Abstract B100: Genomic copy number alterations associated with the early brain metastasis of non-small cell lung cancer

Abstract

Abstract Frequent early development of systemic metastasis leads unfavourable clinical prognosis of the non-small cell lung cancer (NSCLC). Although the brain metastasis (BM) contributes significantly to the morbidity and mortality of NSCLC, relevant driver mechanisms are largely unknown. To elucidate genetic alterations and prognostic markers associated with early BM of NSCLC, we retrospectively collected 18 NSCLC patients with BM (12 adenocarcinomas (ADC) and 6 squamous cell carcinomas (SQCC)) whose surgical tissues of primary and/or metastatic tumors were preserved as formaldehyde fixed and paraffin embedded (FFPE) pathologic samples. When chromosomal copy number alterations (CNAs) of those FFPE samples were analysed by the Molecular Inversion Probe (MIP) technology, the most frequent CNAs detected in primary ADCs were gains of 3q, 5p, 5q, 6p, 8q, 9p, 11p, 15q, 17q and losses of 10q and 22q whereas primary SQCCs revealed gains in 4q and 12q and loss in 9q. Moreover, comparative MIP analysis on 11 matched cases demonstrated the fact that the BM carried the majority of genetic alterations present in the corresponding primary tumor but with a slightly higher frequency including gain of 9p11 and loss of 2p11 in ADCs. Especially, when primary 12 ADCs were analyzed depending on the pattern of BM to uncover predetermining signatures that can predict the risk of BM, selectively amplified regions of primary lung ADCs (5q35, 10q23 and 17q23-24) were identified as significantly associated with the development of early BM within 3 months after first diagnosis of primary tumor. Small interfering RNA silencing of ACTA2, which is one of several candidate genes revealed in this study, reduced the in vitro migratory and invasive potential of human ADC cell line PC14PE6-GFP tagged cells without affecting on proliferation. Although more validation is needed, the genetic signatures elucidated in this study shed light on the molecular mechanisms involved in BM and help to identify prognostic markers stratifying the subgroup at high risk of developing recurrence or distant metastasis within heterogeneous NSCLC patients. Citation Format: Hye Won Lee, Se Jeong Lee, Mi Young Song, Kyeung Min Joo, Do-Hyun Nam. Genomic copy number alterations associated with the early brain metastasis of non-small cell lung cancer. [abstract]. In: Proceedings of the AACR Special Conference on Tumor Invasion and Metastasis; Jan 20-23, 2013; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2013;73(3 Suppl):Abstract nr B100.