Cancer Detection and Prevention 26 (2002) 343–349 Loss of heterozygosity at loci of candidate tumor suppressor genes in microdissected primary non-small cell lung cancer William L. Ho, MD a , Jer-Wei Chang, MS b , Ruo-Chia Tseng, MS c , Jung-Ta Chen, MD a , Chih-Yi Chen, MD d , Yuh-Shan Jou PhD e,1 , Yi-Ching Wang, PhD c,∗ a Department of Pathology, Veterans General Hospital, Taichung, Taiwan, ROC b Institute of Toxicology, Chung Shan Medical College, Taichung, Taiwan, ROC c Department of Biology, National Taiwan Normal University, No. 88, Sec. 4, Tingchou Road, Taipei 116, Taiwan, ROC d Department of Thoracic Surgery, Veterans General Hospital, Taichung, Taiwan, ROC e Division of Molecular and Genomic Medicine, National Health Research Institutes, No. 128, Sec. 2, Yen-Chiu-Yuan Road, Taipei 115, Taiwan, ROC Accepted 2 July 2002 Abstract To investigate the etiological association of allelic loss at chromosomal regions containing tumor suppressor genes (TSGs) in non-small cell lung cancer (NSCLC) in Taiwan, we examined 48 microdissected NSCLC samples for loss of heterozygosity (LOH) at nine loci where TSGs are localized nearby. The associations of LOH at each locus with clinicoparameters and prognosis were also examined. The frequent LOH was observed using markers, D3S1285 near the FHIT gene (58.3%), D17S938 near the p53 gene (56.7%), D9S925 near the p16 gene (54.5%), and D13S153 near the RB gene (47.6%). The occurrence of LOH at each TSG locus was compared with the patients’ clinicoparameters. The incidence of LOH at D17S938 (p53 gene) and D3S4545 (VHL gene) was significantly higher in squamous carcinoma tumors than in adenocarcinoma tumors (P = 0.003 and 0.024, respectively). LOH of these two loci also occurred frequently in tumors from smoker patients compared to that from nonsmoker patients (P = 0.013 and 0.025, respectively). LOH at D13S153 (RB gene) was also associated with smoking (P = 0.008). In addition, the prognostic analyses indicated that the patients with LOH at D18S535 (18q21, near the SMAD2/4 gene) had significantly longer post-operative survival time compared to those without LOH (P = 0.03). Our results suggested that LOH at FHIT, p53, and p16 genes may occur frequently in NSCLC patients in Taiwan. In addition, LOH at p53, RB, and VHL may associate with smoking or squamous carcinoma patients and LOH at SMAD2/4 may be correlated with better prognosis. © 2002 International Society for Preventive Oncology. Published by Elsevier Science Ltd. All rights reserved. Keywords: FHIT; p53; p16; RB; VHL; Prognosis 1. Introduction Lung cancer is a major health problem worldwide and is the leading causes of cancer death in Taiwan [1]. Cy- togenetic and comparative genomic hybridization studies have shown that alterations of proto-oncogenes and tumor suppressor genes (TSGs) are critical in the multi-step de- velopment and progression of lung cancer [2,3]. Recently, using the polymorphic microsatellite markers to detect the loss of heterozygosity (LOH) in lung cancer cells reveals that deletions at multiple chromosomal regions are often observed and several TSGs located in these regions are ∗ Corresponding author. Tel.: +886-2-2933-6876x211; fax: +886-2-2931-2904. E-mail addresses: jou@nhri.org.tw (Y.-S. Jou), t43017@cc.ntnu.edu.tw (Y.-C. Wang). 1 Co-corresponding author. Tel.: +886-2-2652-4123; fax: +886-2-2789-0484. frequently inactivated genetically in lung cancer cells. For example, LOH on chromosome arms 3p, 13q, and 17p is the most frequent alteration in both small cell lung cancer (SCLC) and non-small cell lung cancer (NSCLC) [3,4]. LOH on 6p, 9p, and 19p is also frequently detected in NSCLC [4,5]. In addition, LOH on 2q, 18q, 21q, and 22q is detected preferentially in advanced NSCLC [6]. Although loss of multiple chromosomal segments in lung cancers seems to be a non-random event, only a limited num- ber of TSGs have been identified as targets for these chro- mosomal deletions. Among them, p53, RB, p16, and FHIT genes have been well accepted as the major targets for chro- mosomal deletions in lung cancer. LOH and/or mutation at the p53 gene (at 17p13.1) occur in more than 50% of NSCLC [4,7]. The p53 protein functions as a transcription factor in response to DNA damage and regulates cell cycle and apop- tosis pathways [7,8]. The p16 (at 9p21) and RB (at 13p14.2) are involved in the regulation of the G1/S transition of the 0361-090X/02/$ – see front matter © 2002 International Society for Preventive Oncology. Published by Elsevier Science Ltd. All rights reserved. PII:S0361-090X(02)00088-0 300