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Departments of Anatomical and Cellular Pathology [K-W. L., A. B-Y. H., K-F. T., Y-S. T., S. Y-Y. C., K-F. M., J. C. K. L., D. P. H.], and Clinical Oncology [P. M. L. T.], Prince of Wales Hospital, The Chinese University of Hong Kong, Hong Kong SAR, China
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ABSTRACT |
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Introduction |
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Previous etiological studies demonstrated that the development of NPC might be attributable to a complex interaction of genetic factors, dietary exposure to chemical carcinogens, and EBV infection (1) . Relatively little information of the NPC-associated genetic alterations is known. Hence, identification of genetic changes in this cancer is crucial in revealing the molecular basis of NPC tumorigenesis. This may lead to the development of molecular markers for early diagnosis, prognosis, and monitoring of disease progression. Previous studies have shown that mutations of the common tumor suppressor, Rb and p53 genes, are rare in NPC (1) . LOH studies unveiled frequent allelic losses on chromosomes 3p, 9p, 11q, 13q, and 14q (2, 3, 4, 5, 6, 7, 8, 9) . The highest frequencies of allelic deletion were found on 3p and 9p. By detailed mapping and investigation of candidate tumor suppressor genes in 9p, we illustrated the inactivation of the p16 gene to be important in the tumorigenesis of NPC (4 , 10 , 11) . A functional tumor suppressor locus has also been identified on 3p21 by monochromosome transfer (12) . Recently, CGH study has illustrated high incidences of loss and gain of multiple chromosome arms (3p, 9q, 11q, 12q, and 14q) in this cancer (13) . To further investigate the critical genetic events leading to the tumor evolution, we performed a comprehensive allelotype analysis of microdissected primary NPC using 382 microsatellite markers. We aim to determine the frequency of chromosomal deletion and the extent of deleted regions on all autosomal arms. The subsequent high-resolution allelotypes will identify MDRs of the genome that may harbor candidate tumor suppressor genes important for the development and progression of NPC.
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Materials and Methods |
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Microdissection and DNA Extraction.
For each primary tumor, 40–60 serial frozen sections (5 µm thick)
were subjected for microdissection manually or by laser capture
microdissection, under the guidance of a pathologist. All sections were
lightly stained with hematoxylin. Neoplastic cells of the tumor samples
were isolated and collected for DNA extraction. Isolated tumor cells
and blood samples were digested with proteinase K and extracted with
phenol/chloroform as described (2)
.
High-Resolution Allelotyping.
Three hundred and eighty-two microsatellite loci derived from the 22
autosomes were examined in this high-resolution allelotyping study.
Fluorescent dye-labeled primer pairs flanking polymorphic
microsatellite loci were obtained from Applied Biosystems (Foster City,
CA). All primer pairs used were from the ABI PRISM Linkage Mapping Set
MD-2.4
The average interval of the loci is about 10 cM. Multiplex PCR was set
up to examine two loci in each reaction. Each PCR reaction mixture
contained 50 ng of DNA, 0.33 µM each primer, 10
mM Tris (pH 8.3), 50 mM KCl, 2.5 mM
MgCl2, 250 µM each deoxynucleotide
triphosphate, and 0.6 unit AmpliTaq Gold polymerase (Applied
Biosystems, Foster City, CA) in a total volume of 7.5 µl. The PCR
reactions were performed in an ABI PRISM 877 integrated thermal cycler
(Applied Biosystems). Following the directions of the manufacturer,
amplification was started with 15 min at 95°C, followed by 10 cycles
composed of 15 s at 94°C, 15 s at 55°C, and 30 s at
72°C, and then 23 cycles composed of 15 s at 89°C, 15 s
at 55°C, and 30 s at 72°C. Amplified PCR products for multiple
loci were pooled, electrophoresed on an ABI PRISM 377 automated DNA
sequencer (Applied Biosystems), and analyzed with Genescan 2.1 software
(Applied Biosystems).
Assessment of LOH.
For each informative locus of the NPC samples and its corresponding
normal control, the allelic ratio (AR) was calculated. The
AR was determined by measuring the peak height of the
smaller allele (allele 1) relative to that of the large allele (allele
2). The LOH value was defined as follows: LOH value = AR of normal/AR of tumor. Depending on which
allele is lost, allele 1 or allele 2, the LOH values of <0.5 or >1.5
were considered to be indicative of LOH. Both allelic loss and gain can
be presented as LOH in microsatellite analysis. We have used CGH to
confirm whether our allelic imbalance refers to gain or loss. CGH
analyses have been performed in 15 of 27 cases of these NPCs and
reported previously (13)
. Gains of chromosomes 1q, 8q,
12p, and 12q were detected frequently in these cases. As a result, LOH
on these chromosome arms were considered as allelic imbalance. MSI was
defined as shifts of bands of tumor sample when compared with the
corresponding normal control.
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Results |
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TopABSTRACTIntroductionMaterials and MethodsResultsDiscussionREFERENCES |
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. LOH of each locus was scored according to the criteria mentioned in
"Materials and Methods." Figs. 2
and 3
summarize the percentage of LOH at each chromosomal arm. LOH affecting
loci on multiple chromosomes were observed in all of the NPC samples.
Frequencies of LOH for individual chromosomal arms varied between 7.4%
(21q) and 96.3% (3p). The mean percentage of LOH was 32.8% ± 19.4%. In the present study, 52.2% (mean percentage + SD: 32.8 + 19.4%) was chosen to be a significant
percentage of LOH in NPC. This represents the 99% confidence upper
limit for the overall rate of random chromosome loss or imbalance in
tumors. Frequencies of LOH on 3p (96.3%), 9p (85.2%), 9q (88.9%),
11q (74.1%), 12q (70.4), 13q (55.6%), 14q (85.2%), and 16q (55.6%)
were higher than this baseline level (52.2%). Among these eight
chromosome arms, the remarkable high frequency of LOH on 3p, 9p, 9q,
and 14q indicated that such alterations play critical roles in NPC. The
high incidences of LOH on 3p, 9p, 9q, 11q, 13q, and 14q had also been
implicated in previous studies (2, 3, 4, 5, 6, 7, 8, 9)
. However, the
frequent microsatellite abnormalities of chromosomes 12q and 16q are
novel findings in NPC and appear as new candidates in the search for
tumor suppressor genes or amplicons. In addition, LOH on chromosomes 1p
(37.0%), 5q (44.4%), and 12p (44.4%) were also higher than the mean
percentage of LOH (32.8%) in NPC. Because only a limited number of
tumor samples were examined in the current study, no significant
association of LOH on specific chromosomal arms with the staging of NPC
was identified.
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shows the five MDRs that were defined by the tumors containing deletion
on these chromosomal arms. On chromosome 3p, a 43.2-cM MDR between
D3S1266 (3p22–24.2) and D3S1285 (3p14–21) was
delineated from the 27 microdissected NPCs. Deletion of this region was
found in 88.9% of tumors. A MDR on chromosome 11q was confined to a
20.6-cM region that lay between D11S898 (11q21–22) and
D11S925 (11q23). Twenty of 27 (74.1%) primary NPCs showed
loss of such region. Two MDRs were identified on chromosome 13q. A
32.8-cM region at 13q12–14.3 was flanked by the loci
D13S217 (13q12) and D13S153 (13q14.1–14.3).
Another deletion region is about 7.2 cM and located at
13q31–32, between D13S170 (13q31) and
D13S265 (13q31–32). The frequencies of deletion at the
regions 13q12–14.3 and 13q 31–32 were 51.9 and 48.1%, respectively.
A MDR on chromosome 14q with frequency of 23 of 27 (85.2%) in NPC was
delineated. The 28.3-cM region was mapped between D14S280
(14q24.3–31) and D14S292 (14q32.1–32.3). In chromosome
16q, the MDRs identified were flanked by the loci D16S515
(16q22.3–23.1) and D16S3091 (16q22.3–23.1). The size of
this MDR is 21.4 cM, and the frequency is 55.6% (15 of 27).
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MSI was observed in 17 of 27 (63.0%) cases of NPC. The number of loci with MSI in these tumors ranged from 1 to 4. No specific loci susceptible to these genetic alterations were observed in this cancer. On the basis of the guidelines in a recent report by Boland et al. (16) , all NPC cases were considered either as low-frequency MSI or microsatellite stable in this study. No tumors with high-frequency MSI were found.
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Discussion |
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TopABSTRACTIntroductionMaterials and MethodsResultsDiscussionREFERENCES |
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Comprehensive genomic screening has demonstrated the involvement of nonrandom chromosome abnormalities on 3p, 9p, 9q, 11q, 12q, 13q, 14q, and 16q in NPC tumorigenesis. Aberrations of tumor suppressor genes or cancer-related genes on these chromosomal arms play important roles in the development and progression of NPC. The identification of multiple genetic changes in each of the NPC tumor is consistent with the multiple-step model of tumorigenesis as in most other solid tumors. One of the unique features of NPC is the consistent presence of the EBV in all malignant cells. The expression of several viral genes, such as the EBNA-1 and LMP-1 genes, may contribute to the transformation of the nasopharyngeal epithelial cells (1) . The close association of the EBV with NPC may imply different tumorigenesis processes in NPC when compared with the other human cancers. Compared with the allelotypes of other head and neck cancers, a lower incidence of LOH on 17p and higher frequency of LOH on 16q were found in NPC (18) . It is proposed that a distinct pathway for the genesis of NPC may occur in this viral-related cancer at the head and neck region.
In concordance with our present findings, frequent LOH on 3p, 9p, 11q, 13q, and 14q have also been reported in a previous allelotyping study of NPC in Thailand, where a median incidence of this cancer is observed (17) . They have examined for genome-wide chromosome deletions in 27 primary tumors by using 56 microsatellite markers. The frequent allelic alterations on these regions have also been reported in multiple LOH studies (2, 3, 4, 5, 6, 7, 8, 9) . However, the frequencies of LOH detected on most of these reports were lower than those of the current study. Our results demonstrated that the sensitivity of LOH study was highly increased with the use of microdissection and a large panel of microsatellite markers. In addition to confirming most of the formerly reported genetic alterations, we have found frequent LOH on chromosome 16q and significant allelic imbalance on 12q. Moreover, the common chromosomal abnormalities on 1p, 5q, and 12p were first illustrated in this cancer.
Our NPC allelotype illustrated similar genetic changes to the previously reported CGH study. In CGH study, frequent losses of 3p, 9p, 9q, 11q, 13q, 14q, and 16q and gain of chromosome 12 were reported. Among the 27 microdissected tumors, 15 cases have also been subjected to CGH analysis (13) . The findings of these two analyses on the 15 samples were consistent. However, we noted that deletion of several chromosomal regions, such as 9p and 3p, were detected by allelotyping analysis but not by CGH in some of the cases. Failure in the detection by CGH might be attributable to the small size of deletion or resulting from duplication of the remaining chromosome after loss of the functional alleles. Comparison of the allelotype and CGH results indicated that the allelic imbalance in chromosome 12q and 1q were attributable to an increased copy number of these chromosome regions. It is suggested that the combination of allelotyping and CGH analysis will be the most effective approach for the identification of the genetic changes in human cancers.
The most striking finding in this study is the LOH of chromosome 3p in
almost all NPC samples (96.3%). This is in concordance with previous
reports of genetic alteration in NPC (2
, 3
, 17) . The
frequency of 3p LOH varied from 67 to 100% in different studies. Our
recent LOH study of 3p on 40 microdissected NPCs from different
geographic regions have also shown a similar frequency (95%).
Moreover, a high incidence of LOH of 3p was also detected in the normal
epithelial cells and precancerous lesions of the nasopharynx (data not
shown). These results implied that the inactivation of tumor suppressor
genes on 3p is an important and early event during the development of
NPC. According to our high-resolution allelotype, we delineated a
43.2-cM (or 
29.2 Mb) MDR region on 3p14 to 3p24.2, flanked by
D3S1285 and D3S1266. The region overlapped with
the small deletion regions identified in previous studies (2
, 3)
. One of the candidate tumor suppressors located at 3p14.2 is
the FHIT gene. The gene overlapped with the locus
D3S1300 and closed to D3S1285. Alterations of
this gene have been demonstrated in several NPC cell lines, suggesting
that the aberrant FHIT gene may be associated with the
development of NPC (19)
. Cheng et al.
(12)
have demonstrated a region with 11 Mb at 3p21
(between D3S1298 and D3S1578) that showed tumor
suppressor function in a NPC cell line HONE-1 by the monochromosome
transfer. These loci were located within our MDR region and overlapped
with the tumor suppressor loci identified in a variety of human
cancers, such as breast cancer, head and neck cancers, lung cancers,
and renal cancers (20)
. To identify the major target
gene(s) involved in NPC tumorigenesis, we will perform a detailed
deletion mapping on a larger panel of microdissected tumors, cell
lines, and xenografts. A high incidence of LOH was detected on
chromosome 9p (85.2%). This is similar to our former studies on the
frequent deletion of 9p21 and inactivation of the p16 gene
in NPC (4
, 10)
. The tumor suppressor function of the
p16 gene in NPC was further confirmed by inhibiting
tumorigenic potential with restoration of p16 in a NPC cell line
(11)
. Because the homozygous deletion of 9p21 was common
in NPC, the inactivation of other candidate genes such as
p15 and p14ARF may also involve
in the development of this cancer. Our preliminary result has also
shown aberrant methylation of the p15 gene in some NPC
primary tumors. Although LOH of 9q was found in 88.9% of NPCs in this
study, almost all of these cases showed the deletion of 9p. The loss of
both arms of chromosome 9 or the entire chromosome appeared to be a
common event in NPC.
In this study, we targeted an important tumor suppressor locus on 14q to a 28.3-cM (or 10-Mb) MDR that was between D14S280 (14q24.2–31) and D14S292 (14q32.1–32.2). The high frequency of LOH of 14q (85.2%) implicated that inactivation of this tumor suppressor may play a critical role in NPC as well as those on 3p and 9p. LOH on chromosome 3p, 9p, and 14q in almost all NPC tumors suggested that inactivation of the tumor suppressor genes on these three chromosomal arms are essential events for the development of this cancer.
In this genome-wide study of NPC, we have detected high incidence of loss on 11q (74.1%) and 13q (55.6%). The association of these deletions with high FAL value also suggested that such changes might be correlated with the progression of NPC. The MDR region identified at 11q21–23 (20.6 cM or 18 Mb) overlapped with those we reported previously. Hence, the candidate tumor suppressor genes, ATM and SDHD, located within this region may be associated with the development of NPC. SDHD encodes a mitochondrial respiratory chain protein, the small subunit of cytochrome b in succinate-ubiquinone oxidoreductase (cybS) and mutated in hereditary paraganglioma (21) . This gene is considered as a candidate tumor suppressor involved in NPC tumorigenesis. We also identified two distinct MDRs on chromosome 13q. The first region on 13q12–14.1 included the tumor suppressor genes Rb and BRCA2. The other deletion region on 13q31–32 was refined to 7.2 cM (or 8.5 Mb) in this study. No candidate tumor suppressor was mapped to this region.
Frequent LOH of 16q on NPC is a novel finding in this allelotyping study. We have mapped a 21.4-cM (5.7-Mb) MDR to 16q22.3–23.1. The region is adjacent to the E-cadherin gene, which encoded a cell adhesion molecule and is associated with tumor invasiveness and metastasis. Zheng et al. (22) showed that loss of E-cadherin expression was common in this cancer and significantly associated with advanced stages of this disease. The other candidate tumor suppressor at 16q, pRb-2/p130, is located at 16q12 and mapped between D16S415 and D16S503. This region was also deleted in 48.1% NPC tumors. Claudio et al. (23) has reported the mutation of the pRb-2/p130 gene in 30% of NPC from North Africa. To confirm the involvement of this gene in NPC, we will investigate the genetic and epigenetic changes of this gene in our primary tumor samples in the near future.
Gain of chromosome 12 is a major finding in our previous CGH analysis. In the current study, we have found a high incidence (70.4%) of allelic imbalance on 12q in NPC. These findings suggest that activation of proto-oncogenes in this region may be involved in the development of this cancer. Oncogenes mapped to chromosome 12q include CDK4, INT1, and MDM2. However, our microsatellite analysis has shown multiple distinct regions of allelic imbalance. The target oncogene(s) involved in NPC tumorigenesis require further investigation.
In summary, our study revealed the existence of a multiplicity of genetic changes in NPC tumorigenesis. The identification of novel MDRs on multiple chromosome arms allows us to locate the target genes involved in the development of this cancer. Moreover, consistent allelic deletion of chromosomes 3p, 9p, and 14q were detected in almost all tumors in the current study. These findings suggest that inactivation of tumor suppressor genes on these regions are critical events for the development of NPC. It is believed that early diagnosis of NPC can be achieved with examination of 3p, 9p, and 14q deletions in high-risk groups. The microsatellite polymorphic markers on these chromosomal arms may be useful for the detection of NPC-specific genetic changes in the plasma or brushed nasopharyngeal biopsies of the patients. The high-resolution allelotype allows us to better understand the molecular basis of NPC and also enables the development of new tools for the early detection of this cancer.
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FOOTNOTES |
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1 This work was carried out within the Hong Kong
Cancer Research Group supported by the Kadoorie Charitable Foundations,
a Central Allocation Grant from the Hong Kong Research Grants Council,
and a Hong Kong Research Grant Council Direct Grant (Project Code
2040737). D. P. H. is the recipient of these grants. 
2 To whom requests for reprints should be
addressed, at Department of Anatomical and Cellular Pathology, Prince
of Wales Hospital, The Chinese University of Hong Kong, Shatin, N.T.,
Hong Kong SAR, China. Phone: 852-26321136; Fax: 852-26497286; E-mail: kwlo{at}cuhk.edu.hk
3 The abbreviations used are: NPC, nasopharyngeal
carcinoma; LOH, loss of heterozygosity; MSI, microsatellite
instability; FAL, fractional allelic loss; MDR, minimally deleted
region; CGH, comparative genomic hybridization.
4 Internet address:
http://www.pebio.com/ab/apply/dr/lmsv2/.
Received 3/15/00. Accepted 5/18/00.
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, LOH; 
, retention of heterozygosity. All chromosomal arms
of these 27 tumors are informative. The FAL value of each tumor is
shown in the bottom of each column. Tumors are arranged from low to
high FAL values. Right, frequency of LOH for each
chromosomal arm.
