Table 4.

Representative genomic and molecular studies on MPLC within the recent 10 years.

Year	Reference	Materials	Genomic biomarker (methods)	Main Conclusions
2016	Schneider et al. PMID:27080983	60 patients with MPLCs	KRAS, EGFR, BRAF, PIK3CA, ALK, MET, ROS1, PIK3CA and p16 (mutations)	Concordance between histological and molecular staging was observed in 89% of adenocarcinomas and 56% of squamous cell carcinomas, and that the comprehensive genotypic and morphological assessment of surgically treated multifocal lung cancers is not sufficient to establish their clonal relationship and prognosis.
2016	Liu et al. PMID:27767028	6 patients with multiple synchronous lung cancers	WGS, WES and aCGH	Different lung cancers in the same individual may have distinct genomic profiles and can be driven by distinct molecular events.
2016	Yang et al. PMID:27796337	129 patients with MPLCs	EGFR, BRAF, ROS1 and KRAS mutations and EML4-ALK rearrangement	More than half of second primary lung cancers result from different mechanisms compared with primary cancers.
2017	Patel et al. PMID:28866070	11 patients with MPLCs and 8 patients with primary tumors and their metastasis	50 gene AmpliSeq Cancer Hotspot Panel v2	High mutational concordance was found in primary-metastatic pairs, and 8 of 11 MPLC patients had completely discordant mutations.
2017	Asmar et al. PMID:28647671	45 patients with primary tumors and their metastases and 69 patients with MPLCs	EGFR, KRAS, ALK and BRAF mutations	Oncogenic mutation concordance rate was 96% in patients with primary tumors and their metastase and 36% of MPLCs wrer indentified as primary by genomic profiling.
2017	Ma et al. PMID:29018192	4 patients with multiple synchronous lung cancers	WES	Each multicentric primary tumor harbors distinct oncogenic alterations, and robust evolutionary pressures can shape the expansion and constraint of genomic diversity simultaneously.
2017	Ma et al. PMID:29018192	5 patients with 18samples in the lung	Whole-exome sequencing and Clonality analysis	The results highlight the robust evolutionary pressures that simultaneously shape the expansion and constraint of genomic diversity, a principle that holds important implications for understanding tumor evolution and optimizing therapeutic strategies.
2018	Takahashi et al. PMID:30216592	37 multiple lung cancer patients	20 lung cancer‐related oncogenes mutations	Among 17 histopathological multiple priamry cases,a discordant of 47% (8 cases) was yielded by mutational evaluation. Multiplex mutational analysis could be a useful complementary tool for distinguishing between MP and IM in addition to histopathological evaluation.
2018	Roepman et al. PMID:29625247	50 patients with multiple lung lesions	50-gene panel and p53 protein expression	In 39% (19 cases) matching tumor samples, sequencing results were in contradiction to the initial immuno-histopathology diagnosis, and for about one-third of the patients, panel sequencing provided additional information to improve the differentiationbetween multiple primary lung cancers or pulmonary metastases.
2018	Chen et al. PMID:29092754	96 patients with MPLCs	EGFR, Tp53, KRAS, PIK3CA, and BRAF (somtatic mutation), and EML4-ALK, ROS1, RET (fusion gene)	A high rate of discordance of genetic alterations (89.7%) was found between cancers within individual patients.
2018	Santamaria et al. PMID:30032819	1 patient with three lung tumors	A targeted 50-gene DNA sequencing panel	Targeted DNA sequencing significantly increases diagnostic accuracy in patients with multiple lung tumors. NGS panels should be available for patients presenting with multiple lung tumors.
2018	Haratake et al. PMID:29254651	59 patients with multifocal lung cancer	PD-L1 expression	Among 43 patients with MPLC, disagreement of PD-L1 expression was i27.9% (12 patietns), and among 16 patients with pulmonary metastasis, disagreement of PD-L1 expression was 6.3% (1 patient). Higher levels of agreement of PD-L1 expression in pulmonary metastasis compared with in MPLC was found.
2019	Chang et al. PMID:31471310	60 patients with multifocal lung cancers	341-468 gene MSK-IMPACT NGS assay	Prospective histologic prediction was discordant with NGS in 17 cases (22%), particularly in the prediction of IPMs (44% discordant). Comprehensive NGS allows unambiguous delineation of clonal relationship among NSCLCs.
2019	Murphy et al. PMID:31103780	37 cases of multiple lung cancers	Mate-pair sequencing, EGFR, BRAF, KRAS, HRAS, NRAS, ALK, ERBB2, and MET (mutations) and ALK, ROS1, RET, and NTRK1 (gene fusions).	Histologic review appeared to misclassify lineage in 27% same-histology tumor pair comparisons, the highly unique nature and prevalence of chromosomal rearrangement in lung cancers provide a useful and definitive technique for calling lineage in multifocal lung cancer.
2020	Li et al. PMID:31699841	154 subsolid nodules samples from 120 patients	Whole-exome sequencing	Mutations in EGFR were the most prominent and significant variation, followed by those in RBM10, TP53, STK11 and KRAS.
2020	Higuchi et al. PMID:32093372	37 patients with multiple lung cancers	A panel covering the exons of 53 lung cancer-related genes	In multicentric primary lung cancers, the driver mutation profile was mutually exclusive among the individual tumors, while it was consistent between metastasized tumors and the primary lesion.
2021	Hu et al. PMID:34887263	112 patients with 255 tumors	1021-gene panel	MPLCs are driven by different molecular events and often exhibit low TMB, low PD-L1, and a heterogeneous immune infiltration landscape. The most frequently mutated genes were EGFR (56%), ERBB2 (12%), TP53 (12%), and BRAF (11%). 87 (77.7%) patients were with diverse genomic profiles, and 61 (54.5%) shared at least one putative driver gene between different tumors presented more aggressive tumors.
2021	Motohiro et al. PMID:33707471	17 patients with 38 specimens	409 cancer-associated genes panel	Comprehensive genetic analyses suggested different mutation profiles in tumours within the same individuals, with some exceptions. EGFR, KRAS, TP53, or PARP1 mutations were concomitantly detected in some MPLC cases.
2021	Daryn et al. PMID:33845213	40 patients with multiple lung cancers	A gene panel (Ion 318 Chip v2 or Ion 314 Chip) greater than 50 genes, including ALK, BRAF, EGFR, FGFR1, KIT, KRAS, MET, NRAS, PIK3CA, PTEN, RET, and TP53.	Mutational profiling was concordant with clinicopathologic diagnosis in most cases, and seven cases (17.5%) revealed shared mutations suggesting metastatic disease and this was associated with a substantial reduction in overall survival.
2021	Zhang et al. PMID:33820821	1 patient received immunotherapy	WES, IHC, single-cell sequencing	The genomic disparities among responding and non-responding nodules were detected at various levels, suggesting that neoadjuvant PD-1/PD-L1 inhibitors alone may not be optimal for MPLC.
2022	He et al. PDIM:35874770	3 GGOs patients	Single-cell sequencing	Cancer cells in the S components, which showed relatively malignant phenotypes, were likely to originate from both the GG and S components and monitor the surrounding tumor microenvironment (TME) through an intricate cell interaction network.
2022	Yu et al. PMID:36029220	334 resected pulmonary nodules from 262 Chinese patients	A custom 1021-gene panel, IHC, imaging data	They demonstrates a driver landscape of radiologically detectable GGO-associated pulmonary nodules in Chinese patients and supports that different driver patterns in RTK/RAS pathway are corresponding to different radiologic features.
2022	Wang et al. PMID:36531058	141 and 44 lesions from single and multiple primary lung adenocarcinoma	Next-generation sequencing-based YuanSu450TM gene panel	Mutation analysis of SP- and MP-LUAD patients could identified genomic alterations and evolutionary trajectories underlying MP-LUAD and will provide new insights into the oncogenesis of MP-LUAD and useful information for development novel approach to target MP-LUAD.