Poor prognosis of stage I lung adenocarcinoma patients determined by elevated expression over pre/minimally invasive status of COL11A1 and THBS2 in the focal adhesion pathway

Around 20% stage I lung adenocarcinoma (LUAD) patients die within five years after surgery, and efforts for developing gene-expression based models for risk-tailored post-surgery treatment are largely unsatisfactory due to overfitting-related lack of validation and extrapolation. Because patients with adenocarcinomas in situ (AIS) and minimally invasive (MIA) LUAD are completely curable by surgical resection, we hypothesize that poor-prognosis stage I patients may exhibit key molecular characteristics deviating from AIS/MIA. We first found focal adhesion (FA) as the only pathway significantly perturbed at both genomic and transcriptomic levels by comparing 98 AIS/MIA and 99 invasive LUAD patients. Then, we identified two FA pathway genes (COL11A1 and THBS2) strongly upregulated from AIS/MIA to stage I while expressed steadily from normal to AIS/MIA. Furthermore, unsupervised clustering separated stage I patients into two molecularly and prognostically distinct subtypes (S1 and S2) based solely on the expression levels of COL11A1 and THBS2 (FA2). Subtype S1 looked like AIS/MIA, whereas S2 exhibited more somatic alterations, elevated expression of COL11A1 and THBS2, and more activated cancer-associated fibroblast (CAF). The prognostic performance of the knowledge-driven and overfitting-resistant FA2 model was validated with 12 external data sets and may help reliably identify high-risk stage I patients for more intensive post-surgery treatment.

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Poor prognosis of stage I lung adenocarcinoma patients determined by elevated expression over pre/minimally invasive status of COL11A1 and THBS2 in the focal adhesion pathway

10.21203/rs.3.rs-1218087/v1 ◽

2022 ◽

Author(s):

Leming Shi ◽

Jun Shang ◽

Yue Zhao ◽

He Jiang ◽

Jingcheng Yang ◽

...

Keyword(s):

Minimally Invasive ◽

Lung Adenocarcinoma ◽

Focal Adhesion ◽

Poor Prognosis ◽

Stage I ◽

Molecular Characteristics ◽

Cancer Associated Fibroblast ◽

Post Surgery ◽

Elevated Expression ◽

Invasive Status

Abstract Patients with adenocarcinomas in situ (AIS) and minimally invasive (MIA) lung adenocarcinoma (LUAD) are curable by surgery, whereas 20% stage I patients die within five years post-operative. We hypothesize that poor-prognosis stage I patients may exhibit key molecular characteristics deviating from AIS/MIA. Focal adhesion (FA) was identified as the only pathway significantly perturbed at both genomic and transcriptomic levels by comparing 98 AIS/MIA and 99 LUAD. Then, two FA genes (COL11A1 and THBS2) were found strongly upregulated from AIS/MIA to stage I while steadily expressed from normal to AIS/MIA. Furthermore, unsupervised clustering separated stage I patients into two molecularly and prognostically distinct subtypes (S1 and S2) based on COL11A1 and THBS2 expressions (FA2). Subtype S1 resembled AIS/MIA, whereas S2 exhibited more somatic alterations and activated cancer-associated fibroblast. The simple knowledge-driven model was validated with 12 external datasets, showing potential in identifying high-risk stage I patients for more intensive post-surgery treatment.

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MYH9-dependent polarization of ATG9B promotes colorectal cancer metastasis by accelerating focal adhesion assembly

Cell Death and Differentiation ◽

10.1038/s41418-021-00813-z ◽

2021 ◽

Author(s):

Yan Zhong ◽

Ting Long ◽

Chuan-Sha Gu ◽

Jing-Yi Tang ◽

Ling-Fang Gao ◽

...

Keyword(s):

Colorectal Cancer ◽

Focal Adhesion ◽

Poor Prognosis ◽

Cancer Metastasis ◽

Integrin Β1 ◽

Independent Manner ◽

Interacting Protein ◽

Tumour Metastasis ◽

Elevated Expression ◽

Dependent Polarization

AbstractTumour metastasis is a major reason accounting for the poor prognosis of colorectal cancer (CRC), and the discovery of targets in the primary tumours that can predict the risk of CRC metastasis is now urgently needed. In this study, we identified autophagy-related protein 9B (ATG9B) as a key potential target gene for CRC metastasis. High expression of ATG9B in tumour significantly increased the risk of metastasis and poor prognosis of CRC. Mechanistically, we further find that ATG9B promoted CRC invasion mainly through autophagy-independent manner. MYH9 is the pivotal interacting protein for ATG9B functioning, which directly binds to cytoplasmic peptide segments aa368–411 of ATG9B by its head domain. Furthermore, the combination of ATG9B and MYH9 enhance the stability of each other by decreasing their binding to E3 ubiquitin ligase STUB1, therefore preventing them from ubiquitin-mediated degradation, which further amplified the effect of ATG9B and MYH9 in CRC cells. During CRC cell invasion, ATG9B is transported to the cell edge with the assistance of MYH9 and accelerates focal adhesion (FA) assembly through mediating the interaction of endocytosed integrin β1 and Talin-1, which facilitated to integrin β1 activation. Clinically, upregulated expression of ATG9B in human CRC tissue is always accompanied with highly elevated expression of MYH9 and associated with advanced CRC stage and poor prognosis. Taken together, this study highlighted the important role of ATG9B in CRC metastasis by promoting focal adhesion assembly, and ATG9B together with MYH9 can provide a pair of potential therapeutic targets for preventing CRC progression.

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Expression of nucleolar protein p120 predicts poor prognosis in patients with stage I lung adenocarcinoma

Annals of Oncology ◽

10.1023/a:1011617707999 ◽

2001 ◽

Vol 12 (8) ◽

pp. 1121-1125 ◽

Cited By ~ 13

Author(s):

Y. Saijo ◽

G. Sato ◽

K. Usui ◽

M. Sato ◽

M. Sagawa ◽

...

Keyword(s):

Lung Adenocarcinoma ◽

Poor Prognosis ◽

Nucleolar Protein ◽

Stage I

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Thyroid Transcription Factor 1 Is an Independent Prognostic Factor for Patients With Stage I Lung Adenocarcinoma

Journal of Clinical Oncology ◽

10.1200/jco.2008.17.0043 ◽

2009 ◽

Vol 27 (2) ◽

pp. 271-278 ◽

Cited By ~ 74

Author(s):

Valsamo K. Anagnostou ◽

Konstantinos N. Syrigos ◽

Gerold Bepler ◽

Robert J. Homer ◽

David L. Rimm

Keyword(s):

Transcription Factor ◽

Protein Expression ◽

Lung Adenocarcinoma ◽

Stage I ◽

Data Sets ◽

Risk Of Death ◽

Thyroid Transcription Factor 1 ◽

Thyroid Transcription Factor ◽

The Impact ◽

Transcription Factor 1

Purpose Thyroid transcription factor 1 (TTF1) is a transcription factor that regulates the expression of multiple genes involved in lung development. It is preferentially expressed in adenocarcinomas of the lung and has been investigated as a potential prognostic parameter in patients with lung cancer, with conflicting results. We quantitatively assessed TTF1 protein expression in two large and independent data sets to investigate the impact of TTF1 nuclear expression on patient survival. Patients and Methods Automated quantitative analysis, a fluorescent-based method for analysis of in situ protein expression, was used to assess a series of cell lines to find the threshold of detection of TTF1 expression. Then two independent cohorts (176 and 237 cases, respectively) were measured by the same technique, and TTF1 expression was correlated with survival. Results Tumors expressed TTF1 in 45% and 58% of the cases in each cohort. TTF1 was consistently expressed in adenocarcinomas (n = 61 and 73; Spearman ρ = 0.313 and 0.4 for the first and second set, respectively; P < .0001) independent of their differentiation and stage. Survival analysis showed that patients with stage I adenocarcinoma with TTF1 expression had a longer median overall survival than those without expression (n = 43, 44.3 v 26.2 months, P = .05 for the first cohort; n = 87; 49.7 v 38.5 months, P = .03 for the second cohort) Multivariate analysis revealed an independent lower risk of death for patients with stage I adenocarcinoma with TTF1-expressing tumors (hazard ratio = 0.479, 95% CI, 0.235 to 0.977; P = .043). Conclusion TTF1 expression defines a subgroup of patients with a favorable outcome and may be useful for prognostic stratification of patients with stage I lung adenocarcinoma.

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The cribriform pattern identifies a subset of acinar predominant tumors with poor prognosis in patients with stage I lung adenocarcinoma: a conceptual proposal to classify cribriform predominant tumors as a distinct histologic subtype

Modern Pathology ◽

10.1038/modpathol.2013.188 ◽

2013 ◽

Vol 27 (5) ◽

pp. 690-700 ◽

Cited By ~ 69

Author(s):

Kyuichi Kadota ◽

Yi-Chen Yeh ◽

Camelia S Sima ◽

Valerie W Rusch ◽

Andre L Moreira ◽

...

Keyword(s):

Lung Adenocarcinoma ◽

Poor Prognosis ◽

Stage I ◽

Histologic Subtype

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Elevated Expression of LYPD3 Is Associated with Lung Adenocarcinoma Carcinogenesis and Poor Prognosis

DNA and Cell Biology ◽

10.1089/dna.2019.5116 ◽

2020 ◽

Vol 39 (4) ◽

pp. 522-532 ◽

Cited By ~ 1

Author(s):

Ping Hu ◽

Ying Huang ◽

Yuanyuan Gao ◽

Hui Yan ◽

Xiaoge Li ◽

...

Keyword(s):

Lung Adenocarcinoma ◽

Poor Prognosis ◽

Elevated Expression

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Overexpression of T-LAK cell-originated protein kinase predicts poor prognosis in patients with stage I lung adenocarcinoma

Cancer Science ◽

10.1111/j.1349-7006.2011.02197.x ◽

2012 ◽

Vol 103 (4) ◽

pp. 731-738 ◽

Cited By ~ 26

Author(s):

Di-Cing Wei ◽

Yi-Chen Yeh ◽

Jung-Jyh Hung ◽

Teh-Ying Chou ◽

Yu-Chung Wu ◽

...

Keyword(s):

Protein Kinase ◽

Lung Adenocarcinoma ◽

Poor Prognosis ◽

Stage I ◽

Lak Cell

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Impact of the micropapillary component on the timing of recurrence in patients with resected lung adenocarcinoma

European Journal of Cardio-Thoracic Surgery ◽

10.1093/ejcts/ezaa138 ◽

2020 ◽

Vol 58 (5) ◽

pp. 1010-1018 ◽

Cited By ~ 1

Author(s):

Katsuya Watanabe ◽

Kentaro Sakamaki ◽

Hiroyuki Ito ◽

Tomoyuki Yokose ◽

Kozo Yamada ◽

...

Keyword(s):

Lung Adenocarcinoma ◽

Poor Prognosis ◽

Cox Regression ◽

Postoperative Recurrence ◽

Early Recurrence ◽

Stage I ◽

Hazard Curves ◽

And Gender ◽

The Impact

Abstract OBJECTIVES A micropapillary (MIP) component is reported to be associated with a poor prognosis in patients with completely resected lung adenocarcinoma. The purpose of this study was to investigate the impact of an MIP component on the timing of postoperative recurrence using hazard curves. METHODS A total of 1289 patients with lung adenocarcinoma who underwent complete pulmonary resection from 2008 to 2015 were studied. Hazard curves representing the changes in hazard over time were evaluated. RESULTS The hazard curve displayed an initial wide, high peak within 1 year after surgery in patients with an MIP component, whereas some gentle peaks around the second year were noted in patients without an MIP component. The presence of an MIP component was associated with a worse recurrence-free survival and an early recurrence in stage I patients but not in advanced-stage patients. In multivariable Cox regression, the presence of an MIP component and lymph node metastasis, pleural invasion and gender were associated with a poor prognosis. CONCLUSIONS Patients with an MIP component retained a high risk of early recurrence after surgery, and the risk for recurrence persisted over the long term. Even after complete resection in stage I lung adenocarcinoma patients, an MIP component remains correlated with a poor prognosis.

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