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Primary Adenocarcinomas of the Lung in Nonsmokers Show a Distinct Pattern of Allelic Imbalance¹

Departments of Pathology [M. P. W., L. P. C.] and Medicine [W. K. L., C. L. L.], University of Hong Kong, Queen Mary Hospital, Hong Kong, and Department of Pathology [E. W.] and Cardiothoraxic Unit [S. W. C.], The Grantham Hospital, Hong Kong

	ABSTRACT

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Lung cancer development in nonsmokers, particularly in females, has long been observed,but the genetic pathways of oncogenesis are still unclear. The purpose of this study was to identify important targets of chromosomal alteration involved in non-tobacco-related adenocarcinomas of lung. In this study, loci of recurrent allelic imbalance (AI) were identified by microsatellite analysis, focusing on tumors with low frequencies of AI (FAL) relative to the mean level. We reasoned that studying such tumors would facilitate the identification of essential genetic changes needed for the malignant phenotype, which could be masked by genomic instability and widespread nonspecific alterations, especially in tumors showing high FAL. Forty-two adenocarcinomas from nonsmokers (NT-ADs) were analyzed by a broad spectrum of 84 markers covering all nonacrocentric chromosomal arms. Using the mean AI frequency (40%) as the threshold, loci in 7q31, 8p23.2, 10p14-p15, 13q12.3, 16q24, 17p13.1-p13.3, 17q22, 19q13.3, and Xq11.2-q12 showed recurrent AI in the low-FAL tumors, which suggested that essential targets of carcinogenesis may be present. To analyze whether loci, frequently altered in NT-ADs, were uniquely involved in these tumors, 43 loci were also studied in 29 adenocarcinomas from smokers. 2q, 6p, 10p, 13q, 16q, 17q, 19p, 19q, 20p, and 20q showed frequent aberrations in NT-ADs, whereas 1q, 2p, 3p, 3q, 7q, 8p, 9p, 9q, 10q, 11q, 13q, 14q, TP53, 17p, 18q, and 21q were commonly altered in both of the tumor groups. Further comparison of their low-FAL tumors showed that AI involving 16q24, 17q22, and 19q13.3 were significantly associated with NT-ADs; whereas those involving 7q31, 8p23.2, 10p14-p15, 13q12.3, and 17p13.1-p13.3 were observed in both. The findings suggest that oncogenesis in the lung of smokers and nonsmokers involve overlapping yet distinct genetic pathways, whereas the recurrent loci of alteration in NT-ADs may provide a basis for the further mapping of critical molecular targets in these pathways.

	INTRODUCTION

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Lung cancer is a common malignancy etiologically related to smoking. Genotoxic tobacco metabolites form bulky DNA adducts in the genome resulting in frequent chromatid breaks and mutations (1) . In recent years, it is increasingly recognized that factors not related to direct cigarette smoking, such as passive smoking, toxicity from vaporized cooking oil, indoor fossil fuel combustion, and so forth, might also contribute to lung cancer development, particularly in women (2 , 3) . From studies in Hong Kong and mainland China, where relatively few (30–40%) female Chinese lung cancer patients smoke (4) , it has long been observed that the incidence and mortality rate of female lung cancers are high compared with world standards (5) .

The carcinogenic pathway of lung cancer development in nonsmokers is unclear, but probably involves a complex interplay of genetic and environmental mechanisms that lead to progressive accumulation of multiple genetic aberrations. Some of the aberrations may form part of overall genomic damages caused by the carcinogenic events. Others may accumulate from genomic instabilities that occur during tumor progression. However, not all altered loci are expected to harbor genes with determinant roles in tumor development. Thus, it is likely that some genetic alterations constitute "genetic noise" that may mask the essential aberrations. On the other hand, clinical tumors that show less extensive AIs would be expected to harbor less genetic noise and yet include the minimal combination of essential aberrations required for the malignant phenotype. In this study, we aimed to identify the essential molecular targets of lung carcinogenesis in nonsmokers by focusing on these tumors and detecting recurrent genetic aberrations represented by loci with high AI frequency.³ Forty-two adenocarcinomas from nonsmokers (NT-ADs) were first studied by microsatellite analysis using a broad panel of markers covering all nonacrocentric autosomes. To investigate whether the identified targets were unique to nonsmoker lung cancers, a selective panel of markers consisting of those with the highest AI frequencies in NT-ADs were analyzed in 29 T-ADs for comparison.

	MATERIALS AND METHODS

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Study Samples.
Seventy-one primary lung adenocarcinomas were collected after informed consent from 42 nonsmokers (41 never-smokers, 1 passive-smoker) and 29 smokers (25 chronic smokers, 4 ex-smokers), including 28 men and 43 women ages 38–81 (mean ± SD, 59.8 ± 10.4). The patients were recruited from the Grantham Hospital, Hong Kong, during the period 1992–1999. All of them were ethnic Chinese, and none had received any preoperative radiation or chemotherapy. Demographic data were obtained through patient interviews conducted by the designated clinician-in-charge (S. W. C.) at the first hospital admission according to a standardized protocol and were verified by a review of the hospital charts recorded in subsequent visits. For never-smokers, only patients who were lifetime nonsmokers and not exposed to smoking spouses were recruited. One patient was originally recruited as a never-smoker, but subsequent information revealed possible environmental tobacco smoke exposure, and she was designated as a passive-smoker. Chronic smokers had 15–60 pack-years of cigarette-smoking history and included those who had stopped smoking for <6 months. The ex-smokers had stopped smoking for <10 years, and those beyond this duration were excluded from the study. Smokers of tobacco products other than cigarettes were also excluded. The nonsmokers were predominantly women, and the smokers were predominantly men (P < 0.0001). Significant differences in age, tumor grade, and pathological stages were not present between the two populations (Table 1) . Tumor classification was according to the WHO histological classification of lung tumors (1991), and the study cases included all subtypes of adenocarcinoma but not adenosquamous carcinoma.

Microsatellite Analysis.
Genomic DNA from the tumors, normal lung, and peripheral leukocytes was extracted using proteinase K digestion, phenol-chloroform extraction, and ethanol precipitation according to standard methods. For NT-ADs, 84 markers covering all nonacrocentric chromosomal arms and spanning common regions of genetic gain or loss in lung and other common carcinomas were selected after literature review and were analyzed using commercial primers (Research Genetics, Huntsville, AL). For T-ADs, a subset of 43 markers including those with high AI frequencies in the NT-ADs, as well as loci in chromosomes 3p, 9p21-p23, and 11q22-q24 that contain well-known hot spots of allelic loss in lung cancers, were analyzed (Table 2 ; see loci with footnote c citation). PCR was performed with 20- to 50-ng DNA template, 1.5–2.5 mM MgCl₂, forward and reverse primers (0.2 µM each), 200 µM dNTPs, 1.5 unit of Taq polymerase (Platinum Taq; Life Technologies, Inc.) and 1x PCR buffer (20 mM Tris-HCl [ph 8.4], 50 mM KCl). Denaturation (25–30 cycles) at 94°C for 60 s, annealing at 50°C to 63°C for 60 s according to individual markers, and extension at 72°C for 60 s was performed. PCR products were radiolabelled by nucleotide incorporation, resolved in 6% polyacrylamide gel containing urea and formamide, and exposed to X-ray films for 6–48 h. Cases were scored as heterozygous when two alleles were distinguished in the control DNA and as noninformative when only one allele was visualized. Heterozygous cases showing obvious reduction in the relative intensity of one allele in the tumor DNA was scored as AI. Results were recorded independently by at least two investigators (L. P. C. and M. P. W.). The percentages of agreement of results were generally more than 90%. Cases with discrepant interpretation were resolved by consensus and, if necessary, were repeated using DNA from microdissected tumor samples. Six markers (D1S 1597, D1S 518, D10S 2325, D10S 1223, TP53, and D19S 586) were additionally studied by fluorescence-labeled primers using ABI Prism 377 and Genescan fragment analysis software to ensure that criteria applied in visual interpretation of AI were reliable and reproducible.

	RESULTS

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AI in NT-ADs.
Microsatellite analysis of 84 markers was performed in NT-ADs from 39 women and 3 men, and the mean AI frequency was 37.0 ± 12.3% (range, 10–64%). The extent of chromosomal alteration in each NT-AD was evaluated by the FAL, which ranged from 3 to 76% (mean, 40.0 ± 20.4%). No significant correlation was found between the FAL and age, tumor grade, tumor stage, nodal stage, metastasis, or pathological stages. The mean FAL was used as the threshold to designate two groups, each of 21 tumors, with high or low FAL. No significant differences in the distribution of sex and other clinicopathological parameters between the low or high-FAL tumors were found. The low-FAL tumor group was examined for loci of high AI frequency, defined as those with AI of >40% using the approximated overall mean (37%) as the cutoff. The loci of frequent AI comprised 10 loci in 7q31, 8p23.2, 10p14-p15, 13q12.3, 16q24, 17p13.1-p13.3, 17q22, 19q13.3, and Xq11.2-q12 (Table 2 ; see loci with footnote d citation). These loci also showed AI of 40% or above in the high-FAL tumors, and a significant difference with the low-FAL tumors was observed in 13q12.3 (P = 0.002) only. The remaining 74 loci showed relatively infrequent AI (40% or less) in the low-FAL tumors compared with the high-FAL tumors, with the difference reaching statistical significance in 26 loci (P of <0.0001 to 0.05; ² test, Table 2 ).

AI in T-ADs.
To investigate the uniqueness of involvement of the frequently altered loci in non-tobacco-related tumors, a selective panel of markers (Table 2 ; see loci with footnote c citation), including those with AI >40% in NT-ADs, were then analyzed in 29 T-ADs from 25 male and 4 female patients for comparison. The FAL of the T-ADs ranged from 4 to 84% (mean, 44.5 ± 24.7%). No statistical correlation was found between the FAL and the clinicopathological variables of age, tumor grade, tumor stage, nodal stage, metastasis, or pathological stage. Loci in 2q33, 6p23-p24, 10p14-p15, 13q14.1, 16q24, 17q11-q12, 17q22 (P = 0.06), 19p13.2, 19q13.3, 20p12, and 20q12 showed more frequent alterations in NT-ADs than in T-ADs (Fig. 1 , solid bars). Although the differences did not reach statistical significance, these loci were relatively infrequently altered in T-ADs: they showed AI frequency lower than the mean level (49.7 ± 14.5%) for T-ADs. Loci in 1q24-q25, 2p24-p25, 3p22.3, 3p14.2, 3q25.2-q26, 7q31, 8p23.2, 9p22, 9q34, 10q26, 11q23.1, 13q12.3, 14q32, 17p13.1-p13.3, 18q23, and 21q22 showed closely similar AI frequencies in both groups (within 10%; Fig. 1 , dotted bars), or more frequent alterations in T-ADs (Fig. 1 , hatched bars).

View larger version (45K): [in this window] [in a new window]   Fig. 1. Comparison of loci with frequent AI in adenocarcinomas from non-smokers (NT-ADs, lower bars in each pair) and smokers (T-ADs, upper bars in each pair). Solid bars, loci with higher AI in NT-ADs than in T-ADs; hatched bars, loci with higher AI in T-ADs; dotted bars, loci with similar AI (within 10%) in both groups. Number immediately to the right of each bar, the AI frequency (%). Ps were calculated from 2 tests comparing NT-ADs and T-ADs for the individual marker; loci without a stated P value show no significant difference.

	DISCUSSION

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To investigate whether frequently altered genetic loci identifie d in NT-ADs were uniquely involved in non-tobacco-mediated carcinogenesis, loci with frequent AI were also analyzed in 29 adenocarcinomas from smokers (T-ADs) for comparison. The results indicated a wide overlap in genetic aberrations when all tumors of both groups were analyzed, including 11 regions (2q33, 6p23-p24, 10p14-p15, 13q14.1, 16q24, 17q11-q12, 17q22, 19p13.2, 19q13.3, 20p12, and 20q12) of frequent AI in NT-ADs but relatively infrequent changes in T-ADs, and 17 regions (1q24-q25, 2p24-p25, 3p22.3, 3p14.2, 3q25.2-q26, 7q31, 8p23.2, 9p22, 9q34, 10q26, 11q23.1, 13q12.3, 14q32, TP53, 17p13.1-p13.3, 18q23, and 21q22) with genetic gain/loss at a similar or higher frequency in T-ADs. Comparison between low-FAL tumors of nonsmokers and smokers revealed that among the 10 loci of recurrent alterations found in NT-ADs, changes in 16q, 17q, and 19q were significantly more frequent than in the low-FAL T-ADs, which indicated that they are likely to be critically and uniquely involved in non-smoking-related cancers. On the other hand, alterations in 7q, 8p, 10p, 13q, and 17p were not found to be significantly different, and they could be related to similarities in tumor development in smokers and nonsmokers, such as exposure to common mutagenic compounds, involvement of common susceptibility factors, disruption of tissue-specific regulatory mechanisms of the lung, and so forth. Interestingly, 17q22 is located in a syntenically conserved region in the mouse genome that contains the mouse pulmonary adenoma resistance gene 1 (PAR1) involved in the genesis of the urethane-induced mouse model of lung adenocarcinoma (6) . Because lung cancers developing in this animal model have been shown to share pathogenetic and biological behavior that is similar to that in human lung cancers (7) , our finding of frequent AI in this region suggests that important tumor suppressor genes for human lung cancer could be located in 17q22. Fong et al. (8) have also reported 42% alterations of 17q in NSCLC, a frequency similar to that in our findings. 16q23-q24, which spans the common fragile site FRA16D, shows frequent allelic loss or homozygous deletions in cancer cell lines or primary cancers (9) . The H-cadherin gene located in this region shows frequent down-regulation and methylation in NSCLC, but mutations have not been identified (10 , 11) . 10p15 and 19q13.3 are novel regions of genetic alterations identified in a genome-wide screening study of lung cancer cell lines using high-density marker sets (12 , 13) . Frequent alterations in 7q31 have not been previously reported in allelotype studies; however, karyotyping and comparative genomic hybridization studies have consistently reported polysomy of chromosome 7 or amplification of 7q31 in NSCLC (14 , 15) . Because amplified copies of a DNA fragment may manifest as AI, our results may be a reflection of the polysomy and may indicate the presence of potential oncogenes in this region.

Because of the small number of male nonsmoking and female smoking patients who present with excisable lung cancers in our population, the effect of gender differences on AIs cannot be independently evaluated in our study. The high proportion of nonsmoking women with lung cancers may reflect potential influences of female-specific factors or differences in susceptibility to common carcinogenic agents. In a study of Chinese subjects, significantly higher DNA adduct levels were found in the nontumor lungs of female nonsmokers than in those of male nonsmokers (16) , which suggests that female susceptibility to DNA damage derived from environmental carcinogen exposure may be a confounding factor in lung cancer development. A higher expression level of gastrin-releasing peptide receptor in women, which is involved in the regulation of cellular proliferation and is induced in smokers, has also been proposed as a mechanism for the increased susceptibility (17) .

Our findings of frequent genetic changes in NT-ADs, with a mean AI frequency of 40%, and the involvement of an overlapping spectra of loci compared with T-ADs, are different from those reported by Sanchez-Cespedes et al. (18) in a recent study in which AI was infrequent in 18 adenocarcinomas from nonsmokers. None of 54 markers from 28 chromosomal arms showed alteration of >25%. Changes at 9p21, 12p, and 19q13.3, each occurring at 22%, were the commonest alterations found. Our data support frequent involvement of 19q13.3 (48%) and 9p21 (45%) in NT-ADs in general, but we have not found 12p alterations to be a frequent event. Furthermore, 19q13.3 involvement is also frequent in our low-FAL tumors, which suggests that genes that are critically essential for lung cancer oncogenesis in nonsmokers may be linked to this region. The reason for the discrepant findings between the two studies is not clear, but variations in genetic, environmental, and lifestyle factors may be involved. It would be interesting to compare the patient data, particularly sex distribution, of nonsmoking subjects in the reported study.

In summary, we have shown that AI in 16q24, 17q22, and 19q13.3 may represent essential alterations in lung adenocarcinomas arising in nonsmoking patients, particularly for females. They represent useful sites for additional mapping of genetic targets in non-tobacco-associated lung carcinogenesis by high-density microsatellite marker sets.

	ACKNOWLEDGMENTS

 
We thank May Wong, Discipline of Dental Public Health, Dental Faculty, University of Hong Kong, Prince Philip Dental Hospital, Hong Kong, for her help in statistical analysis.

	FOOTNOTES

 
The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

¹ Supported by Grants RGC HKU 7311/98M administered by the Hong Kong government and CRCG 10202685/12253/21200/323/01 administered by The University of Hong Kong.

² To whom requests for reprints should be addressed, at Department of Pathology, University of Hong Kong, Queen Mary Hospital, Pokfulam Road, Hong Kong. Phone: 852-2855-4881; Fax: 852-2872-5197; E-mail: lpchung{at}hkucc.hku.hk

³ The abbreviations used are: AI, allelic imbalance; FAL, frequency/frequencies of AI; T-AD, tobacco-associated adenocarcinoma; NT-AD, non-T-AD; NSCLC, non-small cell lung cancer.

Received 9/20/01. Accepted 5/31/02.

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