concurrent ALK fusions (8.2%) or EGFR mutations (45.9%). Approximately 13% of MTAP "loss" cases showed a heterogenous staining pattern by IHC. Concordance of NGS and IHC for detection of MTAP deficiency in NSCLC was 97.3%, following careful quality control (including recognition of a single case with partial deletion of 3' MTAP) and exclusion of NGS results from tumors with ≤30% tumor content. The remaining two discordant cases included one case with non-diploid genome and multiple copy states resulting in an incorrect NGS interpretation and one case with copy neutral NGS result and complete loss of protein expression by IHC. MTAP protein loss was therefore observed in the absence of a sequencing alteration in <1% of cases. MTAP gene deletion appears enriched in NSCLC with certain molecular drivers. NGS and IHC can show excellent concordance for detection of MTAP loss in NSCLC, with IHC showing superior sensitivity in the context of low tumor content or subclonal events.