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(American Journal of Pathology. 2000;157:985-993.)
© 2000 American Society for Investigative Pathology

Regular Articles

Topographical Distributions of Allelic Loss in Individual Non-Small-Cell Lung Cancers

Yasushi Yatabe*, Hiroyuki Konishi{dagger}, Tetsuya Mitsudomi{ddagger}, Shigeo Nakamura* and Takashi Takahashi{dagger}

From the Department of Pathology and Clinical Laboratories*
and the Department of Thoracic Surgery,{ddagger}
Aichi Cancer Center Hospital, Nagoya; and the Laboratory of Ultrastructure Research,{dagger}
Aichi Cancer Research Institute, Nagoya, Japan


   Abstract
Top
 Abstract
Introduction
 Materials and Methods
 Results
 Discussion
 References
 
Non-small-cell carcinomas of the lung, especially adenocarcinomas, are characterized by a high degree of morphological heterogeneity. As carcinogenesis has been suggested to be a multistep process involving sequential accumulation of multiple genetic alterations, morphological heterogeneity may represent a cross-sectional view of genetic alterations within individual tumors. We therefore examined the topographical distribution of loss of heterozygosity (LOH) events within 10 non-small-cell lung cancers to investigate whether, and which, genetic alterations are accumulated in relation to morphological progression. LOH at the TP53, 17p13.3, and 3p loci was detected in six, eight, and six of 10 informative cases, respectively. In each case, all portions of the tumor shared concordant LOH despite morphological diversity. In contrast, distributions of LOH at 2q, 9p, and 22q, which have been reported to be associated with the advanced stages of tumors, were divergent in two of three, four of eight, and one of one cases with LOH, respectively. In these cases, presence of LOH was mostly related to the morphological tumor grades. These findings suggest the accumulative feature of genetic alterations in particular loci that can be seen even in individual tumors. Furthermore, the present study indicated that cross-sectional examination of individual tumors is also important for better understanding of molecular pathogenesis of lung cancers.


   Introduction
Top
 Abstract
 Introduction
Materials and Methods
 Results
 Discussion
 References
 
Lung cancers are categorized into four major subtypes including small cell carcinoma, adenocarcinoma, squamous cell carcinoma, and large cell carcinoma. Among these histological subtypes of lung cancers, the incidence of adenocarcinoma is the highest in Japan and is gradually increasing, as it is in the United States1 and other economically advanced countries. One of the most characteristic features of adenocarcinoma is the high degree of morphological heterogeneity, which in turn implies both intra- and intertumor diversities.

Unfortunately, morphological and genetic progression schemes of lung cancers have not been elucidated as clearly as those of colon cancers,2 which are by far the best-investigated example among human cancers in this regard. This has been especially true for adenocarcinomas of the lung, but atypical adenomatous hyperplasia (AAH) is now considered as a possible premalignant lesion.3-7 In addition to solitary AAHs, morphologically low-grade AAH-like lesions and carcinoma in situ (bronchioloalveolar carcinoma component) are often observed at the periphery of invasive adenocarcinomas. It is therefore possible that such morphological heterogeneity represents a cross sectional view of clonal evolutions within individual tumors, although one might argue that AAH-like lesions at the periphery may be nonneoplastic changes resembling reactive proliferation of type II pneumocytes.

It has been suggested that sequential accumulation of multiple genetic alterations occurs in a multistep, sequential progression from adenoma with low-grade dysplasia eventually to invasive and metastatic overt carcinoma.2 A number of chromosomal regions have been shown to be affected in invasive lung cancers, which include 1p, 2q, 3p, 5q, 8p, 9p, 11p, 13q, 17p, 18q, and 22q.8-11 Among these, loss of heterozygosity (LOH) on 2q, 5q, 9p, 18q, and 22q was previously reported to be associated with advanced disease stage and/or tumor metastasis.12,13 In contrast, many studies showed that LOH at 3p and 17p lack such associations,14-18 suggesting that they occur as early molecular events during tumor progression. Furthermore, allelic loss at 3p and 17p was frequently demonstrated in histologically normal epithelium of smokers.19-21 Three distinct putative tumor suppressor genes on 3p25, 3p21.3, and 3p14 have been suggested to be involved,22 whereas the p53 gene at 17p13.1 has been identified as a target for 17p deletions.23 In addition, we have recently shown the presence of a commonly deleted region at 17p13.3.24 Interestingly, LOH at 17p13.3 was observed even in cases without LOH at 17p13.1, suggesting its independent and early occurrence. Nevertheless, previous arguments on genetic progression in lung cancer development, including ours, were essentially based on the statistical correlation between frequencies of each genetic alteration and histological and/or disease progression.

In the present study, we examined topographical distribution of LOH events occurring in the process of neoplastic progression within individual tumors and asked whether previous inferences are indeed applicable to the progression scheme within individual tumors. Accordingly, we examined multiple pathologically well-defined specimens from individual tumors to investigate whether and which genetic alterations are accumulated in relation to morphological progression in individual tumors.


   Materials and Methods
Top
 Abstract
 Introduction
 Materials and Methods
Results
 Discussion
 References
 
Lung Cancer Tissues

Eight cases of adenocarcinoma and two cases of squamous cell carcinoma were selected from the files of the Department of Pathology and Clinical Laboratories, Aichi Cancer Center Hospital. Using serial sections of paraffin-embedded tissues, three individual lesions in each tumor were microdissected with a micromanipulator (Narishige, Tokyo, Japan). Microdissected specimens were digested in a lysis buffer as previously reported25 and used as templates for polymerase chain reactions. Normal control DNAs were extracted from the corresponding lymph nodes without metastasis. In the present study, the term "adenocarcinoma in situ " was used in accordance with the criteria previously used by Hung et al26 and included the lesions with nuclear features falling within the cytological criteria of malignant cells but without invasive or destructive growth.

Assays for LOH

Polymerase chain reaction amplification was performed to examine LOH at each of the 10 microsatellite markers. Primer sequences were obtained from the Genome Database through their on-line server (http//:www.gdb.org). Chromosomal locations and types of repeats of each microsatellite marker for polymerase chain reaction are listed in Table 1 . Using AmpliTaq Gold polymerase (Perkin Elmer, Foster City, CA), polymerase chain reaction amplification was performed for 45 cycles in a solution of 10 mmol/L Tris-HCl (pH 8.3), 50 mmol/L KCl, 1.5 mmol/L MgCl2, 0.2 mmol/L dNTP, and 0.5 µmol/L each of primers in the presence of [32P]-dCTP. Polymerase chain reaction products were electrophoretically separated on 6% denaturing polyacrylamide gels and visualized by exposure to X-ray films. Microsatellite analysis detects allelic imbalances including both allelic gains and losses. Karyotypic8,27 and comparative genomic hybridization analyses,28 however, have indicated the frequent occurrence of allelic losses, but not gains in the regions examined here. This suggests that the observed allelic imbalance was likely to have resulted from allelic losses rather than gains.


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  		Table 1. Microsatellite Markers Used in the Present Study

 

   Results
Top
 Abstract
 Introduction
 Materials and Methods
 Results
Discussion
 References
 
Selection of the Lesions Examined

We first reviewed a consecutive panel of adenocarcinomas in our department, and selected cases representative of the following two types: five adenocarcinoma cases showing heterogeneous morphology within each tumor mass and three with a relatively homogenous morphology. Two cases with squamous cell carcinoma, which were accompanied with adjacent hyperplastic and/or dysplastic regions, were also included. Detailed histological features of each lesion are summarized in Table 2 . In each case, the selection of three portions for analysis was done as follows. In the five cases with morphologically heterogeneous adenocarcinomas, three morphologically distinct portions were selected such that they represent a range from the lowest-grade morphology (designated hereafter as A) to the most malignant, invasive regions, designated C. Portions with intermediate-grade morphology, designated B, were also examined, which mostly showed in situ carcinoma appearances. In the three cases with morphologically homogeneous adenocarcinomas, three regions of each tumor were microdissected from peripheral (A) and central (C) portions as well as from an area in-between (B), and examined individually. In the cases of squamous cell carcinoma, portions designated as A were from hyperplastic bronchial epithelium, B from either high-grade dysplasia or carcinoma in situ, and C from the most invasive portions, all of which were contiguous in each tumor. Representative figures are shown in Figures 1, 2, and 3 .


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  		Table 2. Histopathological Characteristics of Tumors Examined

 


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  		Figure 1. Analysis of LOH in an adenocarcinoma (case 5) with a heterogeneous histological appearance (mixed adenocarcinoma with bronchioloalveolar component in WHO classification of 1999). This tumor is composed of carcinoma in situ (bronchioloalveolar carcinoma component) at the periphery (A), invasive carcinoma with a solid growth pattern in the central region (C) and papillary carcinoma in-between (B). Note that heterozygosity of the TP53 locus at 17p13.1 is retained, whereas D17S1174 at 17p13.3 is deleted in all of the portions examined. LOH is absent at D3S1151. LOH at the INFA locus at 9p21 is seen in both B and C portions, but not in the lowest-grade portion at the periphery of the tumor.

 


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  		Figure 2. Analysis of LOH in an adenocarcinoma (case 7) with a homogeneous histological appearance throughout the tumor. LOH at TP53, D17S1174, and D17S695 is present in all three samples from peripheral (A), intermediate (B), and central (C) regions. In contrast, both alleles at D354103 are retained.

 


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  		Figure 3. Analysis of LOH in a squamous cell carcinoma case (case 9) showing contiguous lesions of hyperplasia (A), severe dysplasia (B), and invasive squamous cell carcinoma with central necrosis (C). LOH at 2q (D2S1384) and on 9p (INFA) is seen solely in invasive carcinoma (C).

 
Genetic Analysis of Samples from Different Portions in Individual Tumors (Table 3)

LOH at the TP53 locus in the morphologically most advanced regions in each tumor were present in six of 10 cases, whereas eight carried LOH at 17p13.3. Notably, LOH at 17p13.3 was detected in the absence of LOH at TP53 (cases 4 and 5), confirming our previous study on a different set of lung cancer patients.24 When LOH was present in adenocarcinomas, topographical differences in LOH among the three-microdissected lesions were not seen, and the allelic pattern of deletions was concordant in each lesion.


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  		Table 3. Genetic Analysis of Samples from Different Portions in Individual Tumors

 
LOH in at least one or more loci on 3p was observed in six of 10 cases. Six of the 10 informative cases showed LOH at 3p14.2 (FHIT), three of six at 3p21 and three of eight at 3p25. Topographically, these genetic alterations were also uniformly distributed in the three lesions examined in each tumor.

We then examined an additional four loci including 2q, 9p, 18q, and 22q, which have been suggested to be related to the progression of lung cancers. LOH at 9p21 was observed in all of the eight informative cases. It was notable that the presence of LOH in cases 1, 5, and 9 was restricted to the portions with higher-grade lesions, suggesting the acquisition of genetic heterogeneity during progression. Although case 7 exhibited homogeneous morphology throughout the tumor, LOH of 9p was detected only in the central (C) and intermediate (B) portions, but not in the peripheral region. Notably, case 7 had low proliferative activity in all of the portions examined, which might have allowed genetically heterogeneous clonal expansion in this morphologically homogenous tumor. LOH at 2q33 was present in all three portions in case 2, whereas it was identified solely in the invasive carcinoma portion of case 9 and in the carcinoma in situ lesion of case 10. LOH at 18q21 and 22q13 was detected in the invasive carcinoma portion of a single case (case 1), although this case also had LOH at 18q21 in all three portions examined.


   Discussion
Top
 Abstract
 Introduction
 Materials and Methods
 Results
 Discussion
References
 
It has been suggested that certain types of tumor suppressor genes may be involved in the early phase of tumorigenesis, whereas others might play a role in late events during tumor progression. However, such inferences were obtained based essentially on statistical arguments through the analysis of a set of different tumors and it has not been specifically addressed in lung cancer whether they are indeed applicable to the progression scheme in individual tumors. An alternative approach for those relying on the statistical correlation between the frequencies of each genetic alteration and histological and/or disease progression thus seemed to be necessary, but it has rarely been taken in the studies of genetic changes involved in lung cancer. In this regard, Ohshima et al29 previously reported occasional presence of K-ras gene mutations in adjacent preneoplastic lesions such as AAH-like lesions. In the present study, we examined topographical distribution of LOH events at multiple chromosomal loci occurring during neoplastic progression within individual tumors.

Using multiple microdissected specimens representative of morphological progression within individual tumors, we have shown that LOH at 3p and 17p are present at high frequency even in the lowest-grade portions and that identical alleles were found to be deleted in all portions examined in each affected tumor, even though they are morphologically quite divergent. These results suggest that LOH at 3p and 17p may be crucial steps in the early phase of tumorigenesis and that they are retained throughout successive clonal evolutions. This is supported by the evidence that in the cases without LOH at 3p and/or 17p, all of the portions carried retained alleles, and the LOH was not acquired with the progression to higher-grade morphology and invasive properties. Another important point of this study is that LOH at 17p13.3 was detected even in the absence of 17p13.1, where the p53 gene resides, showing clonal stability throughout morphological progression within individual tumors. The present findings thus support our previous inference that a putative tumor suppressor gene at 17p13.3 may play a role in the early phase of lung carcinogenesis.24

We observed LOH on at least one of the three loci on 3p and/or the two loci on 17p in every tumor examined. However, it is uncertain at present why these presumably early lesions are not present in all tumors. It is possible that LOH at 3p and/or 17p is detected at higher frequency with the aid of additional markers closer to the putative target genes. A number of cell types are thought to be potential precursors of lung cancers and distinct initiation events may be involved depending on which differentiation pathway they are committed. Therefore, it may also be probable that certain cell types do not require inactivation of all of the putative tumor suppressor genes on 3p and 17p.

A similar approach was previously used by Boland et al30 for the analysis of tumor progression schemes in colon cancers. They used multiple microdissected samples from colonic tumors showing cross sections of "adenoma-carcinoma sequence." At one time point a clear and abrupt occurrence of LOH at 5q at the transition phase from normal epithelium to adenoma was revealed. Therefore, it is surmised that LOH at 3p and 17p in the neoplastic progression of lung cancers might have a role as early events comparable to that of 5q in colon cancers.

It should be noted that marked distinctions between LOH at 3p and 17p, and those on other loci such as 9p deletions and the latter, were often present in restricted portions within individual tumors. Shiseki et al13 reported an association between LOH at 9p and the advanced disease stage, whereas Kishimoto et al25 described this as one of the earliest events during tumor progression through analysis of preneoplastic lesions independent from main tumors. In the present study, the highest-grade, most malignant portions were shown to carry 9p deletions at even higher frequency than 3p or 17p deletions. However, it should be noted that the present findings also suggest that the accumulation of LOH at 9p can occur at various stages of tumor progression within individual tumors, indicating a clear distinction with LOH at 3p and 17p. Although a few of the tumors thus far examined showed genetic homogeneity despite great morphological divergence, genetic alterations might be present on loci other than those examined in the present study.

In summary, we examined the topographical distribution of LOH at 3p and17p as well as other loci including 2q, 9p, 18q, and 22q. The present findings suggest early occurrence of 3p and/or 17p deletions and successive clonal expansion during the progression of individual tumors. In contrast, LOH at other loci, such as 9p, seemed to be acquired at various stages during tumor progression. Similar future studies analyzing more genetic loci with a larger number of cases are warranted. Furthermore, as lung cancers result from various genetic and epigenetic alterations, it should also be interesting to examine the topographical differences of other changes such as DNA methylation.


   Footnotes
 
Address reprint requests to Dr. Yasushi Yatabe, Department of Pathology and Clinical Laboratories, Aichi Cancer Center Hospital, 1-1 Kanokoden, Chikusa-ku, Nagoya 464-8681, Japan. E-mail: yyatabe{at}aichi-cc.pref.aichi.jp

Supported by a Grant-in-Aid for the Second Term Comprehensive Ten-Year Strategy for Cancer Control and a Grant-in-Aid for Cancer Research from the Ministry of Health and Welfare, Japan.

Accepted for publication June 6, 2000.


   References
Top
 Abstract
 Introduction
 Materials and Methods
 Results
 Discussion
 References
 

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