Abstract 5232: Next-generation sequencing revealed clonal architecture and faciliated diagnosis of patients with multiple lung tumors: An analysis of 12 cases

Abstract

Abstract Diagnosing multiple lung tumors as multiple primary lung cancer (MPLC) or intrapulmonary metastasis (IPM) has important therapeutic implications. The clinical applicability of next-generation sequencing (NGS) has been explored, although there is currently no consensus regarding how to integrate its findings for cancer staging. We performed a retrospective analysis of the mutational landscape of 13 patients with multiple tumors and underwent surgery at Renmin Hospital of Wuhan University from Sep. 2018 to Dec. 2020.The cohort consisted mostly of women (11/13, 84.6%) and non-smokers (12/13, 92.3%). Median age was 58 years (range 26-71). No patient manifested relapse after a median follow-up duration of 11.2 months (range 8.2-36.0). NGS was performed with a large panel (≥ 350 genes) in most cases (11/13, 84.6%). Most nodules were invasive adenocarcinomas (25/41, 61.0%), followed by adenocarcinomas in situ (13/41, 31.7%), and minimally invasive adenocarcinomas (3/41, 7.3%). Four patients were clinically diagnosed with IPM, of whom 1 had only one nodule sequenced. Of the 12 patients with genomic profiles from multiple nodules, 10 (83.3%) had consistent NGS inference and clinical diagnosis of MPLC or IPM. Of the remaining two, P1 was clinically diagnosed with IPM but NGS did not detect any genomic aberrations from one nodule, which may have missed evidence that could have led to inference of clonal relationship. P8 was diagnosed with MPLC but had two nodules that harbored EGFR L858R mutation. NGS revealed clonal relationships that enabled high-confidence differential diagnosis in the concordant cases. For instance, the 3 nodules in P10 each harbored an oncogenic driver: EGFR exon 19 deletion, EGFR L858R, and ALK fusion, which were suggestive of tumor clones of separate origins. Similar mutual exclusion was also observed in P6 (EGFR exon 19 deletion vs L858R), P2 (EGFR exon 19 deletion vs MAP2K1), and P7 (2 EGFR exon 18 mutations G719A and E709 in one nodule vs EGFR E746_A750del in another). On the other hand, P9 illustrates a case of complex clonal architecture, in which 8 nodules were derived from 5 origins. Further analysis found that alterations in KRAS were associated with smaller nodule size, whereas those in TP53, CDKN2A, NKX2-1, or GNAS were associated with greater size.In summary, NGS achieved highly concordant MPLC/IPM differentiation with clinical diagnosis based on histopathologic and radiographic evidence. However, caution is warranted when NGS detects no aberration from any of the multiple sequenced nodules. Examination of the mutational landscape found that altered proto-oncogene KRAS was associated with smaller tumors whereas altered tumor suppressors TP53 and CDKN2A associated with smaller ones, suggesting different roles in these molecules play in tumor growth. Citation Format: Wenyang Jiang, Wei Wang, Luting Qiu, Xiao Zou, Zhiqiu Chen, Qing Geng. Next-generation sequencing revealed clonal architecture and faciliated diagnosis of patients with multiple lung tumors: An analysis of 12 cases [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 5232.