Comparative mutational evaluation of multiple lung cancers by multiplex oncogene mutation analysis

Abstract

In patients presenting with synchronous or metachronous multiple lung cancer (MLC), it is important to distinguish between multiple primary lung cancer (MP) and intrapulmonary metastasis (IM). The present study was aimed at investigating the mutational profiles of synchronous/metachronous MLC and to compare the classification of paired tumors by multiplex gene mutation analysis with the histopathological evaluation. We carried out targeted sequencing of 20 lung cancer‐related oncogenes using next‐generation sequencing (NGS) in 82 tumors from 37 MLC patients who underwent surgical resection at our department. The patients were diagnosed as MP or IM cases based on the Martini and Melamed criteria, histopathological and gene mutational evaluations. Matching mutations between paired tumors was observed in 20 (54%) patients, who were diagnosed as IM cases by mutational evaluation. Patients who could not be clearly diagnosed by histopathological evaluation were classified as equivocal cases. Among the histopathological IM cases (n = 7), six (86%) were confirmed as IM cases also by mutational evaluation, and most of the paired tumors of these cases (n = 5) harbored multiple matching mutations. Among the histopathological MP cases (n = 17), mutational evaluation yielded a discordant diagnosis in eight (47%) cases. Of these, the paired tumors of four cases harbored multiple matching mutations, suggesting that the mutational diagnosis might be more suitable in these patients. Our findings suggest that multiplex mutational analysis could be a useful complementary tool for distinguishing between MP and IM in addition to histopathological evaluation.

Application of large-scale targeted sequencing to distinguish multiple lung primary tumors from intrapulmonary metastases

“…2 ) of the tumors from all patients were generated. EGFR alteration was the most frequently detected (77%), which was observed in 93.75% of patients (15/16), followed by TP53 alteration (32%), consistent with a previous study on multiple lung cancers reported in 2018 24 . Notably, RBM10 exhibited a significantly high mutation frequency (eight tumors, 25%) in stage I–II adenocarcinomas (32 tumors) (Fig.…”

“…Considering that lung cancer usually displays a series of histological subtypes, different lesions often share overlapping histological features, which suggests that the morphology of MLC might not always be completely different. Therefore, the histological similarity between different tumors might be suggestive rather than conclusive 22 , 24 . In addition, lymph node metastases revealed that the two lesions were generated from the same clone.…”

<p>Multiple Primary Lung Cancers: A New Challenge in the Era of Precision Medicine</p>

“…This study sequencing only 20 genes had no equivocal cases, in part because some indefinite cases sharing only one hotspot driver mutation were classified as IM. 55 In other studies, 53,54,[56][57][58] relationship of 95% of lung adenocarcinomas although the most appropriate detection number of genes remains unknown. Additionally, as shown in Table 2, the molecular classification by NGS conflicts with the histological classification in many cases, and to some extent compensates for the shortcomings of a histological classification.…”

“…Subsequently, NGS screening from 20 to 468 cancer-related genes was applied to identify MPLCs. [52][53][54][55][56][57][58] Seven small studies enrolled a total of 237 patients (range, 11 to 60) and compared the diagnostic efficacy and robustness of the molecular classification with the different histological classifications (Table 2). Overall, NGS provides better discrimination than the clinicopathological classification because it is able to classify more indefinite cases, indicating the importance of NGS.…”

“…For the latter, it is inappropriate to diagnose IM based on one common driver mutation. EGFR and KRAS have been reported to be the most frequent driver mutations, [54][55][56]58 leading to the fair probability of coincidentally sharing one hotspot driver mutation in independent primary tumors. Under these circumstances, combination with histopathology or more comprehensive genomic profiles is essential.…”