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Cancer. 2019 Jul 9. doi: 10.1002/cncr.32372. [Epub ahead of print]

Genes associated with increased brain metastasis risk in non-small cell lung cancer: Comprehensive genomic profiling of 61 resected brain metastases versus primary non-small cell lung cancer (Guangdong Association Study of Thoracic Oncology 1036).

Wang H1, Ou Q2, Li D3,4,5, Qin T6, Bao H2, Hou X3,4,5, Wang K3,4,5, Wang F4,5,7, Deng Q1, Liang J4,5,8, Zheng W4,5,9, Wu X2, Wang X10, Shao YW2,11, Mou Y4,5,12, Chen L3,4,5.

Author information

1
Department of Microbial and Biochemical Pharmacy, School of Pharmaceutical Sciences, Sun Yat-Sen University, Guangzhou, China.
2
Translational Medicine Research Institute, Geneseeq Technology Inc., Toronto, Ontario, Canada.
3
Department of Medical Oncology, Sun Yat-Sen University Cancer Center, Guangzhou, China.
4
State Key Laboratory of Oncology in South China, Guangzhou, China.
5
Collaborative Innovation Center for Cancer Medicine, Guangzhou, China.
6
Department of Medical Oncology, Sun Yat-Sen Memorial Hospital, Sun Yat-Sen University, Guangzhou, China.
7
Department of Molecular Diagnostics, Sun Yat-Sen University Cancer Center, Guangzhou, China.
8
Department of Pathology, Sun Yat-Sen University Cancer Center, Guangzhou, China.
9
Department of Ultrasound, Sun Yat-Sen University Cancer Center, Guangzhou, China.
10
Nanjing Geneseeq Technology, Inc, Nanjing, China.
11
School of Public Health, Nanjing Medical University, Nanjing, China.
12
Department of Neurosurgery, Sun Yat-Sen University Cancer Center, Guangzhou, China.

Abstract

BACKGROUND:

Patients with brain metastases (BMs) have a poor prognosis and limited therapeutic options. Lung cancer is the most common primary malignancy giving rise to BMs; thus, understanding the molecular mechanisms behind increased BM risk is essential for identifying therapeutic targets and developing effective interventions.

METHODS:

Sixty-one patients who underwent surgical resection of primary non-small cell lung cancer (NSCLC) and BMs were retrospectively studied. Comprehensive genomic profiling of primary NSCLC and matched BMs was performed with next-generation sequencing targeting 416 cancer-relevant genes.

RESULTS:

Mutations of major drivers, including EGFR, KRAS, TP53, and ALK, were highly concordant between primary NSCLC and matched BMs (>80%), whereas discordance suggested the unique genomic evolution and oncogenic mechanisms of NSCLC BMs. BMs also demonstrated higher levels of copy number variations in comparison with primary NSCLC. Furthermore, the alterations of genes encoding CDK4/CCND1, CDKN2A/2B, and PI3K signaling pathways were enriched in BMs, and this suggested their correlation with increased metastatic risk. Indeed, patients with activated PI3K signaling in their primary NSCLC had significantly shorter BM-free survival (hazard ratio, 8.49; P = .0005). In addition, mutated TP53 or an activated WNT pathway via CTNNB1, APC, and AXIN2 mutations trended toward shorter BM-free intervals but not significantly so.

CONCLUSIONS:

These findings yield detailed insights into the genomic complexity and heterogeneity of primary NSCLC and matched BMs. This study highlights the significant correlation of PI3K signaling with increased metastatic risk in patients with NSCLC and identifies genomic alterations enriched in NSCLC BMs that could serve as prognostic markers and potential therapeutic targets for treating patients with NSCLC BMs.

KEYWORDS:

CDK4/CCND1; CDKN2A/2B; PI3K pathway; brain metastasis; genomic instability; non-small cell lung cancer (NSCLC); prognosis

PMID:
31287555
DOI:
10.1002/cncr.32372

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