多原发肺癌（MPLC）合并淋巴结转移（LNM）是一种罕见的多中心肺癌现象。MPLC的基因组景观以及原发性肺部病变和淋巴结转移之间的克隆演化模式尚未得到充分说明。我们对11名MPLC合并LNM患者的52个Formalin-fixed Paraffin-Embedded（FFPE）样本进行了全外显子组测序（WES）。进行了基因组分析和系统进化分析以推断每个患者的进化轨迹。我们研究中最常见的5个基因突变是TTN（76.74％），MUC16（62.79％），MUC19（55.81％），FRG1（46.51％）和NBPF20（46.51％）。对于我们研究中的大多数患者，在同一患者的多个肺肿瘤之间，大量基因变异是相互独立的，说明它们具有异源性。就单个患者而言，淋巴结转移病灶的基因组学资料在不同程度上与多个肺癌有重叠，但与特定肺部病灶有更高的遗传关联性。SETD2是MPLC的潜在转移生物标记物。原发性肿瘤的平均假定新抗原数（646.5）比淋巴结转移病灶（300，p = 0.2416）更高。原发性肺肿瘤和淋巴结转移在免疫库存方面高度异质性。我们的研究描绘了MPLC合并LNM的全面基因组景观。我们描述了不同肿瘤之间的基因组异质性。我们提供了MPLC和其淋巴转移之间的克隆演化的新线索，从而推进了MPLC合并LNM的治疗策略和预防方法。 ©2023作者。

Multiple primary lung cancer (MPLC) with lymph node metastasis (LNM) is a rare phenomenon of multifocal lung cancer. The genomic landscapes of MPLC and the clonal evolution pattern between primary lung lesions and lymph node metastasis haven't been fully illustrated. We performed whole-exome sequencing (WES) on 52 FFPE (Formalin-fixed Paraffin-Embedded) samples from 11 patients diagnosed with MPLC with LNM. Genomic profiling and phylogenetic analysis were conducted to infer the evolutional trajectory within each patient. The top 5 most frequently mutated genes in our study were TTN (76.74%), MUC16 (62.79%), MUC19 (55.81%), FRG1 (46.51%), and NBPF20 (46.51%). For most patients in our study, a substantial of genetic alterations were mutually exclusive among the multiple pulmonary tumors of the same patient, suggesting their heterogenous origins. Individually, the genetic profile of lymph node metastatic lesions overlapped with that of multiple lung cancers in different degrees but are more genetically related to specific pulmonary lesions. SETD2 was a potential metastasis biomarker of MPLC. The mean putative neo-antigen number of the primary tumor (646.5) is higher than that of lymph node metastases (300, p = 0.2416). Primary lung tumors and lymph node metastases are highly heterogenous in immune repertoires. Our findings portrayed the comprehensive genomic landscape of MPLC with LNM. We characterized the genomic heterogeneity among different tumors. We offered novel clues to the clonal evolution between MPLC and their lymphatic metastases, thus advancing the treatment strategies and preventions of MPLC with LNM.© 2023. The Author(s).