Utility of whole exome sequencing analysis in differentiating intrapulmonary metastatic multiple ground-glass nodules (GGNs) from multiple primary GGNs

Abstract

Purpose Clinical evidence of metastasis with ground-glass nodules (GGNs) has been reported, including pulmonary metastasis and distant metastasis. However, the clonal relationships of multiple GGNs at the genetic level remain unclear. Experimental design Sixty tissue specimens were obtained from 19 patients with multiple GGN lung cancer who underwent surgery in 2019. Whole exome sequencing (WES) was performed on tissue samples, and genomic profiling and clone evolution analysis were conducted to investigate the genetic characteristics and clonality of multiple GGNs. Results A total of 15,435 nonsynonymous mutations were identified by WES, and GGNs with shared nonsynonymous mutations were observed in seven patients. Copy number variant (CNV) analysis showed that GGNs in ten patients had at least one shared arm-level CNV. Mutational spectrum analysis showed that GGNs in three patients had similar six substitution profiles and GGNs in fou patients had similar 96 substitution profiles. According to the clone evolution analysis, we found that GGNs in five patients had shared clonal driver gene mutations. Taken together, we identified that 5 patients may have multiple primary GGNs without any similar genetic features, 2 patients may have intrapulmonary metastatic GGNs with ≥ 3 similar genetic features, and the other 12 patients cannot be determined due to insufficient evidences in our cohort. Conclusions Our findings suggest that the intrapulmonary metastasis exist in multiple GGNs, but the number of GGNs was not associated with the probability of metastasis. Application of genomic profiling may prove to be important to precise management of patients with multiple GGNs.

Towards the molecular era of discriminating multiple lung cancers

“… aCGH for CNVs Girard [2009] 42 Arai [2012] 43 Liu [2016] 44 Sun [2018] 26 Vincenten [2019] 45 Noise: 8% (2/24 pairs); Equivocal calculation: 18% (4/22 pairs) 0% 33% (2/6) 0% 17% (7/41 pairs) 22% (4/18 pairs) 17% (2/12) 25% (1/4) 35% (7/20 pairs) 38% (13/34 pairs) Acceptable accuracy of discrimination; Wide detection range. Low throughput WES for CNVs Zhou [2022] 46 63% (12/19) NA Acceptable accuracy of discrimination; High throughput; Wide detection range. Mate-pair NGS for rearrangements Murphy [2014] 47 Murphy [2019] 48 0% 0% 27% (3/11) 24% (9/37) Complex bioinformatic analysis MicroRNA qRT-PCR for 5 miRNAs Zhou [2016] 49 0% 25% (6/24) Simple operation; Help reveal the post-transcriptional regulation in MLCs Unproven accuracy Dynamic change of miRNA and overlap between individuals doubt the reliability.…”

“…In most circumstance, they are considered as MPLCs, 7 however, differential diagnosis is still in need since some appear to be IPMs based on genomic profiles. 46 , 70 , 71 , 89 , 90 Moreover, patients with multiple GGNs have been found to exhibit no-response to PD-1 inhibitors, negative PD-L1 expression, downregulation of HLA-related genes, and defective T-cell functions. 91 In these patients, testing negative or low-level TME markers would hardly benefit the differential diagnosis.…”

Multidimensional biological characteristics of ground glass nodules

“…Clinical decisions regarding the treatment of SM-GGNs are complicated by the difficulty in distinguishing synchronous multiple primary lung cancers from intrapulmonary metastases. According to some studies, SM-GGNs may have a common origin, and intrapulmonary metastasis may occur even in the early stages of lung cancer ( 11 , 31 , 40 ). However, some studies have found that SM-GGNs mostly originate independently ( 28 , 33 ).…”

Multiple primary lung cancer: Updates and perspectives

“…Multiple ground glass nodules (GGNs) represent a distinct subtype of LUAD characterized by favorable prognosis, rare occurrence of metastases, and pathology diagnosis often falling into categories such as AIS, MIA, or LPA. Recent studies have demonstrated that most multiple GGNs are unrelated clones, 44,45 yet several studies identified explicit metastatic foci among GGNs, 46,47 even between AIS and AAH, 48 considering STAS. AIS or MIA are usually treated as separate tumors, 49 the impact of potential metastatic foci on prognosis remains underexplored, lacking sufficient evidence to prompt alterations in clinical decision-making.…”