Genomic Profiling and Prognostic Value Analysis of Genetic Alterations in Chinese Resected Lung Cancer With Invasive Mucinous Adenocarcinoma

Abstract

BackgroundInvasive mucinous adenocarcinoma (IMA) of the lung is a distinct histological subtype with unique clinical and pathological features. Despite previous genomic studies on lung IMA, the genetic characteristics and the prognosis-related biomarkers in Chinese surgically resected lung IMA remain unclear.MethodsWe collected 76 surgically resected primary tumors of invasive lung adenocarcinoma, including 51 IMA and 25 non-mucinous adenocarcinomas (non-IMA). IMA was further divided into pure-IMA (mucinous features≥90%) and mixed-IMA subgroups. Comprehensive genomic profiling based on targeted next-generation sequencing (NGS) of 425 genes was explored and genomic characteristics were evaluated for the correlation with postoperative disease-free survival (DFS).ResultsIMA had a unique genetic profile, with more diverse driver mutations and more tumor drivers/suppressors co-occurrence than that of non-IMA. The frequency of EGFR (72.0% vs. 40.0% vs. 23.1%, p=0.002) and ALK (undetected vs. 20.0% vs. 26.9%, p=0.015) alterations showed a trend of gradual decrease and increase from non-IMA to mixed-IMA to pure-IMA, respectively. The frequency of KRAS mutations in pure-IMA was higher than that in mixed-IMA, albeit statistically insignificant (23.1% vs. 4.0%, p=0.10). TP53 mutation was significantly less in pure-IMA compared to mixed-IMA and non-IMA (23.1% vs. 52.0% vs. 56.0%, p=0.03). Besides, IMA exhibited less arm-level amplifications (p=0.04) and more arm-level deletions (p=0.004) than non-IMA, and the frequency of amplification and deletion also showed a trend of gradual decrease and increase from non-IMA to mixed-IMA to pure-IMA, respectively. Furthermore, prognosis analysis in stage III IMA patients showed that patients harboring alterations in EGFR (mDFS=30.3 vs. 16.0 months, HR=0.19, P=0.027) and PI3K pathway (mDFS=36.0 vs. 16.0 months, HR=0.12, P=0.023) achieved prolonged DFS, while patients with poorly differentiated tumors (mDFS=14.1 vs. 28.0 months, HR=3.75, p=0.037) or with KRAS mutations (mDFS=13.0 vs. 20.0 months, HR=6.95, p=0.027) had shorter DFS. Multivariate analysis showed that KRAS mutations, PI3K pathway alterations, and tumor differentiation status were independent factors that have statistically significant influences on clinical outcomes of IMA patients.ConclusionOur study provided genomic insights into Chinese surgically resected lung IMA. We also identified several genomic features that may serve as potential biomarkers on postoperative recurrence in IMA patients with stage III disease.

Clinical features and prognosis of resectable pulmonary primary invasive mucinous adenocarcinoma

“…IMA is regarded as a distinct pathological type of LUAD based on its unique clinical and genetic features (17). However, while there have been many studies on the prognosis of pulmonary IMA, the conclusions among these studies have been highly contradictory.…”

Prognosis of resected invasive mucinous adenocarcinoma compared with the IASLC histologic grading system for invasive nonmucinous adenocarcinoma: Surgical database study in the TKIs era in Korea

“…Due to this difference, the RFS and OS results were different from those of previous studies. The clinical outcome of IMA has been controversial 10,23,30,31 due to its low incidence, which is approximately 1.5% of total lung cancers. 27 Lee et al reported a relatively favorable prognosis of IMA and that it was better than acinar or papillary predominant type INMA in disease-free survival.…”

“…In the case of advanced cancer, adjuvant therapy is performed according to genetic alterations, such as EGFR, ALK, ROS, and KRAS mutations. In the case of IMA, there is almost no EGFR mutation, 31 , 43 , 44 , 45 therefore tyrosine kinase inhibitors (TKIs) are not used, affecting survival. Due to these differences in adjuvant treatments, we believe that RFS is a better assessment tool for comparing clinical prognosis in various histologic findings.…”

Clinical Relevance of PD-L1 Expression and CD8+ T Cells’ Infiltration in Patients With Lung Invasive Mucinous Adenocarcinoma

“…Moreover, in the present study, 16.1% of IMA patients have EGFR mutations and 29.0% with ALK rearrangement, which was consistent with previous studies indicating that IMA patients have a lower frequency of EGFR mutations and a higher frequency of ALK rearrangements than non-IMA patients ( 8 , 9 , 12 ). Our former next-generation sequencing (NGS)-based study using a panel of 425 genes has identified that KRAS mutations were the most frequent oncogenic driver mutations in IMAs (23.1% in pure-IMA group and 4.0% in mixed-IMA group) ( 22 ). However, owing to the rarity or absence of targetable mutations, there are few studies on the target therapy of IMA ( 23 ).…”