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[Cancer Research 59, 1437-1441, April 1, 1999]
© 1999 American Association for Cancer Research

Advances in Brief

Allelotype of Gastric Adenocarcinoma1

Aron S. Yustein, Jeffery C. Harper, Gina R. Petroni, Oscar W. Cummings, Christopher A. Moskaluk and Steven M. Powell2

Divisions of Gastroenterology and Hepatology [A. S. Y., J. C. H., S. M. P.] and Biostatistics and Epidemiology [G. R. P.], and Department of Pathology [C. A. M.], University of Virginia Health Sciences Center, Charlottesville, Virginia 22908-0013, and Department of Pathology, Indiana University School of Medicine, Indianapolis, Indiana 46202 [O. W. C.]


   ABSTRACT
Top
 ABSTRACT
Introduction
 Materials and Methods
 Results
 Discussion
 REFERENCES
 
Gastric adenocarcinoma is a leading cause of cancer mortality worldwide. Yet, the underlying molecular events important in the development of this cancer are largely undefined. Thus, we performed a comprehensive survey for allelic loss on our panel of xenografted human gastric carcinomas.

Contaminating normal stromal cells of primary cancers often limit mutational analyses. Xenografted samples of our gastric carcinomas provided optimally enriched tumors for neoplasia that clearly and sensitively demonstrated genetic alterations. Additionally, total absence of allelic signals in these xenografted samples confirmed true loss of alleles rather than just allelic imbalance.

Analysis of at least two highly polymorphic microsatellite markers per nonacrocentric chromosomal arm in our xenografted human gastric carcinomas demonstrated significant loss of heterozygosity well above background levels at 3p, 4p, 5q, 8p, 9p, 13q, 17p, and 18q. Several of these loci represent novel findings of significant loss in gastric cancers. On chromosome 17p, p53 is known to be inactivated either by mutation or deletion in a majority of gastric carcinomas. The critical target(s) of inactivation in gastric cancers at these other loci remain to be characterized.


   Introduction
Top
 ABSTRACT
 Introduction
Materials and Methods
 Results
 Discussion
 REFERENCES
 
Gastric adenocarcinomas account for an estimated 10% of all malignancies worldwide (1) . It is the number one cause of cancer mortality in many developing nations such as Costa Rica, Chile, and Brazil and endemic in areas of China, Japan, and Korea (2) . It is estimated that 22,600 individuals will be diagnosed with stomach cancer, and 13,700 will die from this illness in the United States during 1998 (3) . Thus, gastric cancer remains a significant contributor to the world’s health burden.

Carcinogenesis is now established to be a multistep process characterized by the accumulation of genetic alterations involving a variety of oncogenes and tumor suppressor genes. TSGs3 are felt to participate in tumor formation and progression when inactivated, commonly by gene mutation or allelic deletion. LOH analysis of colon cancers led to the identification of important loci critical to its development (4) . Regions that demonstrate high rates of LOH represent loci that potentially harbor tumor suppressor genes. When analysis of LOH is extended to multiple chromosomal arms for a particular tumor, a distinct allelotype can be generated.

Characterization of the genetic events that occur during tumorigenesis has been facilitated through recent advances in the field of molecular genetics. Unveiling the human genome has revealed distinct areas that feature simple tandem bp repeats. These sequences, called microsatellites, are ubiquitous, and they can serve as markers to define the allelic status of a tumor at a variety of chromosomal positions.

Xenografting human tumor tissue into immunodeficient mice provides samples enriched for neoplastic cells that are optimal for molecular analysis. Contamination with normal DNA, which creates false-negative results with respect to LOH, has been a major limitation in these analyses. Xenografted tumors virtually eliminate that contamination problem because they are composed of neoplastic human cells supported by nonneoplastic murine stromal cells, which usually fail to amplify with primers designed from nonintronic human DNA sequences. Xenografted tumor DNA has been shown to remain stable in relation to the primary lesion’s DNA (5) . Studies using this technique have thus far led to important discoveries of genetic changes underlying colorectal (i.e., SMAD2) and pancreatic (i.e., SMAD4) cancers (6 , 7) .

The genetic events that drive the neoplastic process in gastric adenocarcinoma remain largely unknown. Inactivation of the tumor suppressor gene p53 on chromosome 17p has been demonstrated in a majority of gastric cancers (8) . Limited LOH studies have shown other frequent allelic loss on chromosomes 1q, 5q, 12q, and 18q (9, 10, 11) . One of the most frequently lost chromosomal regions, 3p, has had homozygous deletions observed in several gastric cancer cell lines (12) .

To systematically characterize sites of candidate tumor suppressor genes involved in gastric carcinogenesis, we surveyed the human genome for significant allelic loss in 18 xenografted gastric adenocarcinomas. Rates of LOH were determined for each of the 39 nonacrocentric chromosomal arms by studying at least two highly informative microsatellite markers per arm. Herein, we demonstrate high degrees of allelic loss (>=50%) on several chromosomal arms, some of which have not previously been reported for gastric carcinomas.


   Materials and Methods
Top
 ABSTRACT
 Introduction
 Materials and Methods
Results
 Discussion
 REFERENCES
 
Specimens.
From 1995 through 1998, fresh tissue from 18 surgically resected gastric adenocarcinomas was collected from surgical pathology at the Universities of Indiana and Virginia according to Internal Review Board protocols. Specimens were collected in standard RPMI 1640 and stored on ice for xenografting. Xenografted tumor tissue was also processed for histopathological confirmation. Normal tissue from resected specimens or peripheral blood samples was also procured.

Xenografting and DNA Extraction.
Small pieces of tumor tissue were soaked in Matrigel (Collaborative Biomed Research) and then implanted s.c. into the flanks of immunodeficient mice (nu/nu from Harlan or SCID from Charles River) for xenografting growth. First-passage tumors were harvested when their diameter reached ~1 cm, and genomic DNA was extracted by a standard organic method. Corresponding normal tissue from each patient was also extracted for DNA in a similar fashion.

Allelotyping.
Highly informative microsatellite map-pair primers were obtained from Research Genetics (Huntsville, Alabama) and end-labeled with [{gamma}-32P]ATP in a standard tyrosine kinase reaction. A list of those primers used for PCR amplification is shown in Table 1Citation . Optimal PCR conditions were obtained for each marker using control human DNA and confirmed not to amplify mouse tissue using genomic mouse DNA as template. Amplification was performed on each tumor and normal DNA sample pair and subsequently electrophoresed on 7% acrylamide gels.


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  		Table 1 Clinicopathological features of xenografted human gastric carcinomas

 
Normal samples with two distinctly sized alleles at a particular marker were termed "informative." Each informative case’s tumor and normal DNA were then compared with respect to allelic band intensity using a PhosphorImager (Molecular Dynamics, Sunnyvale, California). A comparative ratio was produced by dividing the tumor allelic ratio by the normal allelic ratio. A comparative ratio >=1.5 was considered to represent allelic loss, and <1.5, allelic retention. Those normal samples with only one allelic band were termed "non-informative." Tumors that demonstrated differently sized alleles compared with their respective normal sample were scored as "microsatellite instable."

Statistical Methods.
For each sample, overall allelic loss (fractional allelic loss) was defined as the number of chromosomal arms displaying allelic loss divided by the number of informative arms. The Shapiro-Wilk test was used to test whether allelic loss was normally distributed. There was no indication that the normality assumption was inappropriate (P = 0.51); therefore, individual regression models were used to investigate potential association between overall allelic loss and clinical prognostic factors such as age, stage of disease, site, Lauren’s histopathological subtype (i.e., intestinal or diffuse; Ref. 13 ), and degree of differentiation. T-statistics were used to test the null hypothesis that the parameter was equal to zero. All significant tests were considered to be exploratory, and a P < 0.10 was interpreted to indicate a meaningful association.


   Results
Top
 ABSTRACT
 Introduction
 Materials and Methods
 Results
Discussion
 REFERENCES
 
We comprehensively surveyed 18 xenografted human gastric adenocarcinomas for LOH. The clinicopathological features of these cases are summarized in Table 1Citation . The histopathological morphology of the primary gastric carcinomas and the xenografted tumors were similar on analysis by pathologists (O. W. C. and C. A. M.).

A panel of 78 highly informative microsatellite map-pair primers for microsatellite amplification was used (Table 2)Citation . Each nonacrocentric chromosomal arm was analyzed with two different markers, ensuring that at least 67% of the tumors were informative on each chromosomal arm. On average, >90% of the tumors were informative for at least one of these markers at each chromosomal arm.


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  		Table 2 Microsatellite markers

 
Allelic losses were clearly observed in these enriched neoplastic xenografted samples. Fig. 1Citation illustrates typical loss of heterozygosity or retention of heterozygous alleles or noninformative cases for several different markers. Moreover, absence of an allele (e.g., total loss) rather than just imbalance was also able to be distinguished on analyzing these xenografted samples.



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  		Fig. 1. LOH analysis. Displayed are representative examples of LOH noted at three microsatellite loci. At marker D3S2402, cases 1, 2, and 3 exhibit LOH in the tumor DNA (Lane T) compared with their corresponding normal DNA (Lane N), whereas case 4 is noninformative at this locus. At marker D4S2639, cases 2, 3, and 4 exhibit LOH in the tumor DNA compared with the corresponding normal DNA, whereas case 5 displays retained alleles and case 1 is not informative at this locus. At marker D9S741, cases 1and 2 exhibit LOH, whereas case 3 illustrates retained alleles at this locus.

 
The highest rates of LOH were seen at D17S974 (77%), D5S393 (73%), D17S947 (70%), D5S816 (69%), D3S2402 (64%), D3S1234 (64%), D4S2639 (64%), D4S1601 (60%), D9S1118 (60%), D5S816 (60%), D9S171 (58%), D8S1106 (58%), D18S474 (58%), D13S162 (57%), ERC-5 (55%), and D18S46 (53%). Fig. 2ACitation displays the overall tumor status (alleles lost or retained or informativeness) at each chromosomal arm. LOH rates for each chromosomal arm were calculated by dividing the number of tumors that showed allelic loss by the total number of informative cases for that particular arm. High degrees of allelic loss on several chromosomal arms [3p (81%), 4p (64%), 5q (69%), 8p (57%), 9p (64%), 13q (59%), 17p (80%), and 18q (61%)] are demonstrated in our xenografted gastric cancers. These rates of loss are significantly above background losses that were observed at other loci. Several of these frequently lost loci have not been reported previously in gastric cancer. Fig. 2BCitation illustrates the comprehensive allelotype and rate of losses observed at the different chromosomal arms.



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  		Fig. 2. Allelotype of xenografted gastric cancers. A, overall tumor status of 18 xenografted human carcinomas. Black L box, allelic loss; gray R box, retained heterozygous alleles; white N box, noninformative cases observed. The Arm column designates the 39 nonacrocentric arms examined. The Loss column displays the rate of loss at each chromosomal arm as a percentage of informative cases in analysis of two highly informative microsatellite markers per arm. B, the rate of allelic loss observed on designated chromosomal arms in our study of informative human xenografted gastric cancers in graphic form.

 
With 18 cases, the power to assess associations between allelic loss and clinical prognostic factors is limited. Exploratory analyses did indicate possible associations between amount of allelic loss with site (P = 0.07, with proximal location indicating lower overall rates of loss) or degree of differentiation (P = 0.05, with poorly differentiated samples indicating lower overall rates of loss than well or moderately differentiated cases). Xenografted tumor 155, a poorly differentiated distal stage III gastric cancer, had the most frequent overall rate of allelic loss, whereas tumor 169, a moderately differentiated proximal stage I gastric cancer, had the second most frequent overall rate of allelic loss. Xenografted tumor 171, a moderately differentiated proximal stage II gastric cancer, had minimal overall allelic loss, whereas similar or earlier staged cases had significant overall allelic losses (i.e., tumor 170, 49%, and tumor 159, 39%). These data did not indicate a strong association with particular histopathological subtypes according to Lauren’s criteria (i.e., intestinal or diffuse, P = 0.13).

Additionally, during our microsatellite analysis we also observed instability in 3 of our 18 xenografted tumors. Fig. 3Citation illustrates examples of instability observed in these cases. Two tumors, 165 and 175, exhibited a relatively high rate of microsatellite instability (>10 loci instable), whereas one other tumor, 162, exhibited a relatively low rate of instability (only 1 loci instable). This instability was confirmed in corresponding primary gastric cancers in all three cases. This finding is in agreement with previous reports of microsatellite instability noted in a subset of gastric cancers (14) . Interestingly, these instable cases also exhibited a significant rate of allelic loss.



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  		Fig. 3. Microsatellite instability. Illustrated are representative cases of microsatellite instability observed in our study of LOH. On analysis of marker D4S1601, case 2 exhibits an abnormally sized allele in the tumor DNA (Lane T) compared with its corresponding normal DNA (Lane N). Case 1 at this locus displays LOH, and case 3 is noninformative. At marker D3S1234, case 2 exhibits an abnormally sized allele in the tumor DNA compared with its corresponding normal DNA. Case 5 displayed LOH, case 4 retained alleles, and cases 1 and 3 showed noninformativity at this locus.

 

   Discussion
Top
 ABSTRACT
 Introduction
 Materials and Methods
 Results
 Discussion
REFERENCES
 
Our data generated a comprehensive allelic loss pattern for gastric adenocarcinomas. The allelotype defined by our results of specific significant loss using xenografted primary tumors suggests the presence of candidate TSGs involved in gastric carcinogenesis on chromosomes 3p, 4p, 5q, 8p, 9p, 13q, 17p, and 18q. The involvement of several chromosomes is consistent with the multistep process known to govern cellular transformation.

Interstitial deletions on 3p have been reported in a variety of malignancies including nonpapillary renal cell carcinoma and breast cancers (15 , 16) . In gastric cancers, Kastury et al. (12) found 46% loss at 3p14. Our xenografted tumors show an overall LOH of >50% on 3p, with 64% loss at D3S1234, which is known to be near 3p14.2. These results support the presence of a putative TSG on the short arm of chromosome 3 involved in gastric carcinogenesis. The Von Hippel Landau gene at 3p25–26 is an established TSG on chromosome 3. FHIT is known to reside at 3p14 with aberrant transcripts and loss of protein expression of this gene observed in a majority of gastric carcinomas studied, implicating a role in gastric tumorigenesis (17 , 18) .

Our gastric cancer allelotype also demonstrates high rates of loss on the short arm of chromosome 4. Significant loss in this region is a novel finding for gastric cancers. Research involving other solid tumors including colorectal and ovarian cancers have found 20–40% LOH on 4p (4 , 19) . The critical target(s) of inactivation on 4p has yet to be characterized. Our results indicate relatively high rates of LOH in the region of 4p15, supporting the existence of a novel TSG important in gastric tumorigenesis.

Chromosome 8p has been shown to demonstrate significant loss of heterozygosity in different cancers, most notably bladder and prostate cancers (20 , 21) . It has been suggested that this region may harbor genes responsible for tumor invasion and/or metastasis (22) . There are no previous reports of significant LOH on 8p in gastric cancers; thus, our finding of significant LOH on this chromosomal arm appears novel for gastric cancer.

Several chromosomal arms with high LOH in our study are known to harbor defined TSGs. The Adenomatous Polyposis Coli gene, which has documented importance in colorectal tumorigenesis, is located on 5q. Several reports of 5q loss in gastric malignancies exist, but the majority report LOH rates around 35% near the Adenomatous Polyposis Coli locus (10) . Our results of 69% LOH at 5q would appear to indicate the presence of a unique TSG involved in gastric tumorigenesis on this chromosomal arm. Likewise, our data suggest the possibility of a novel TSG on chromosome 9p. The p16 gene has been shown to play an important role in multiple tumor types including pancreas, lung, and head/neck cancers (7 , 23 , 24) . However, evaluation of gastric malignancies have failed to reveal any significant mutations of this gene (25) .

At least two well-defined TSGs, the Retinoblastoma and BRCA1 (breast cancer) genes, are located on chromosome 13p. Other solid tumors, such as prostate, have been shown to have significant LOH on 13q at loci distinct from these two TSGs (26) . Intermediate LOH in gastric cancers has been described in a study that found an overall rate of 41% in 36 primary tumors (27) . Our high rate of LOH (59%) at markers telomeric to Retinoblastoma and BRCA1 support the presence of a TSG on 13q involved in gastric tumor development.

Chromosome 18q has been extensively studied in various malignancies, particularly those of the digestive tract. The SMAD4 gene has been shown to be an important factor in the development of pancreatic and colon neoplasms (28) . SMAD2 and Deleted in Colon Cancer have been found inactivated in subgroups of colon cancers (6 , 29 , 30) . Studies of gastric malignancies using markers near the SMAD4 and Deleted in Colon Cancer genes have found moderate rates of LOH but infrequent gene mutations (31 , 32) . Our findings of 61% allelic loss at 18q support the existence of a putative TSG(s) in this region involved in gastric tumorigenesis.

Chromosome 17p is known to harbor the well-characterized p53 tumor suppressor gene. Loss or inactivation of p53 function is well documented in the majority of human tumors including gastric cancers. Chromosomal loss of 17p ranging from 36 to 64% have been reported in sporadic gastric adenocarcinomas (9 , 33) . Our results with markers near the p53 locus support these prior findings.

In conclusion, this comprehensive allelotyping of gastric adenocarcinomas demonstrated the usefulness of xenografted human gastric cancers that allowed us to analyze neoplastic-enriched samples, thereby facilitating accurate allelic loss status determination. Significant allelic loss well above background levels at 3p, 4p, 5q, 8p, 9p, 13q, 17p, and 18q suggests the involvement of several tumor suppressor genes in gastric tumorigenesis. Further studies of these loci, some of which are novel findings for gastric cancer, are planned to identify target(s) of inactivation and better assess associations between allelic loss and clinical prognostic factors.


   ACKNOWLEDGMENTS
 
We are grateful to our colleagues who helped us obtain tissue for xenografting.


   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 in part by NIH Grant CA6790001. Back

2 To whom requests for reprints should be addressed, at University of Virginia Health Sciences Center, Box 10013, Charlottesville, Virginia 22906-0013. Back

3 The abbreviations used are: TSG, tumor suppressor gene; LOH, loss of heterozygosity. Back

Received 12/17/98. Accepted 2/16/99.


   REFERENCES
Top
 ABSTRACT
 Introduction
 Materials and Methods
 Results
 Discussion
 REFERENCES
 

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A. Vecchione, H. Ishii, Y.-H. Shiao, F. Trapasso, M. Rugge, J. F. Tamburrino, Y. Murakumo, H. Alder, C. M. Croce, and R. Baffa
Fez1/Lzts1 Alterations in Gastric Carcinoma
Clin. Cancer Res., June 1, 2001; 7(6): 1546 - 1552.
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M. J. Fisher, A. K. Virmani, L. Wu, R. Aplenc, J. C. Harper, S. M. Powell, T. R. Rebbeck, D. Sidransky, A. F. Gazdar, and W. S. El-Deiry
Nucleotide Substitution in the Ectodomain of TRAIL Receptor DR4 Is Associated with Lung Cancer and Head and Neck Cancer
Clin. Cancer Res., June 1, 2001; 7(6): 1688 - 1697.
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Y. H. Kim, N.-G. Kim, J. G. Lim, C. Park, and H. Kim
Chromosomal Alterations in Paired Gastric Adenomas and Carcinomas
Am. J. Pathol., February 1, 2001; 158(2): 655 - 662.
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T. Grundei, H. Vogelsang, K. Ott, J. Mueller, M. Scholz, K. Becker, U. Fink, J. R. Siewert, H. Höfler, and G. Keller
Loss of Heterozygosity and Microsatellite Instability as Predictive Markers for Neoadjuvant Treatment in Gastric Carcinoma
Clin. Cancer Res., December 1, 2000; 6(12): 4782 - 4788.
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R. Mei, P. C. Galipeau, C. Prass, A. Berno, G. Ghandour, N. Patil, R. K. Wolff, M. S. Chee, B. J. Reid, and D. J. Lockhart
Genome-wide Detection of Allelic Imbalance Using Human SNPs and High-density DNA Arrays
Genome Res., August 1, 2000; 10(8): 1126 - 1137.
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R. Baffa, R. Santoro, F. Bullrich, B. Mandes, H. Ishii, and C. M. Croce
Definition and Refinement of Chromosome 8p Regions of Loss of Heterozygosity in Gastric Cancer
Clin. Cancer Res., April 1, 2000; 6(4): 1372 - 1377.
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T. Ushijima, M. Yamamoto, M. Suzui, T. Kuramoto, Y. Yoshida, T. Nomoto, M. Tatematsu, T. Sugimura, and M. Nagao
Chromosomal Mapping of Genes Controlling Development, Histological Grade, Depth of Invasion, and Size of Rat Stomach Carcinomas
Cancer Res., February 1, 2000; 60(4): 1092 - 1096.
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