Targeted Sequencing Analysis of Predominant Histological Subtypes in Resected Stage I Invasive Lung Adenocarcinoma

e21067 Background: Lung adenocarcinoma (LADC) is classified into 5 main histological subtypes with distinct clinicopathologic characteristics: lepidic-predominant adenocarcinoma (LPA), acinar-predominant adenocarcinoma (APA), papillary-predominant adenocarcinoma (PPA), micropapillary component (MPC) and solid-predominant adenocarcinoma (SPA). However, the mutational profiles of predominant histological subtypes have not been well defined. In this study, we aimed to reveal the genomic landscape of the 5 main histological subtypes. Methods: Surgically resected tumor samples were obtained from 86 patients with pathological stage I invasive lung adenocarcinoma who underwent surgery between January 2015 and December 2018. No patient had received preoperative chemotherapy or radiotherapy. Capture-based targeted sequencing was performed in a cohort of 86 stage I invasive adenocarcinoma (IAC) patients spanning 5 subtypes using a panel consisting of 168 lung cancer-related genes. Results: Our analysis identified a total of 302 genomic alterations. Five subtypes showed distinct mutation profiles with LPA, APA, PPA, MPC and SPA had an average mutation rate of 1.95 (range: 0–5), 2.56 (range: 1–6), 3.5 (range: 1–7), 3.75 (range: 1-8) and 6.05 (range: 2-12), respectively (p = 4.17e-06). In this cohort, 96.55% (83/86) of all patients had mutations in classic lung cancer drivers with EGFR (73.3%), KRAS (9.3%), ALK (4.7%) and MET (4.7%) being the most commonly mutated drivers. TP53 is the top mutated tumor suppressor gene. It has been reported that SPA and MPC have unfavorable prognosis comparing to the rest subtypes. Interestingly, LRP1B mutations, which has been reported to be associated with high tumor mutation burden and better response to immunotherapy, were only detected from 5 SPA patients (p = 0.001). No MPC patients from this cohort harbored LRP1B mutations. Conclusions: We revealed distinctive mutation landscape of the 5 major histological subtypes of LADC, evident by distinctive average mutation rate with SPA and PLA having the highest and lowest average mutation rate, respectively. Furthermore, we also showed that SPA patients harboring LRP1B mutations may benefit from immunotherapy.

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Driver mutation status in resected stage I lung adenocarcinoma: correlation with chest computed tomography findings

Journal of the American College of Surgeons ◽

10.1016/j.jamcollsurg.2014.07.402 ◽

2014 ◽

Vol 219 (4) ◽

pp. e5

Author(s):

Michael Lanuti ◽

Haiyu Zhou ◽

Carol C. Wu ◽

Mari Mino-Kenudson ◽

Wen Chen ◽

...

Keyword(s):

Computed Tomography ◽

Lung Adenocarcinoma ◽

Stage I ◽

Driver Mutation ◽

Mutation Status ◽

Chest Computed Tomography ◽

Resected Stage

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Evaluation of grading systems in stage I lung adenocarcinomas: a retrospective cohort study

Journal of Clinical Pathology ◽

10.1136/jclinpath-2016-204302 ◽

2017 ◽

Vol 71 (2) ◽

pp. 135-140 ◽

Cited By ~ 3

Author(s):

Tamás Zombori ◽

József Furák ◽

Tibor Nyári ◽

Gábor Cserni ◽

László Tiszlavicz

Keyword(s):

Lung Adenocarcinoma ◽

Disease Free Survival ◽

Stage I ◽

Low Grade ◽

Intermediate Grade ◽

Independent Prognostic Marker ◽

Kaplan Meier ◽

Grading Systems ◽

Cox Proportional Hazard Regression ◽

Resected Stage

AimsThere is no internationally accepted grading system for lung adenocarcinoma despite the new WHO classification. The architectural grade, the Kadota grade and the Sica score were evaluated and compared with overall (OS) and disease-free survival (DFS).MethodsComprehensive histological subtyping was used in a series of resected stage I lung adenocarcinoma to identify subtypes of adenocarcinomas, the architectural grade, the Kadota grade, the Sica grade, the mitotic count, nuclear atypia, the presence of lymphovascular, vascular and airway propagation, necrosis, and micropapillary or solid growth pattern in any percentage. Statistical models fitted included Kaplan-Meier estimates and Cox proportional hazard regression models.Results261 stage I adenocarcinomas were included. The 5-year survivals of different subtypes were as follows: lepidic (n=40, OS: 92.5%; DFS 91.6%), acinar (n=54, OS: 81.8%; DFS: 68.6%), papillary (n=49, OS: 73.6%; DFS: 61.0%), solid (n=95, OS: 64.7%; DFS: 57.8%) and micropapillary (n=23, OS: 34.8%; DFS: 33.5%). Concerning the architectural grade, there were significant differences between OS and DFS of low and intermediate (pOS=0.005, pDFS<0.001), low and high (pOS<0.001, pDFS<0.001) and intermediate and high grades (pOS=0.002, pDFS<0.001). Low-grade and intermediate grade tumours did not differ in survival according to Kadota grade and Sica grade. In the multivariable model, architectural grade was found to be an independent prognostic marker. In another model, architectural pattern proved to be superior to architectural grade.ConclusionsOf the three grading systems compared, the architectural grade makes the best distinction between the outcome of low-grade, intermediate-grade and high-grade stage I adenocarcinomas.

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The impact on mediastinal recurrence based on the number of harvested mediastinal lymph nodes and assessed N2 Stations in patients with stage I invasive lung adenocarcinoma

Journal of Thoracic Disease ◽

10.21037/jtd.2018.11.31 ◽

2018 ◽

Vol 10 (12) ◽

pp. 6803-6810 ◽

Cited By ~ 1

Author(s):

Chunji Chen ◽

Yiyang Wang ◽

Shijie Fu ◽

Xufeng Pan ◽

Jun Yang ◽

...

Keyword(s):

Lymph Nodes ◽

Lung Adenocarcinoma ◽

Stage I ◽

Mediastinal Lymph Nodes ◽

Invasive Lung Adenocarcinoma ◽

The Impact

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The mutations of the EGFR and K-ras genes in resected stage I lung adenocarcinoma and their clinical significance

Surgery Today ◽

10.1007/s00595-013-0589-2 ◽

2013 ◽

Vol 44 (3) ◽

pp. 478-486 ◽

Cited By ~ 14

Author(s):

Taro Ohba ◽

Gouji Toyokawa ◽

Takuro Kometani ◽

Kaname Nosaki ◽

Fumihiko Hirai ◽

...

Keyword(s):

Lung Adenocarcinoma ◽

Clinical Significance ◽

Stage I ◽

Ras Genes ◽

Resected Stage

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Impact on disease-free survival of adjuvant erlotinib or gefitinib in patients with resected lung adenocarcinomas that harbor epidermal growth factor receptor (EGFR) mutations

Journal of Clinical Oncology ◽

10.1200/jco.2009.27.15_suppl.7523 ◽

2009 ◽

Vol 27 (15_suppl) ◽

pp. 7523-7523

Author(s):

Y. Y. Janjigian ◽

B. J. Park ◽

M. G. Kris ◽

V. A. Miller ◽

G. J. Riely ◽

...

Keyword(s):

Lung Adenocarcinoma ◽

Egfr Mutation ◽

Disease Free Survival ◽

Stage I ◽

Egfr Mutations ◽

Free Survival ◽

Resected Stage ◽

Lung Adenocarcinomas ◽

Disease Free ◽

Exon 19

7523 Background: Patients with stage IV adenocarcinoma whose tumors harbor EGFR mutations have high rates of response (∼ 75%) and prolonged progression free survival after EGFR tyrosine kinase inhibitor (TKI) treatment. Adjuvant cisplatin-based chemotherapy improves disease free survival (DFS) and overall survival (OS) in patients with resected stages IB-IIIA NSCLC. To see if adjuvant treatment with EGFR TKI (gefitinib or erlotinib) improves DFS in patients with EGFR mutation NSCLC, we conducted a retrospective review of patients with resected lung adenocarcinoma harboring EGFR mutations, some of whom received EGFR TKIs postoperatively. Methods: With Institutional Review Board approval, clinical information was obtained on all patients with stage I-III lung adenocarcinoma harboring EGFR exon 19 or 21 mutations that underwent resection at MSKCC between May 2002 and August 2008. Age, gender, type of surgery, histology, EGFR mutation status (exon 19 deletions and exon 21 L858R), stage, perioperative therapy and survival were recorded. Kaplan-Meier analysis and Cox regression analysis were performed. Results: We studied 150 patients (112 women, 38 men) with completely resected stage I-III lung adenocarcinoma whose resection specimens contained EGFR activating mutations in exon 19 or 21. Median age was 69. Forty two patients (28%) received cytotoxic chemotherapy. Forty eight (32%) received either erlotinib (n=26) or gefitinib (n=22) postoperatively. The median time on TKI was 16 months. The median DFS was 43 months in the group that received a TKI vs. 31 months for those that did not. After controlling for stage, individuals who received adjuvant gefitinib or erlotinib had a better DFS (HR=0.38, 95%CI: 0.16–0.90) than the non-TKI group (p=0.03). The median overall survival has not been reached. Conclusions: These data indicate that the adjuvant use of either gefitinib or erlotinib improves DFS in patients with completely resected stage I -III lung adenocarcinomas with mutations in EGFR exons 19 and 21. These data justify a randomized trial in similar patients. [Table: see text]

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GRP75-upregulated HMGA1 Expression Promotes Stage I Lung Adenocarcinoma Progression by Activating the JNK/c-JUN Signaling Pathway

10.21203/rs.3.rs-92170/v1 ◽

2020 ◽

Author(s):

Guo-Bing Qiao ◽

Ren-Tao Wang ◽

Shu-Nan Wang ◽

Shaolin Tao ◽

Qun-You Tan ◽

...

Keyword(s):

Cell Growth ◽

Lung Adenocarcinoma ◽

Signaling Pathway ◽

Early Stage ◽

High Mobility ◽

Stage I ◽

Sequencing Analysis ◽

Hmga1 Expression

Abstract Background: Recurrence is a major challenge in early-stage lung adenocarcinoma (LUAD) treatment. However, the recurrence mechanism is still unclear, and no biomarkers can predict recurrence in early-stage LUAD. Here, we investigated the role and mechanism of high-mobility group AT-hook 1 (HMGA1) and glucose-regulated protein 75-kDa (GRP75) in stage I LUAD and evaluated their potential as biomarkers for predicting the recurrence and prognosis of stage I LUAD.Methods: A TCGA dataset was used to investigate the clinical significance of HMGA1 and GRP75 in early-stage LUAD. Western blotting and immunohistochemistry were used to measure protein expression levels. The biological functions of HMGA1 and GRP75 in LUAD were investigated both in vitro and in vivo through overexpression and knockdown experiments. The interaction and regulation between HMGA1 and GRP75 were evaluated with coimmunoprecipitation and ubiquitination assays. The downstream signaling pathway of the GRP75/HMGA1 axis was investigated by mRNA-sequencing analysis.Results: High expression of HMGA1 and GRP75 was associated with recurrence and a poor prognosis in stage I LUAD patients. In particular, HMGA1 had potential as an independent prognostic factor. Overexpression of GRP75 or HMGA1 promoted LUAD cell growth and metastasis, while silencing GRP75 or HMGA1 inhibited LUAD cell growth and metastasis. In vitro and clinical data showed that the expression level of GRP75 positively regulated HMGA1 in LUAD and that GRP75 played an HMGA1-dependent role. In addition, GRP75 prolonged the half-life of HMGA1 by inhibiting HMGA1 ubiquitination via direct binding to HMGA1. Finally, we demonstrated that the GRP75/HMGA1 axis played a role by activating JNK/c-JUN signaling in LUAD.Conclusions: The activation of GRP75/HMGA1/JNK/c-JUN signaling is an important mechanism that promotes the progression of stage I LUAD, and a high level of HMGA1 is a novel biomarker for predicting recurrence and prognosis in patients with stage I LUAD.

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