蛋白质基因组特征识别表皮生长因子受体（EGFR）和ALK野生型从不吸烟者肺腺癌的临床亚组-动脉网

Proteogenomic characterization identifies clinical subgroups in EGFR and ALK wild-type never-smoker lung adenocarcinoma

Nature 等信源发布 2024-09-19 15:53

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AbstractPatients with lung adenocarcinoma who have never smoked (NSLA) and lack key driver mutations, such as those in the EGFR and ALK genes, face limited options for targeted therapies. They also tend to have poorer outcomes with immune checkpoint inhibitors than lung cancer patients who have a history of smoking.

摘要从未吸烟（NSLA）且缺乏关键驱动突变（如EGFR和ALK基因突变）的肺腺癌患者面临有限的靶向治疗选择。与有吸烟史的肺癌患者相比，他们使用免疫检查点抑制剂的结果往往较差。

The proteogenomic profile of nonsmoking lung adenocarcinoma patients without these oncogenic driver mutations is poorly understood, which complicates the precise molecular classification of these cancers and highlights a significant area of unmet clinical need. This study analyzed the genome, transcriptome, and LC‒MS/MS-TMT-driven proteome data of tumors obtained from 99 Korean never-smoker lung adenocarcinoma patients.

没有这些致癌驱动突变的不吸烟肺腺癌患者的蛋白质基因组学特征知之甚少，这使这些癌症的精确分子分类复杂化，并突出了未满足临床需求的重要领域。这项研究分析了从99名韩国从不吸烟者肺腺癌患者获得的肿瘤的基因组，转录组和LC-MS/MS TMT驱动的蛋白质组数据。

NSLA tumors without EGFR or ALK driver oncogenes were classified into four proteogenomic subgroups: proliferation, angiogenesis, immune, and metabolism subgroups. These 4 molecular subgroups were strongly associated with distinct clinical outcomes. The proliferation and angiogenesis subtypes were associated with a poorer prognosis, while the immune subtype was associated with the most favorable outcome, which was validated in an external lung cancer dataset.

没有EGFR或ALK驱动癌基因的NSLA肿瘤分为四个蛋白质基因组亚组：增殖，血管生成，免疫和代谢亚组。这4个分子亚组与不同的临床结果密切相关。增殖和血管生成亚型与较差的预后相关，而免疫亚型与最有利的结果相关，这在外部肺癌数据集中得到了验证。

Genomic-wide impacts were analyzed, and significant correlations were found between copy number alterations and both the transcriptome and proteome for several genes, with enrichment in the ERBB, neurotrophin, insulin, and MAPK signaling pathways. Proteogenomic analyses suggested several targetable genes and proteins, including CDKs and ATR, as potential therapeutic targets in the proliferation subgroup.

分析了全基因组的影响，发现拷贝数改变与几个基因的转录组和蛋白质组之间存在显着相关性，并富集了ERBB，神经营养因子，胰岛素和MAPK信号通路。蛋白质基因组学分析表明，包括CDK和ATR在内的几种可靶向基因和蛋白质是增殖亚组的潜在治疗靶点。

Upregulated cytokines, such as CCL5 and CXCL13, in the immune subgroup may serve as potential targets for combination immunotherapy. Our comprehensive proteogenomic analysis revealed the .

免疫亚组中上调的细胞因子，如CCL5和CXCL13，可作为联合免疫治疗的潜在靶点。我们全面的蛋白质基因组学分析揭示了。

IntroductionLung cancer is the leading cause of cancer death, with an annual incidence of approximately 2 million cases worldwide1. While smoking remains the primary cause of lung cancer, never-smoker lung cancer is an increasingly concerning public health issue, particularly in Asian female populations, with its incidence steadily rising worldwide over the last several decades2.

引言肺癌是癌症死亡的主要原因，全世界每年发病率约为200万例1。虽然吸烟仍然是肺癌的主要原因，但从不吸烟的肺癌是一个越来越令人担忧的公共卫生问题，特别是在亚洲女性人群中，其发病率在过去几十年中在全球范围内稳步上升2。

Most of these cancers exhibit a biologically simple cancer network, often characterized by a single predominant oncogenic driver, such as an EGFR or ALK mutation. Blockade of these mutations by tyrosine kinase inhibitors (TKIs) typically results in an initial clinical response lasting several months2,3,4.

这些癌症中的大多数表现出生物学上简单的癌症网络，其特征通常是单一的主要致癌驱动因素，例如EGFR或ALK突变。酪氨酸激酶抑制剂（TKIs）阻断这些突变通常会导致持续数月的初始临床反应2,3,4。

However, a considerable proportion of never-smokers with lung cancer lack these identifiable major driver mutations, which poses a challenge for the application of targeted therapies.Recent clinical trials have reported markedly improved survival in lung cancer patients receiving immune checkpoint inhibitors (ICIs) either as monotherapy or in combination with cytotoxic chemotherapy5,6,7.

然而，相当一部分患有肺癌的从不吸烟者缺乏这些可识别的主要驱动突变，这对靶向治疗的应用提出了挑战。最近的临床试验报道，接受免疫检查点抑制剂（ICI）作为单一疗法或联合细胞毒性化疗的肺癌患者的生存率显着提高5,6,7。

While ICIs generally improve clinical outcomes in current- and former-smokers with lung cancer, never-smokers typically exhibit a lower tumor mutation burden (TMB) and a reduced presence of immune components, leading to limited clinical benefit from ICIs8. Never-smoker non-small cell lung cancer (NSCLC) patients often exhibit resistance to ICIs, even those with high PD-L1 expression levels.

虽然ICIs通常可以改善目前和以前吸烟者肺癌的临床结果，但从不吸烟者通常表现出较低的肿瘤突变负担（TMB）和免疫成分的减少，导致ICIs8的临床益处有限。从不吸烟的非小细胞肺癌（NSCLC）患者经常表现出对ICI的抵抗力，即使是那些PD-L1表达水平高的患者。

Despite the use of the TMB as an ICI efficacy biomarker, its clinical implementation faces challenges such as the need to acquire adequate tissue for sequencing, lengthy turnaround times, and high costs8. Moreover, an optimal cutoff value for the TMB as a predictive biomarker has yet to be determined9.In patients with never.

尽管使用TMB作为ICI功效生物标志物，但其临床实施仍面临挑战，例如需要获得足够的组织进行测序，周转时间长和成本高8。此外，TMB作为预测性生物标志物的最佳临界值尚未确定9。对于never患者。

Data availability

数据可用性

For the KNCC NSLA dataset, the raw genomic, transcriptomic, and epigenomic data were deposited in the Korean Nucleotide Archive (https://kobic.re.kr/kona) under accession IDs KAD2100075 and KAD2100133. All genomic and transcriptomic data are available from KoNA upon reasonable request. Processed datasets are provided in Supplementary Tables 1–3.

对于KNCC NSLA数据集，原始基因组、转录组和表观基因组数据保存在韩国核苷酸档案馆(https://kobic.re.kr/kona)根据登录号KAD2100075和KAD2100133。经合理要求，可从KoNA获得所有基因组和转录组数据。补充表1-3提供了经过处理的数据集。

All proteomic and phosphoproteomic data, including raw files, protein databases, and search results, were deposited in the Korea BioData Station (K-BDS) with the bioproject identifier PRJKA108675 and in the ProteomeXchange Consortium via the PRIDE partner repository with the dataset identifier PXD033360.

所有蛋白质组学和磷酸化蛋白质组学数据，包括原始文件，蛋白质数据库和搜索结果，均以生物项目标识符PRJKA108675保存在韩国生物数据站（K-BDS）中，并通过PRIDE合作伙伴存储库以数据集标识符PXD033360保存在ProteomeXchange Consortium中。

The TCGA dataset was downloaded from the Genomic Data Common (GDC) data portal (https://portal.gdc.cancer.gov/) operated by the National Cancer Institute (NCI). The raw genomic, transcriptomic, and epigenomic data were deposited in the Korean Nucleotide Archive (https://kobic.re.kr/bps/kona) under accession ID PRJKA210029.

TCGA数据集是从基因组数据公共（GDC）数据门户下载的(https://portal.gdc.cancer.gov/)由国家癌症研究所（NCI）运营。原始基因组、转录组和表观基因组数据保存在韩国核苷酸档案馆(https://kobic.re.kr/bps/kona)根据登录号PRJKA21029。

All genomic and transcriptomic data for our cohort are available from the KoNA upon request. All proteomic data, including the raw files, protein databases, and search results, were deposited in the ProteomeXchange Consortium via the PRIDE partner repository with the dataset identifier PXD033360..

我们队列的所有基因组和转录组数据均可应要求从KoNA获得。所有蛋白质组学数据，包括原始文件，蛋白质数据库和搜索结果，都通过PRIDE合作伙伴存储库保存在ProteomeXchange Consortium中，数据集标识符为PXD033360。。

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Download referencesAcknowledgementsThis work was conducted under the auspices of a Memorandum of Understanding between the Korea Institute of Science and Technology and the U.S. National Cancer Institute’s International Cancer Proteogenome Consortium (ICPC). The ICPC encourages international cooperation among institutions and nations in proteogenomic cancer research in which proteogenomic datasets are made available to the public.FundingThis study was supported by grants from the Ministry of Science and ICT through the National Research Foundation (NRF) Korea (No.

下载参考文献致谢这项工作是在韩国科学技术研究所和美国国家癌症研究所国际癌症蛋白质基因组联盟（ICPC）之间的谅解备忘录的支持下进行的。ICPC鼓励机构和国家在蛋白质基因组癌症研究方面进行国际合作，向公众提供蛋白质基因组数据集。资助这项研究得到了科学和信息通信技术部通过韩国国家研究基金会（NRF）的资助。

1731530), a grant from NRF (2021R1A2C2014410), grants from the National Cancer Center (Nos. 2211750, 2110140, 2110470, 2410921), and grants from the National Research Foundation of Korea (NRF-2017M3A9F9030559).Author informationAuthor notesThese authors contributed equally: Hyondeog Kim, Wonyeop Lee, Youngwook Kim.Authors and AffiliationsGraduate School of Cancer Science and Policy, National Cancer Center, Goyang, Gyeonggi-do, Republic of KoreaHyondeog Kim & Youngwook KimAnticancer Resistance Branch, Research Institute of National Cancer Center, Goyang, Gyeonggi-do, Republic of KoreaWonyeop Lee & Ji-Youn HanDivision of Cancer Data Science, Research Institute of National Cancer Center, Goyang, Gyeonggi-do, Republic of KoreaYoungwook KimImmuno-oncology Branch, Research Institute of National Cancer Center, Goyang, Gyeonggi-do, Republic of KoreaSang-Jin LeeCancer Molecular Biology Branch, Research Institute of National Cancer Center, Goyang, Gyeonggi-do, Republic of KoreaWonyoung ChoiCancer Diagnostics Branch, Research Institute of National Cancer Center, Goyang, Gyeonggi-do, Republic of KoreaGeon Kook LeeKorea Research Institute of Bioscience and Biotechnology, Daejeon, Republic of KoreaSeung-Jin .

1731530），NRF（2021R1A2C2014410）的资助，国家癌症中心（2211750、2110140、21104702410921）的资助，以及韩国国家研究基金会（NRF-2017M3A9F9030559）的资助。作者信息作者注意到这些作者做出了同样的贡献：Hyondog Kim，Wonyeop Lee，Youngwook Kim。作者和附属机构韩国国家癌症中心癌症科学与政策研究生院，韩国京畿道Goyang Kim&Youngwook KimAnticancer Resistance Branch，韩国国家癌症中心研究所，韩国京畿道Goyang，韩国京畿道共和国癌症数据科学研究所，韩国国家癌症中心研究所，韩国京畿道Goyang，韩国京畿道共和国国家癌症中心研究所免疫肿瘤学分会，韩国国家癌症中心研究所，韩国京畿道Goyang Jin Lee癌症分子生物学分会，韩国国家癌症中心研究所，Goyang韩国京畿道国家癌症中心研究所韩国京畿道国家癌症中心研究所韩国京畿道韩国生物科学与生物技术研究所韩国大田市癌症诊断科。

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PubMed Google ScholarContributionsStudy conception and design: H.D.K., Y.W.K., S.J.L., and J.Y.H. Data analysis: H.D.K., W.Y.L., Y.W.K., W.Y.C., S.J.L., and J.Y.H. Data collection: W.Y.L., Y.W.K., S.J.L., and J.Y.H. Manuscript preparation: H.D.K., W.Y.L., Y.W.K., W.Y.C., S.J.L., and J.Y.H.

PubMed谷歌学术贡献研究概念与设计：H.D.K.，Y.W.K.，S.J.L。和J.Y.H.数据分析：H.D.K.，W.Y.L.，Y.W.K.，W.Y.C.，S.J.L。和J.Y.H.数据收集：W.Y.L.，Y.W.K.，S.J.L。和J.Y.H.手稿准备：H.D.K.，W.Y.L.，Y.W.K.，W.Y.C.，S.J.L。和J.Y.H.（笑声）。

Interpretation of results and editing: all authorsCorresponding authorsCorrespondence to.

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Reprints and permissionsAbout this articleCite this articleKim, H., Lee, W., Kim, Y. et al. Proteogenomic characterization identifies clinical subgroups in EGFR and ALK wild-type never-smoker lung adenocarcinoma.

转载和许可本文引用本文Kim，H.，Lee，W.，Kim，Y。等人。蛋白质基因组学表征确定了EGFR和ALK野生型从不吸烟者肺腺癌的临床亚组。

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