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Clinical Cancer Research Vol. 8, 2266-2272, July 2002
© 2002 American Association for Cancer Research

Molecular Oncology, Markers, Clinical Correlates

Clinicopathological Significance of Loss of Heterozygosity on Chromosome 13q in Hepatocellular Carcinoma1

Chun Ming Wong, Joyce Man Fong Lee, Tracy Ching Man Lau, Sheung Tat Fan and Irene O. L. Ng2

Departments of Pathology [C. M. W., J. M. F. L., T. C. M. L., I. O. L. N.] and Surgery [S. T. F.] University of Hong Kong, Queen Mary Hospital, Pokfulam, Hong Kong


   ABSTRACT
Top
 ABSTRACT
INTRODUCTION
 MATERIALS AND METHODS
 RESULTS
 DISCUSSION
 REFERENCES
 
Purpose: Allelic loss is the most frequently genetic alteration found in hepatocellular carcinoma (HCC). Previous genome-wide studies have indicated that chromosome 13q is one of the most frequently affected chromosomes. However, reports on detailed deletion mapping as well as detailed clinicopathological correlation are scanty.

Experimental Design: We performed high-density allelotyping on chromosome 13q in HCC from 60 patients and investigated the correlation between allelic losses on chromosome 13q and the clinicopathological features.

Results: Allelic loss at one or more of the 29 microsatellite markers was found in 28 (47%) of the 60 HCCs. Allelic losses were more frequently found in tumors with larger size or in tumors at more advanced tumor stages (P = 0.015 and 0.012, respectively). These two clinicopathological features were also significantly associated with the accumulation of allelic losses in terms of fractional allelic loss index (P = 0.028 and 0.018, respectively). In addition, subchromosomal regions located at 13q12.3-14.1 and 13q32 were found to be significantly associated with advanced tumor stages and larger tumor size, respectively (P = 0.008 and 0.007).

Conclusions: The overall findings suggested that allelic losses on 13q might play an important role in contributing to a more aggressive tumor behavior. Putative tumor suppressor genes might be harbored at 13q12.3-14.1 and 13q32, and inactivation of these genes via allelic losses might enhance tumor progression in HCC.


   INTRODUCTION
Top
 ABSTRACT
 INTRODUCTION
MATERIALS AND METHODS
 RESULTS
 DISCUSSION
 REFERENCES
 
HCC3 is one of the most common cancers in the world. It has a characteristic geographical distribution with the highest incidence in Southeast Asia and sub-Saharan Africa. It is the second commonest fatal cancer in Southeast Asia and Hong Kong. Etiological evidence has shown that hepatitis B viral infection, HCV infection, cirrhosis, chronic alcoholism, and aflatoxin B1 intake are the risk factors of HCC (1) . Although the risk factors are well known, the molecular mechanisms contributing to hepatocarcinogenesis have not been well elucidated.

Genetic alterations such as point mutations, chromosomal deletions, small-scale interstitial deletions, or epigenetic phenomenon, such as promoter hypermethylation, or any combination of these mechanisms may lead to inactivation of genes regulating normal cell growth and adhesion. These may then confer selection advantage for increasing the tumorigenic potential of the cell and drive tumor progression. Comparative genomic hybridization and LOH studies are frequently used to highlight chromosomal regions frequently deleted in cancers and help to define the potential regions that likely contain putative tumor suppressor genes (2, 3, 4, 5, 6, 7, 8, 9) . Previous comparative genomic hybridization and LOH studies on HCC have shown that allelic losses are frequently detected in several chromosome regions, including 1p, 4q, 8p, 13q, 16q, and 17p (10, 11, 12) . Chromosome 13q is one of the most frequently affected chromosome arms in HCC and in other cancers such as of the breast (13 , 14) , esophagus (15 , 16) , and prostate (17 , 18) . In HCC, allelic losses on this chromosome have been reported to be 17.5–53% of HCCs (10, 11, 12 , 19, 20, 21) .

However, most of the previous LOH studies have focused on genome-wide investigations, and reports on detailed deletion mapping as well as detailed clinicopathological correlation are scanty. In this study, we constructed a detailed deletion map of chromosome 13q in HCC by high-density allelotyping and investigated the clinicopathological significance of allelic losses on chromosome 13q.


   MATERIALS AND METHODS
Top
 ABSTRACT
 INTRODUCTION
 MATERIALS AND METHODS
RESULTS
 DISCUSSION
 REFERENCES
 
Patients and Specimens.
Sixty randomly selected patients with primary HCC resected between 1992 and 1999 at Queen Mary Hospital were studied. All patients were of Chinese origin. Forty-seven patients were men and 13 were women, with ages ranging from 28 to 82 years (mean, 56 years). None of the 60 patients had received any other therapies including chemoembolization or chemotherapy before resection. Forty-six (79%) patients were positive for serum HBsAg. Of the 32 patients tested for serum anti-HCV, only one (3.1%) was positive. Thirteen (22.4%) patients had a habit of alcohol consumption.

The tumors and their corresponding nontumorous liver samples were snap-frozen in liquid nitrogen immediately after resection. Each frozen sample was embedded in OCT compound (Tissue-Tek) and kept at -80°C. Frozen sections were performed to confirm the homogeneity of the cell population. DNA was extracted from frozen sections with standard phenol-chloroform protocols.

LOH Analysis.
Twenty-nine polymorphic microsatellite markers spanning chromosome 13q were used for LOH analysis and are listed in Table 1Citation . Twenty-one markers were obtained from ABI Prism Linkage Mapping set, panels 17, 19, and 67 (Applied Biosystems, Foster City, CA). Six markers (D13S71, D13S271, D13S225, D13S220, D13S291, and D13S156) were obtained from Research Genetics (Huntsville, AL), and two (D13S260 and D13S267) were synthesized by MWG Biotech AG (Ebersberg, Germany). Microsatellite markers were amplified by multiplex PCR performed on 9700 Perkin-Elmer DNA cycler (Applied Biosystems) in 10 µl of volume of mixture containing 10 pmol of each primer, 0.375 mM deoxynucleoside triphosphate, 2.5 mM MgCl2, 0.6 unit of Amp TaqGold (Applied Biosystems), and 50–100 ng of genomic DNA. Two to five markers were coamplified in any one PCR reaction. Reactions were initiated by hot start at 95°C for 12 min, 10 cycles of amplification (94°C for 15 s, 55°C for 15 s, and 72°C for 30 s) and 20 cycles of amplification with lower denaturing temperature (89°C for 15 s, 55°C for 15 s, and 72°C for 30 s), followed by a final extension at 72°C for 30 min. PCR products were run on ABI 377 Automatic DNA sequencer (Applied Biosystems) and analyzed using the Genotyper 2.5 software (Applied Biosystems). LOH was defined according to the following formula (22 , 23) : LOH index = (T2/T1)/(N2/N1), where T was the tumor sample, N was the nontumorous liver sample, 1 and 2 were the intensities of smaller and larger alleles, respectively. LOH was defined with the values of LOH index <0.6 or >=1.7. All LOH positive loci and some query loci were repeated at least once by individual PCR for confirmation.


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  		Table 1 Microsatellite markers used in LOH analysis

 
The FAL index for individual cases was calculated as follows (24) : FAL index = (total number of chromosomal loci with LOH)/(total number of informative loci examined).

Clinicopathological Parameters.
The clinicopathological features of the patients included sex, age, tumor size, cellular differentiation, presence of venous invasion without differentiation into portal or hepatic venules, tumor encapsulation, direct liver invasion, tumor microsatellite formation, tumor stage (pTNM stage), serum HBsAg and anti-HCV status, and background liver disease in the nontumorous livers were analyzed as we described previously (25) .

Statistical Analysis.
Fisher exact test or {chi}2 test was used for the analysis of categorical data, whereas independent t test or Mann-Whitney U test was used for continuous data whenever appropriate. Binary logistic regression was performed to evaluate the independent effects of clinicopathological parameters on LOH. Cases with missing data were excluded for analysis test by test. Data were analyzed using the SPSS for Windows 10.0 (SPSS, Inc., Chicago, IL). Tests were considered as significant when their Ps were <0.05 or 0.01 whenever appropriate.


   RESULTS
Top
 ABSTRACT
 INTRODUCTION
 MATERIALS AND METHODS
 RESULTS
DISCUSSION
 REFERENCES
 
Allelic Losses on Chromosome 13q.
A total of 29 polymorphic markers located on chromosome 13q were used for LOH analysis, and they had an average distance of 4 cM apart (Table 1)Citation . Representative examples of the LOH results are shown in Fig. 1Citation , and the overall findings of LOH analysis are summarized in Fig. 2Citation . The overall frequency of informative loci was 70%. Among the 60 cases examined, 28 (47%) cases showed LOH at one or more loci. Of these 28 tumors showing allelic losses, 7 (25%) showed LOH at all informative loci (hemizygosity), whereas the remaining 21 (75%) cases showed various frequencies of allelic losses (partial deletions). The mean frequency of LOH for these 29 microsatellite markers was 31.8%. Higher frequencies of LOH were observed at D13S1241 (43.5%), D13S171 (41.9%), and D13S267 (40.0%; Table 1Citation ).



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  		Fig. 1. Representative examples of microsatellite analysis results showing LOH, retention, and noninformative cases.

 


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  		Fig. 2. Summary of LOH analysis results. Case numbers are indicated in the first row. Microsatellite markers are listed in the left column, in an order from the most centromeric (top) to the most telomeric (bottom) end as indicated. Gray boxes, retention; white boxes, noninformative; black boxes, LOH; slashed boxes, failed.

 
Clinicopathological Parameters of Patients.
Among the 60 patients involved in this study, 50% of the patients had cirrhosis in their nontumorous livers, and 26 (43.3%) had chronic hepatitis. The tumor size ranged from 1.8 to 27.0 cm in diameter (mean, 8.3 ± 5.4 cm). Thirty-eight (64.4%) tumors were >5 cm, and 21 (35.6%) were <=5 cm in diameter. Twenty-eight (46.7%) tumors had better cellular differentiation (Edmondson’s grades I and II), and 32 (53.3%) had poorer cellular differentiation (Edmondson’s grades III and IV). Eighteen (31.6%) patients had tumor at earlier stages (pTNM stages I and II), and 39 (68.4%) had tumors at more advanced tumor stages (pTNM stages III and IV; Tables 2Citation and 3Citation ). Tumor encapsulation was detected in 22 (36.7%) cases. Thirty-six (60%) patients had venous invasion. Direct liver invasion was found in 20 (40.8%) HCCs, and tumor microsatellites were present in 35 (59.3%) of the 60 HCC cases (Table 3)Citation .


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  		Table 2 Clinicopathological features of 60 patients with primary HCC

 

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  		Table 3 Clinicopathologic correlation of allelic losses on chromosome 13q

 
Clinicopathological Significance of Allelic Losses on Chromosome 13q.
LOH at one or more loci was more frequently found in patients with larger tumor size and at more advanced tumor stages. Of the 28 cases showing LOH at one or more loci, 22 (79%) had tumor size >5 cm in diameter (P = 0.015), and 23 (82%) had more advanced pTNM stages (stages III and IV; P = 0.012). However, no significant association was found between presence of LOH and other clinicopathological parameters, including patients’ age, gender, serum HBsAg status, background liver disease, tumor differentiation, venous invasion, tumor encapsulation, tumor microsatellite formation, and direct liver invasion (Table 3)Citation .

Because larger tumor size and advanced tumor stage were the only two parameters correlated with presence of LOH, to evaluate the independent effects of these two parameters, logistic regression was performed using the presence of LOH as a dependent variable. Results of multivariate analysis indicated that advanced tumor stage was the only independent parameter significantly associated with allelic losses on chromosome 13q (P = 0.016).

To further evaluate the relationship between accumulation of allelic losses and tumor aggressiveness, FAL index of each case was calculated and analyzed using Mann-Whitney U test. Among the 60 cases examined, the FAL index was found to be 0.00 in 32 cases, which was equivalent to the absence of LOH at all informative loci, whereas it was 1.00 in 7 cases, which meant LOH at all informative loci (hemizygosity). For the remaining 21 cases showing partial deletions, the FAL index ranged from 0.19 to 0.90 (mean ± SD, 0.56 ± 0.22). Our results showed that the FAL index was positively and significantly associated with larger tumor size and advanced tumor stages. HCCs that were >5 cm in diameter had significantly higher FAL indices than those <=5 cm in diameter (median, 0.36 and 0.00, respectively; P = 0.025; Fig. 3ACitation ). Moreover, HCCs at more advanced pTNM stages (stages III and IV) often had significantly higher FAL indices when compared with those at earlier pTNM stages (stages I and II; median, 0.36 and 0.00, respectively; P = 0.018; Fig. 3BCitation ). However, no significant correlation was found between the FAL index and other clinicopathological parameters.



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  		Fig. 3. Clinicopathological correlation of FAL index. A, correlation between FAL index and tumor size. B, correlation between FAL index and tumor pTNM stages. Boxplot, the boxes contain the values between the 25th and 75th percentiles; the lines across the boxes indicate the medians; the whiskers extend to the highest values excluding outliers; {diamondsuit}, extreme values.

 
We further investigated the clinicopathological significance of allelic losses on the 28 small genetic intervals between microsatellite markers. To increase the stringency of comparison, tests were considered as significant only when their Ps were <0.01. Among the clinicopathological parameters examined, advanced tumor stages and larger tumor size were found to be significantly associated with allelic losses at two specific subchromosomal regions on 13q (Fig. 4)Citation . In these two specific subchromosomal regions, there was significant association between allelic losses and pTNM stage or tumor size at all genetic intervals between consecutive markers, with P < 0.01. In the proximal region of chromosome 13q, a positive correlation between advanced tumor stages and allelic losses was found at chromosome 13q12.3-13q14.1, spanning three consecutive genetic intervals flanked by microsatellite markers D13S267 and D13S218 (6 cM). Among the 18 patients with allelic losses in all of these three consecutive genetic intervals, 16 (89%) had more advanced pTNM stages (stages III and IV; P = 0.008). In addition, allelic loss on the genetic interval between D13S159 and D13S225 mapped at 13q32 (4 cM) was found to be closely associated with larger tumor size. Larger tumor size was found in 90% patients who showed LOH at this region (P = 0.007). Our results suggest that allelic losses at these two subchromosomal regions may contribute to a more aggressive tumor behavior and therefore may probably be the sites of putative tumor suppressor gene(s).



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  		Fig. 4. Clinicopathologic significance of allelic loess on sub-chromosomal regions of 13q. Sub-chromosomal regions significantly associated with specific clinicopathological parameters are highlighted with vertical lines, and the relationship with the clinicopathological parameters is shown in the 2 boxes.

 

   DISCUSSION
Top
 ABSTRACT
 INTRODUCTION
 MATERIALS AND METHODS
 RESULTS
 DISCUSSION
REFERENCES
 
In this study, allelic losses were frequently observed in the 60 cases of predominantly hepatitis B virus-associated HCC. Allelic loss at one or more loci was found in 28 cases (46.7%), including 7 cases showing LOH at all informative loci. Our result was in agreement with those in previous studies, in which LOH on 13q ranged from 17.5 to 53% (10, 11, 12 , 19, 20, 21) , and confirms that chromosome 13q is one of the most frequently affected chromosome arms in HCC.

We observed that LOH on 13q was significantly correlated with a more aggressive tumor behavior. LOH at one or more informative loci was found more frequently in tumors >5 cm in diameter and at more advanced tumor stages (pTNM stages III and IV). Moreover, accumulation of allelic losses on 13q, as reflected by the FAL index, was also seen in larger tumors and in tumors at more advanced tumor stages. These consistent findings suggested that accumulation of allelic losses on this chromosome might play an important role in tumor progression and supported the notion that cumulative allelic losses were associated with tumor aggressiveness (11) . However, further narrowing down of the potential regions to a reasonable distance is required for identification of these candidate tumor suppressor genes.

Investigation of the clinicopathological correlation of allelic losses at individual loci along the chromosome arm may provide valuable information on the influence of tumor behavior with such genetic alterations. Because allelic losses on chromosome 13q were found to be associated with larger tumor size and advanced tumor stages in HCC, we further evaluated whether allelic losses at some specific regions would be associated with these aggressive tumor characteristics. As expected, our results showed that allelic losses at two distinct subchromosomal regions were significantly associated with larger tumor size and advanced tumor stages, respectively. At chromosomal region 13q12.3-14.1, allelic losses at three consecutive genetic intervals flanked by microsatellite markers D13S267 and D13S218 (6 cM) was found to be related to advanced tumor stages (pTNM stages III and IV). Also, allelic loss at 13q32 between microsatellite markers D13S159 and D13S225 (4 cM) was significantly associated with larger tumor size (>5 cm in diameter). The close association between allelic losses at these regions and aggressive tumor behavior implied that allelic losses within these regions might contribute to a more aggressive tumor behavior and suggested the presence of putative tumor suppressor gene(s), the loss of which is associated with tumor progression.

Association between advanced tumor stages and allelic losses at chromosome 13q12.3-14.1 has implied a target for the identification of putative tumor suppressor genes, the deletion of which may contribute to tumor progression. In fact, allelic losses at chromosome 13q12.3 was found to be involved in carcinogenesis of many different tumors, such as of the breast (13 , 14) , esophagus (15 , 16) , gastric system (26) , lung (27) , and nasopharyngeal system (28) . A known tumor suppressor gene BRCA2 was mapped at this region, and genetic alterations of this gene have been well characterized in breast and ovarian cancer (13 , 14 , 29 , 30) . Apart form BRCA2, another candidate tumor suppressor gene was recently mapped at 13q12.3, i.e., androgen-shutoff gene 3, and has been identified recently as a negative regulator for cell proliferation (31) . However, the genetic alterations of these two genes in HCC have not studied, and further investigations are therefore required to clarify the roles of these candidate tumor suppressor genes in HCC. For the region mapped at chromosome 13q32 between microsatellite markers D13S159 and D13S225, allelic loss was found to be associated with larger tumor size. However, to the best of our knowledge, no candidate tumor suppressor gene has been found within these regions in HCC and other cancers; therefore, additional studies will be necessary to identify and examine candidate tumor suppressor gene(s) within this region.


   ACKNOWLEDGMENTS
 
We thank Drs. Matthew M. T. Ng and Daniel Y. T. Fong for expert advice on 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 The study was supported in part by Research Grants Council Grant HKU 7281/01M. This paper was presented in part at the Hong Kong International Cancer Congress in September 2001, Hong Kong. Back

2 To whom requests for reprints should be addressed, at Department of Pathology, Room 127B, UPB, University of Hong Kong, Queen Mary Hospital, 102, Pokfulam Road, Pokfulam, Hong Kong. Phone: (852) 2855-4859; Fax: (852) 2872-5197; E-mail: iolng{at}hku.hk Back

3 The abbreviations used are: HCC, hepatocellular carcinoma; LOH, loss of heterozygosity; HBsAg, hepatitis B surface antigen; HCV, hepatitis C virus; FAL, fractional allelic loss; TNM, Tumor-Node-Metastasis. Back

Received 12/28/01; revised 3/25/02; accepted 4/ 1/02.


   REFERENCES
Top
 ABSTRACT
 INTRODUCTION
 MATERIALS AND METHODS
 RESULTS
 DISCUSSION
 REFERENCES
 

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Y. Midorikawa, S. Tsutsumi, K. Nishimura, N. Kamimura, M. Kano, H. Sakamoto, M. Makuuchi, and H. Aburatani
Distinct Chromosomal Bias of Gene Expression Signatures in the Progression of Hepatocellular Carcinoma
Cancer Res., October 15, 2004; 64(20): 7263 - 7270.
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C.-M. Wong, J. M.-F. Lee, Y.-P. Ching, D.-Y. Jin, and I. O.-l. Ng
Genetic and Epigenetic Alterations of DLC-1 Gene in Hepatocellular Carcinoma
Cancer Res., November 15, 2003; 63(22): 7646 - 7651.
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Y.-P. Ching, C.-M. Wong, S.-F. Chan, T. H.-Y. Leung, D. C.-H. Ng, D.-Y. Jin, and I. O.-l. Ng
Deleted in Liver Cancer (DLC) 2 Encodes a RhoGAP Protein with Growth Suppressor Function and Is Underexpressed in Hepatocellular Carcinoma
J. Biol. Chem., March 14, 2003; 278(12): 10824 - 10830.
[Abstract] [Full Text] [PDF]

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