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Annals of Surgical Oncology
Published in: Annals of Surgical Oncology 6/2019

01-06-2019 | Translational Research and Biomarkers

Prognostic Effect of TP53 and PKD Co-Mutations in Patients with Resected Epidermal Growth Factor Receptor-Mutated Lung Adenocarcinoma

Authors: Di-Han Liu, MD, Ze-Rui Zhao, MD, PhD, Yao-Bin Lin, MD, Wen-Jie Zhou, MD, Jing-Yu Hou, MD, Zheng-Hao Ye, MD, Hao Long, MD, PhD

Published in: Annals of Surgical Oncology | Issue 6/2019

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Abstract

Background

The impact of specific co-mutations in epidermal growth factor receptor (EGFR)-mutated lung adenocarcinoma is unclear.

Methods

Tissues from 147 consecutive patients with resected EGFR-mutated lung adenocarcinomas treated at Sun Yat-Sen University Cancer Center were analyzed by next-generation sequencing (NGS). Associations between mutation status, patient baseline characteristics, and survival outcomes (disease-free survival [DFS] and overall survival [OS]) after surgical resection were analyzed.

Results

TP53 and protein kinase D (PKD) mutations were the two most frequently observed co-mutations in this cohort. Dual PKD/EGFR and TP53/EGFR mutations were found in 39 (27%) and 72 patients (49%), respectively, with dual TP53/EGFR mutations more commonly observed in male patients (P = 0.021). Both TP53 (hazard ratio [HR] 2.08, 95% confidence interval [CI] 1.23–3.54, P = 0.007) and PKD co-mutations (HR 1.72, 95% CI 1.01–2.93, P = 0.044) were associated with shorter DFS, but not OS, in univariate analysis. In multivariate analysis, patients harboring PKD/TP53 co-mutations had shorter DFS compared with PKD−/TP53− cases (HR 2.49, 95% CI 1.15–5.37, P = 0.02). In a subgroup of never-smokers, TP53 co-mutations were associated with significantly worse OS (HR 50.11, 95% CI 2.39–1049.83, P = 0.012).

Conclusion

TP53 and PKD mutations were the two most frequently observed co-mutations in resected EGFR-mutated lung adenocarcinoma. Both mutations were associated with poorer prognoses in affected patients.
Appendix
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Literature
1.
The Cancer Genome Atlas Research Network. Comprehensive molecular profiling of lung adenocarcinoma. Nature. 2014;511(7511):543–50.CrossRefPubMedCentral
2.
Lynch T, Bell D, Sordella R, et al. Activating mutations in the epidermal growth factor receptor underlying responsiveness of non-small-cell lung cancer to gefitinib. N Engl J Med. 2004;350(21):2129–39.CrossRefPubMed
3.
Hirsh V. Turning mutation-positive non-small-cell lung cancer into a chronic disease: optimal sequential therapy with EGFR tyrosine kinase inhibitors. Ther Adv Med Oncol. 2018;10:1758834017753338.CrossRefPubMedPubMedCentral
4.
Jao K, Tomasini P, Kamel-Reid S, et al. The prognostic effect of single and multiple cancer-related somatic mutations in resected non-small-cell lung cancer. Lung Cancer. 2018;123:22–9.CrossRefPubMed
5.
Molina-Vila M, Bertran-Alamillo J, Gascó A, et al. Nondisruptive p53 mutations are associated with shorter survival in patients with advanced non-small cell lung cancer. Clin Cancer Res. 2014;20(17):4647–59.CrossRefPubMed
6.
Ulivi P, Delmonte A, Chiadini E, et al. Gene mutation analysis in EGFR wild type NSCLC responsive to erlotinib: are there features to guide patient selection? Int J Mol Sci. 2014;16(1):747–57.CrossRefPubMedPubMedCentral
7.
Huang S, Benavente S, Armstrong E, Li C, Wheeler D, Harari P. p53 modulates acquired resistance to EGFR inhibitors and radiation. Cancer Res. 2011;71(22):7071–9.CrossRefPubMedPubMedCentral
8.
Lim S, Kim H, Cho E, et al. Targeted sequencing identifies genetic alterations that confer primary resistance to EGFR tyrosine kinase inhibitor (Korean Lung Cancer Consortium). Oncotarget. 2016;7(24):36311–20.CrossRefPubMedPubMedCentral
9.
Wu Y, Takkenberg JJ, Grunkemeier GL. Measuring follow-up completeness. Ann Thorac Surg. 2008;85(4):1155–7.CrossRefPubMed
10.
Shepherd F, Lacas B, Le Teuff G, et al. Pooled analysis of the prognostic and predictive effects of TP53 comutation status combined with KRAS or EGFR mutation in early-stage resected non-small-cell lung cancer in four trials of adjuvant chemotherapy. J Clin Oncol. 2017;35(18):2018–27.CrossRefPubMedPubMedCentral
11.
12.
Ma X, Le Teuff G, Lacas B, et al. Prognostic and predictive effect of TP53 mutations in patients with non-small cell lung cancer from adjuvant cisplatin-based therapy randomized trials: a LACE-bio pooled analysis. J Thorac Oncol. 2016;11(6):850–61.CrossRefPubMed
13.
Scoccianti C, Vesin A, Martel G, et al. Prognostic value of TP53, KRAS and EGFR mutations in nonsmall cell lung cancer: the EUELC cohort. Eur Respir J. 2012;40(1):177–84.CrossRefPubMed
14.
Labbé C, Cabanero M, Korpanty G, et al. Prognostic and predictive effects of TP53 co-mutation in patients with EGFR-mutated non-small cell lung cancer (NSCLC). Lung Cancer. 2017;111:23–9.CrossRefPubMed
15.
16.
Govindan R, Weber J. TP53 mutations and lung cancer: not all mutations are created equal. Clin Cancer Res. 2014;20(17):4419–21.CrossRefPubMed
17.
Bollag W, Dodd M, Shapiro B. Protein kinase D and keratinocyte proliferation. Drug N Perspect. 2004;17(2):117–26.CrossRef
18.
Liljedahl M, Maeda Y, Colanzi A, Ayala I, Van Lint J, Malhotra V. Protein kinase D regulates the fission of cell surface destined transport carriers from the trans-Golgi network. Cell. 2001;104(3):409–20.CrossRefPubMed
19.
Azoitei N, Cobbaut M, Becher A, Van Lint J, Seufferlein T. Protein kinase D2: a versatile player in cancer biology. Oncogene. 2018;37(10):1263–78.CrossRefPubMed
20.
Azoitei N, Pusapati G, Kleger A, et al. Protein kinase D2 is a crucial regulator of tumour cell-endothelial cell communication in gastrointestinal tumours. Gut. 2010;59(10):1316–30.CrossRefPubMed
21.
22.
Jaggi M, Rao P, Smith D, et al. E-cadherin phosphorylation by protein kinase D1/protein kinase C{mu} is associated with altered cellular aggregation and motility in prostate cancer. Cancer Res. 2005;65(2):483–92.PubMed
23.
Ni Y, Wang L, Zhang J, Pang Z, Liu Q, Du J. PKD1 is downregulated in non-small cell lung cancer and mediates the feedback inhibition of mTORC1-S6K1 axis in response to phorbol ester. Int J Biochem Cell Biol. 2015;60:34–42.CrossRefPubMed
24.
Azoitei N, Diepold K, Brunner C, et al. HSP90 supports tumor growth and angiogenesis through PRKD2 protein stabilization. Cancer Res. 2014;74(23):7125–36.CrossRefPubMedPubMedCentral
25.
Zhao D, Desai S, Zeng H. VEGF stimulates PKD-mediated CREB-dependent orphan nuclear receptor Nurr1 expression: role in VEGF-induced angiogenesis. Int J Cancer. 2011;128(11):2602–12.CrossRefPubMed
Metadata
Title
Prognostic Effect of TP53 and PKD Co-Mutations in Patients with Resected Epidermal Growth Factor Receptor-Mutated Lung Adenocarcinoma
Authors
Di-Han Liu, MD
Ze-Rui Zhao, MD, PhD
Yao-Bin Lin, MD
Wen-Jie Zhou, MD
Jing-Yu Hou, MD
Zheng-Hao Ye, MD
Hao Long, MD, PhD
Publication date
01-06-2019
Publisher
Springer International Publishing
Published in
Annals of Surgical Oncology / Issue 6/2019
Print ISSN: 1068-9265
Electronic ISSN: 1534-4681
DOI
https://doi.org/10.1245/s10434-019-07254-6

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