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• W2162912407 abstract "Hepatocellular carcinoma (HCC) is a common and highly malignant tumor that is prevalent in Southeast Asia. Although the etiological factors associated are now well recognized, the interactions between individual factors and the molecular mechanisms by which they lead to cancer remain unclear. Cytogenetic analysis on HCC has been limited because of poor hepatocyte growth in vitro. The recently developed technique of comparative genomic hybridization (CGH), however, permits screening of the entire genome without the need of cell culture. CGH was applied to the study of genomic aberrations in 67 surgically resected samples of HCC, 3 of adenomatous hyperplasia (AH), and 12 of nontumorous cirrhotic liver surrounding the tumors. All samples were from patients of a racially and etiologically homogeneous population in Southern China, where chronic hepatitis B virus infection is the main etiological factor. CGH analysis of the HCC samples revealed frequent copy number gain of 1q (48/67 cases, 72%), 8q (32/67 cases, 48%), 17q (20/67 cases, 30%), and 20q (25/67 cases, 37%) and common losses on 4q (29/67 cases, 43%), 8p (25/67 cases, 37%), 13q (25/67 cases, 37%), and 16q (20/67 cases, 30%). Our finding of a high incidence of 1q gain strongly suggested this aberration was associated with the development of HCC. Genomic abnormalities were detected in 1 of the 3 AH specimens but absent in all 12 cirrhotic tissues surrounding the tumor. Clinical staging classified 3/67 HCC cases as T1, 53 cases as T2, and 11 cases as T3. No significant difference in the pattern of genomic imbalances was detected between stages T2 and T3. A significant copy number loss of 4q11-q23 was, however, identified in those tumors larger than 3 cm in diameter. Of particular interest was the identification of 8q copy number gain in all 12 cases of HCC that arose in a noncirrhotic liver, compared with only 20/55 cases in HCC arising in a cirrhotic liver. We suggest that 8q over-representation is likely associated with a growth advantage and proliferative stimulation that have encouraged malignant changes in the noncirrhotic human liver. Hepatocellular carcinoma (HCC) is a common and highly malignant tumor that is prevalent in Southeast Asia. Although the etiological factors associated are now well recognized, the interactions between individual factors and the molecular mechanisms by which they lead to cancer remain unclear. Cytogenetic analysis on HCC has been limited because of poor hepatocyte growth in vitro. The recently developed technique of comparative genomic hybridization (CGH), however, permits screening of the entire genome without the need of cell culture. CGH was applied to the study of genomic aberrations in 67 surgically resected samples of HCC, 3 of adenomatous hyperplasia (AH), and 12 of nontumorous cirrhotic liver surrounding the tumors. All samples were from patients of a racially and etiologically homogeneous population in Southern China, where chronic hepatitis B virus infection is the main etiological factor. CGH analysis of the HCC samples revealed frequent copy number gain of 1q (48/67 cases, 72%), 8q (32/67 cases, 48%), 17q (20/67 cases, 30%), and 20q (25/67 cases, 37%) and common losses on 4q (29/67 cases, 43%), 8p (25/67 cases, 37%), 13q (25/67 cases, 37%), and 16q (20/67 cases, 30%). Our finding of a high incidence of 1q gain strongly suggested this aberration was associated with the development of HCC. Genomic abnormalities were detected in 1 of the 3 AH specimens but absent in all 12 cirrhotic tissues surrounding the tumor. Clinical staging classified 3/67 HCC cases as T1, 53 cases as T2, and 11 cases as T3. No significant difference in the pattern of genomic imbalances was detected between stages T2 and T3. A significant copy number loss of 4q11-q23 was, however, identified in those tumors larger than 3 cm in diameter. Of particular interest was the identification of 8q copy number gain in all 12 cases of HCC that arose in a noncirrhotic liver, compared with only 20/55 cases in HCC arising in a cirrhotic liver. We suggest that 8q over-representation is likely associated with a growth advantage and proliferative stimulation that have encouraged malignant changes in the noncirrhotic human liver. Hepatocellular carcinoma (HCC) is responsible for at least 5% of all cancer deaths worldwide.1World Health Organization Cancer Research for Cancer Control. International Agency for Cancer Research, Lyon1997: 5Google Scholar It is particularly common in Southeast Asia, China, and sub-Saharan Africa where the age-standardized annual incidence rate ranges from 20 to over 100 per 100,000.2Doll R Muir C Waterhouse J Cancer Incidence in Five Continents. vol 2. Springer, Berlin1970Google Scholar, 3Waterhouse JAH Muir CS CoRrea P Powell J Cancer Incidence in Five Continents, vol 4. International Agency for Research on Cancer, Lyon1982Google Scholar The main etiological factor is chronic hepatitis B virus (HBV) infection, to which 50% to 80% of all cases are attributable.4Beasley RP Hepatitis B virus: the major etiology of hepatocellular carcinoma.Cancer. 1988; 61: 1942-1946Crossref PubMed Scopus (1157) Google Scholar, 5Munoz N Bosch X Epidemiology of hepatocellular carcinoma.in: Okuda K Ishak KG Neoplasms of the Liver. Springer Verlag, London1987Crossref Google Scholar Other etiological factors include chronic hepatitis C virus infection, exposure to aflatoxin, male gender, and chronic liver disease of any type.5Munoz N Bosch X Epidemiology of hepatocellular carcinoma.in: Okuda K Ishak KG Neoplasms of the Liver. Springer Verlag, London1987Crossref Google Scholar, 6Johnson PJ Williams R Cirrhosis and the aetiology of hepatocellular carcinoma.J Hepatol. 1987; 4: 140-147Abstract Full Text PDF PubMed Scopus (179) Google Scholar, 7Hasan F Jeffers LJ De Medina M Reddy KR Parker T Schiff ER Houghton M Choo QL Kuo G Hepatitis C-associated hepatocellular carcinoma.Hepatology. 1990; 12: 589-591Crossref PubMed Scopus (219) Google Scholar Differences in exposure to these various risk factors account for the wide geographical variation in incidence. Surgical resection of the tumor offers the only hope of long-term survival, but because patients frequently present late in the natural history of the disease and often have poor underlying liver function, it is applicable to only a minority of patients.8Lim R Bongard FS Hepatocellular carcinoma: changing concepts in diagnosis and management.Arch Surg. 1984; 119: 637Crossref PubMed Scopus (37) Google Scholar, 9Lin T-Y Lee CS Chen KM Chen CC Role of surgery in the treatment of primary carcinoma of the liver: a 31 year experience.Br J Surg. 1987; 74: 839-842Crossref PubMed Scopus (189) Google Scholar, 10Fortner JG MacLean BJ Kim DK Howland WS Turnbull AD Goldiner P Carlon G Beattie Jr, EJ The seventies evolution in liver surgery for cancer.Cancer. 1981; 47: 2162-2166Crossref PubMed Scopus (87) Google Scholar The poor liver function is caused both by the tumor itself and by concomitant chronic liver disease, usually cirrhosis, which is present in 70% to 90% of cases. By the time of clinical presentation, intra- and extrahepatic metastases are common, which further limit the scope of surgical resection.11Okuda K Obata H Nakajima Y Ohtsuki T Okazaki N Ohnishi K Prognosis of primary hepatocellular carcinoma.Hepatology. 1984; 4: 3-6Crossref PubMed Scopus (194) Google Scholar, 12Sasaki Y Imaoka S Masutani S Osashi I Ishikawa O Koyama H Iwanaga T Influence of coexisting cirrhosis on longer-term prognosis after surgery in patients with hepatocellular carcinoma.Surgery. 1992; 112: 515-521PubMed Google ScholarMolecular studies have demonstrated frequent loss of heterozygosity (LOH) on chromosomes 1p, 4q, 8p, 11p, 13q, 16q, and 17p13Buetow KH Murray JC Israel JL London WT Smith M Kew M Blanquet V Brechot C Redeker A Govindarajah S Loss of heterozygosity suggests tumour suppressor gene responsible for primary hepatocellular carcinoma.Proc Natl Acad Sci USA. 1989; 86: 8852-8856Crossref PubMed Scopus (193) Google Scholar, 14Nagai H Pineau P Tiollais P Buendia MA Dejean A Comprehensive allelotyping of human hepatocellular carcinoma.Oncogene. 1997; 14: 2927-2933Crossref PubMed Scopus (267) Google Scholar, 15Fujimori M Tokino T Hino O Kitagawa T Imamura T Okamoto E Mitsunobu M Ishikawa T Nakagama H Harada H Yagura M Matsubara K Nakamura Y Allelotype study of primary hepatocellular carcinoma.Cancer Res. 1991; 51: 89-93PubMed Google Scholar, 16Fujimoto Y Hampton LL Wirth PJ Wang NJ Xie JP Thorgeirsson SS Alterations of tumor suppressor genes and allelic losses in human hepatocellular carcinomas in China.Cancer Res. 1994; 54: 281-285PubMed Google Scholar, 17Kuroki T Fujiwara Y Tsuchiya E Nakamori S Imaoka S Kanematsu T Nakamura Y Accumulation of genetic changes during development and progression of hepatocellular carcinoma: loss of heterozygosity on chromosome arm 1p occurs at an early stage of hepatocarcinogenesis.Genes Chromosomes & Cancer. 1995; 13: 163-167Crossref PubMed Scopus (130) Google Scholar, 18Boige V Laurent-Puig P Fouchet P Flejou JF Monges G Bedossa P Bioulas S Capron F Schmitz A Olschwang S Thomas G Concerted nonsyntenic allellic losses in hyperploid hepatocellular carcinoma as determined by a high-resolution allelotype.Cancer Res. 1997; 57: 1986-1990PubMed Google Scholar and multiplications of chromosome 8q19Fuijiwara Y Monden M Mori T Nakamura Y Emi M Frequent multiplication of the long arm of chromosome 8 in hepatocellular carcinoma.Cancer Res. 1993; 53: 857-860PubMed Google Scholar in HCC. Although cytogenetic analysis of HCC has received much less attention20Bardi G Johansson B Pandis N Heim S Mandahl N Andren-Sandberg A Hagerstrand I Mitelman F Cytogenetic findings in three primary hepatocellular carcinomas.Cancer Genet Cytogenet. 1992; 58: 191-195Abstract Full Text PDF PubMed Scopus (42) Google Scholar, 21Chen HL Chen YC Chen DS Chromosome 1p aberrations are frequent in human primary hepatocellular carcinoma.Cancer Genet Cytogenet. 1996; 86: 102-106Abstract Full Text PDF PubMed Scopus (36) Google Scholar, 22Simon D Munoz SJ Maddrey WC Knowles BB Chromosomal rearrangements in a primary hepatocellular carcinoma.Cancer Genet Cytogenet. 1990; 45: 225-260Abstract Full Text PDF Scopus (39) Google Scholar, 23Werner M Nolte M Gergii M Klempnauer J Chromosome 1 abnormalities in hepatocellular carcinoma.Cancer Genet Cytogenet. 1993; 66: 130Abstract Full Text PDF PubMed Scopus (20) Google Scholar due to the poor hepatocyte growth in vitro, structural aberrations of chromosome 1 were consistently reported.20Bardi G Johansson B Pandis N Heim S Mandahl N Andren-Sandberg A Hagerstrand I Mitelman F Cytogenetic findings in three primary hepatocellular carcinomas.Cancer Genet Cytogenet. 1992; 58: 191-195Abstract Full Text PDF PubMed Scopus (42) Google Scholar, 21Chen HL Chen YC Chen DS Chromosome 1p aberrations are frequent in human primary hepatocellular carcinoma.Cancer Genet Cytogenet. 1996; 86: 102-106Abstract Full Text PDF PubMed Scopus (36) Google Scholar, 22Simon D Munoz SJ Maddrey WC Knowles BB Chromosomal rearrangements in a primary hepatocellular carcinoma.Cancer Genet Cytogenet. 1990; 45: 225-260Abstract Full Text PDF Scopus (39) Google Scholar, 23Werner M Nolte M Gergii M Klempnauer J Chromosome 1 abnormalities in hepatocellular carcinoma.Cancer Genet Cytogenet. 1993; 66: 130Abstract Full Text PDF PubMed Scopus (20) Google Scholar Comparative genomic hybridization (CGH), first described by Kallioniemi in 1992,24Kallioniemi A Kallioniemi O-P Sudar D Rutovitz D Gray JW Waldman F Pinkel D Comparative genomic hybridization for molecular cytogenetic analysis of solid tumors.Science. 1992; 258: 818-821Crossref PubMed Scopus (2815) Google Scholar is a powerful molecular cytogenetic tool that allows rapid screening for regions of DNA sequence gains and losses across the entire tumor genome without the need of cell culture. To date, there has been only a single report on the application of CGH to HCC25Marchio A Meddeb M Pineau P Danglot G Tiollais P Bernheim A Dejean A Recurrent chromosomal abnormalities in hepatocellular carcinoma detected by comparative genomic hybridization.Genes Chromosomes & Cancer. 1997; 18: 59-65Crossref PubMed Scopus (260) Google Scholar that described the recurring chromosomal changes of 4q loss (70%), 8p loss (65%), 8q gain (60%), and 1q gain (58%). However, the patients studied were from various, but unspecified, geographic locations, there was no clinicopathological data except all patients being HBV positive, and no attempts were made to correlate CGH findings with the clinical stage or the tumor size.Here, we have applied CGH to the detection of changes in the genetic pattern of 67 cases of HCC and associated nonmalignant tissues (cirrhosis and adenomatous hyperplasia), in relation to clinical disease stage, tumor size, and the presence or absence of underlying liver cirrhosis. By comparing the pattern of genetic aberrations in these groups of tissues, we sought to identify those changes that may be associated with the development and progression of HCC.Materials and MethodsSamples were collected from 70 ethnic Southern Chinese patients (aged 30 to 97 years, 81% male) undergoing hepatic resection of a liver tumor with curative intent. All but one case was tested for hepatitis B surface antigen (HBsAg) and serum α-fetoprotein (AFP), and 89% of cases were seropositive for HBsAg. Serum AFP levels ranged from less than 10 ng/ml (within the reference range) in 13 patients, to minimally elevated in 21 (10 to 50 ng/ml) and markedly elevated in the remaining 35 patients (50 to 40,000 ng/ml). The disease stage of the HCC cases was classified according to the tumor/node/metastasis (TNM) staging criteria.26Beahrs OH Henson DE Hutter RVP Kennedy BJ Handbook for Staging of Cancer. JB Lippincott, Philadelphia1993Google Scholar Three cases (5%) were classified as stage I (T1N0M0), 53 (79%) as stage II (T2N0M0), and 11 (16%) as stage III (T3N0M0). The macro- and microscopic features of the resected specimens were reviewed by an experienced liver pathologist (C.-T. Liew) who confirmed the diagnosis of HCC, assessed the presence or absence of vascular invasion, and recorded the maximal diameter of the tumor. The presence or absence of cirrhosis in the nontumorous part of the resected specimen was also recorded. Cirrhosis was defined as the presence of complete fibrous septa separating regenerating nodules.27Antony PP Ishak KG Nayak NC Poulsen HE Scheuer PJ Sobin LH The morphology of cirrhosis: recommendations on definitions, nomenclature and classification by a working group sponsored by the World Health Organization.J Clin Pathol. 1978; 31: 395-414Crossref PubMed Scopus (381) Google Scholar Within the nontumorous liver parenchyma, an increase in fibrous tissue alone was not classified as cirrhosis.Sixty-seven samples of HCC tissue and three of adenomatous hyperplasia (AH) were received directly from the operating theater. They were snap-frozen in embedding medium (Tissue-Tek, Elkhart, IN) and stored at −80°C until analysis. Each resected specimen was evaluated for its tumor cell content on a hematoxylin and eosin (H&E)-stained section. For CGH analysis of HCC tissues and AH cases, only specimens with more than 80% tumor cell content were used. Twelve cirrhotic tissue samples, taken from the nontumorous part of the resected specimens, were also analyzed for CGH abnormalities.Comparative Genomic Hybridization AnalysisHigh molecular weight DNA was extracted from the resected liver specimen and control DNA from blood lymphocytes of healthy volunteers by standard phenol/chloroform extraction procedures. Normal metaphase chromosomes were prepared from 72-hour phytohematoglutinine-stimulated peripheral blood lymphocyte cultures of healthy donors. The CGH protocol was carried out according to the method described in Chan et al.28Chan WY Wong N Chan ABW Chow JHS Lee JCK Consistent copy number gain in chromosome 12 in primary diffuse large cell lymphomas of the stomach.Am J Pathol. 1998; 152: 11-16PubMed Google Scholar Briefly, tumor and normal DNA labeled with biotin-16-dUTP (Boehringer Mannheim, Mannheim, Germany) and digoxigenin (dig)-11-dUTP (Boehringer Mannheim), respectively, by nick translation were co-precipitated in excess unlabeled Cot-1 DNA (Gibco Life Technologies, Gaithersburg, MD) and redissolved in hybridization solution containing 50% v/v formamide, 10% w/v dextran sulfate, and 2× SSC, pH 7. Slides containing normal metaphase chromosomes were denatured in 70% formamide/2× SSC (pH 7) at 70°C for 110 seconds. The hybridization was performed in a humid chamber at 37°C for 2 days. Biotin signals were detected through avidin-conjugated fluorescein isothiocyanate (FITC) antibodies (Sigma Chemical Co., St. Louis, MO), whereas dig-labeled DNA were visualized using antibodies conjugated with tetramethylrhodamine isothiocyanate (TRITC) (Sigma). The preparations were counterstained with 0.4 μg/ml 4′,6-diamidino-2-phenylindole (DAPI) in anti-fade solution.Hybridized metaphases were captured with a cooled CCD camera mounted on a Leitz DM RB (Leica, Wetzlar, Germany) fluorescence microscope. Three-band-pass filter (DAPI, FITC, and TRITC) sets arranged in an automated filter wheel were employed for image acquisition. CGH software version 3.1 on Cytovision (Applied Imaging, Sunderland, UK) was used for digital image analysis of fluorescence intensity. Chromosome identification was performed on the reverse DAPI banding images. The average ratio profiles were calculated based on the analysis of 5 to 10 selected metaphases. Thresholds for gains and losses were defined as the theoretical value of 1.25 and 0.75, respectively. High-level gain of a whole chromosome arm or amplification of a chromosomal region was considered to be present when ratios exceeded 1.5. Regions rich in heterochromatin (centromeres of chromosomes 1, 9, and 16, p-arm of acrocentromeric chromosomes, and Yq12) were excluded in the CGH analysis because the excess Cot-1 DNA present suppressed hybridization to these regions.29Kallioniemi O-P Kallioniemi A Piper J Isola J Waldman FM Gray JW Pinkel D Optimizing comparative genomic hybridization for the analysis of DNA sequence copy number changes in solid tumours.Genes Chromosomes & Cancer. 1994; 10: 231-243Crossref PubMed Scopus (944) Google ScholarStatistical AnalysisTotal DNA copy number aberrations, whether gains or losses, were compared between various groups by the two-tailed unpaired Student's t-test. A difference was considered significant when the P value was less than 0.05. Individual chromosome copy number changes were compared by the nonparametric χ2 test and considered significant when the P value was less than 0.05.ResultsOf the 67 cases of HCC analyzed, frequent copy number gains were detected on chromosomes 1q (48/67 cases, 72%), 8q (32/67 cases, 48%), 17q (20/67 cases, 30%), and 20q (25/67 cases, 37%). Common losses were identified on 4q (29/67 cases, 43%), 8p (25/67 cases, 37%), 13q (25/67 cases, 37%), and 16q (20/67 cases, 30%). High-level gains of regional and/or the whole of 1q were also identified in 20/67 cases (30%), and a novel amplicon was mapped to 1q21-q22 (Figure 1).No sequence gains or losses were detected in any of the surrounding cirrhotic tissues. One of the three AH cases displayed a gain of 1q32-qter and 20. The remaining two cases had no detectable CGH abnormalities.TNM StagingThere were no significant DNA sequence differences between the two major stage groups (T2 and T3) other than 8q over-representations, which were found mainly in stage T2 (P = 0.027; Table 1). A high incidence of 1q copy number gain was detected in both stage T2 (39/53 cases, 74%) and stage T3 (8/11 cases, 73%). Other common gains include 8q, 17q, and 20q and frequent losses on 4q, 8p, 13q, and 16q (Table 1).Table 1Comparison of Chromosomal Aberrations between Stages T2 and T3Stage T2Stage T3P value+1q39 /53 (74%)8 /11 (73%)0.953+8q29 /53 (55%)2 /11 (18%)0.027+17q17 /53 (32%)3 /11 (27%)0.755+20q19 /53 (36%)5 /11 (46%)0.549−4q22 /53 (42%)5 /11 (46%)0.810−8p20 /53 (38%)4 /11 (36%)0.932−13q20 /53 (38%)4 /11 (36%)0.932−16q17 /53 (32%)17 /53 (32%)0.359 Open table in a new tab Tumor SizeTwenty specimens fell into the category of small tumors (<3 cm) and forty-seven into the category of large tumors (>3 cm).Figure 2 summarizes the chromosomal aberrations detected in the 47 large tumors. No significant difference on the incidence of chromosomal gains and losses could be identified between the two groups, except diminution on 4q11-q23 was more profound in the larger HCC (P = 0.009; Table 2).Figure 2Summary of gains and losses of DNA sequences identified by CGH in 47 HCCs >3 cm in diameter. Gains are shown on the right side of the chromosome ideogram and losses on the left. High-level gains are shown as thick lines. Each vertical line represents the affected chromosomal region seen in a single tumor specimen.View Large Image Figure ViewerDownload Hi-res image Download (PPT)Table 2Comparison of Chromosomal Aberrations between Small (<3 cm) and Large (>3 cm) Tumors<3 cm>3 cmP value+1q12 /20 (60%)36 /47 (77%)0.168+8q9 /20 (45%)23 /47 (49%)0.768+17q6 /20 (30%)14 /47 (21%)0.986+20q5 /20 (25%)20 /47 (43%)0.174−4q7 /20 (35%)22 /47 (47%)0.372−4q11-q213 /20 (15%)20 /47 (43%)0.009−8p9 /20 (45%)16 /47 (40%)0.396−13q6 /20 (30%)19 /47 (40%)0.419−16q4 /20 (20%)16 /47 (34%)0.250 Open table in a new tab Cirrhotic and Noncirrhotic HCCTwelve of the sixty-seven HCC specimens arose in a noncirrhotic liver; the remaining fifty-five cases had associated liver cirrhosis. All 12 tumors that had no underlying liver cirrhosis exhibited an 8q copy number gain. This incidence was significantly lower in the cirrhotic HCC cases (20/55 cases; P = 0.0001). Other significant gains include 20q, which was found in 9/12 of those without cirrhosis but in only 16/55 cases with cirrhosis (P = 0.003). Losses on 4q were also marked in the noncirrhotic cases (9/12 cases) in comparison with the cirrhotic cases (20/55 cases; P = 0.014; Table 3). The mean number (±SD) of DNA sequence copy changes per tumor in the cirrhotic and noncirrhotic groups were 7.4 ± 5.3 and 12.8 ± 5.0, respectively (P = 0.002). On subdivision of the total aberrations into gains (including amplifications) and losses, a mean of 4.1 ± 2.7 gains was found in the cirrhotic group compared with 7.5 ± 2.8 in the noncirrhotic group (P = 0.0002). The mean copy number losses were 3.3 ± 3.3 in the cirrhotic group and 5.3 ± 2.9 in those without underlying cirrhosis (P = 0.046).Table 3Comparison of Chromosomal Aberrations between HCC with and without Underlying Liver CirrhosisCirrhotic HCCNon-cirrhotic HCCP value+1q38 /55 (69%)10 /12 (83%)0.321+8q20 /55 (36%)12 /12 (100%)0.0001+17q15 /55 (27%)5 /12 (42%)0.324+20q16 /55 (29%)9 /12 (75%)0.003−4q20 /55 (36%)9 /12 (75%)0.014−8p18 /55 (33%)7 /12 (58%)0.097−13q18 /55 (33%)7 /12 (58%)0.097−16q15 /55 (27%)5 /12 (42%)0.324 Open table in a new tab DiscussionThe present study represents the first genome-wide investigation on the genetic imbalances in HCC in relation to TNM staging, tumor size, and underlying cirrhosis. Our series has the advantage of being particularly homogeneous, all samples coming from Southern Chinese patients of whom the great majority were chronic carriers of HBV. As noted previously, this series is typical of the majority of cases in Southeast Asia, although there may still be additional etiological factors even among HBV-related cases, such as aflatoxin exposure and HCV co-infection.4Beasley RP Hepatitis B virus: the major etiology of hepatocellular carcinoma.Cancer. 1988; 61: 1942-1946Crossref PubMed Scopus (1157) Google Scholar, 7Hasan F Jeffers LJ De Medina M Reddy KR Parker T Schiff ER Houghton M Choo QL Kuo G Hepatitis C-associated hepatocellular carcinoma.Hepatology. 1990; 12: 589-591Crossref PubMed Scopus (219) Google Scholar, 30Qian G-S Ross RK Yu MC Yuan J-M Gao Y-T Henderson BE Wogan GN Groopman JD A follow-up study of urinary markers of aflatoxin exposure and liver cancer risk in Shanghai, People's Republic of China.Cancer Epidemiol Biomarkers Prevention. 1994; 3: 3-10PubMed Google Scholar The two most striking features of our analysis were the finding of 8q copy number gain in all HCC cases without underlying liver cirrhosis and the very high incidence of 1q gain (48/67 cases, 72%). These observations strongly suggest that 8q plays an important role in the malignant changes in the noncirrhotic liver and that the gain of 1q is an early aberrant event in HCC development.High-level gain of regional and/or whole q-arm of chromosome 1 was also observed in 20 of the 48 HCC cases (42%) that exhibited a 1q copy number gain. This observation, together with the finding of an amplicon on 1q21-22, indicates the likelihood of important proto-oncogenes residing in this region. According to the Genome Data Base, 1q21 harbors the gene that encodes the human mRNA for hepatoma-derived growth factor. The enhanced expression of this gene could be associated with the paracrine and/or autocrine activity that supports tumor growth. CGH studies on soft tissue sarcomas, osteosarcoma, and the Ewing family of tumors have also reported the presence of a recurring 1q21-q22 amplicon.31Forus A Weghuis DO Smeets D Fodstad Ø Myklebost O van Kessel AG Comparative genomic hybridization analysis of human sarcomas. I. Occurrence of genomic imbalances and identification of a novel major amplicon at 1q21–q22 in soft tissue sarcomas.Genes Chromosomes & Cancer. 1995; 14: 8-14Crossref PubMed Scopus (130) Google Scholar, 32Tarkkanen M Karhu R Kallioniemi A Elomaa I Kivioja AH Nevalainen B Karaharju E Hyytinen E Knuutila S Kallioniemi OP Gains and losses of DNA sequences in osteosarcomas by comparative genomic hybridization.Cancer Res. 1995; 55: 1334-1338PubMed Google Scholar, 33Armengol G Tarkkanen M Virolainen M Forus A Valle J Bohling T Asko-Sel javaara S Blomqvist C Elomaa I Karaharju E Kivioja AH Siimes MA Tukiainen E Caballin MR Myklebost O Knuutila S Recurrent gains of 1q, 8 and 12 in Ewing family of tumors by comparative genomic hybridization.Br J Cancer. 1997; 75: 1403-1409Crossref PubMed Scopus (96) Google Scholar Amplification of the FLG and SPRR3 genes, also located on 1q21, have been identified in several sarcoma cell lines.34Forus A Weterman MAJ Van Kessel AG Berner JM Fodstad Ø Myklebost O Characterisation of 1q21–22 amplifications in human sarcomas by CGH and molecular analysis.Cytogenet Cell Genet. 1996; 72: 148Google Scholar An increased expression of CACY and CAPL of the S-100 family calcium-binding proteins have been mapped to the same region and implicated in tumor progression and metastasis.35Engelkamp D Schafer BW Mattei MG Erne P Heizmann CW Six S100 genes are clustered on human chromosome 1q21: identification of two genes coding for previously unreported calcium-binding proteins S100D and S100E.Proc Natl Acad Sci USA. 1993; 90: 6547-6551Crossref PubMed Scopus (174) Google Scholar We are currently examining the significance of 1q21-q22 amplifications using interphase fluorescence in situ hybridization analysis on a large series of archival paraffin-embedded material and examining the expression pattern of candidate genes described in this region. Although a previous CGH study on HCC also noted a raised incidence of 1q gain (58%), the amplicon 1q21-q22 was not detected.25Marchio A Meddeb M Pineau P Danglot G Tiollais P Bernheim A Dejean A Recurrent chromosomal abnormalities in hepatocellular carcinoma detected by comparative genomic hybridization.Genes Chromosomes & Cancer. 1997; 18: 59-65Crossref PubMed Scopus (260) Google Scholar Sequence amplifications detected in the latter study were defined within one band and mapped to 11q12, 12p11, and 14q12 (1/50 cases each) and 19q31.1 (2/50 cases).25Marchio A Meddeb M Pineau P Danglot G Tiollais P Bernheim A Dejean A Recurrent chromosomal abnormalities in hepatocellular carcinoma detected by comparative genomic hybridization.Genes Chromosomes & Cancer. 1997; 18: 59-65Crossref PubMed Scopus (260) Google Scholar In our present study, the amplicons identified by Marchio et al25Marchio A Meddeb M Pineau P Danglot G Tiollais P Bernheim A Dejean A Recurrent chromosomal abnormalities in hepatocellular carcinoma detected by comparative genomic hybridization.Genes Chromosomes & Cancer. 1997; 18: 59-65Crossref PubMed Scopus (260) Google Scholar were not detected. Rather, frequent high-level gains of regional and/or whole chromosome arms were seen.In nearly 90% of our cases the HCC arose in a liver that was cirrhotic. This figure is typical of our area and similar to that reported from most other countries.6Johnson PJ Williams R Cirrhosis and the aetiology of hepatocellular carcinoma.J Hepatol. 1987; 4: 140-147Abstract Full Text PDF PubMed Scopus (179) Google Scholar, 36Okuda K Hepatocellular carcinoma: recent progress.Hepatology. 1992; 15: 948-963Crossref PubMed Scopus (532) Google Scholar Cirrhosis may be considered as the final common pathway of several chronic liver insults, including viral hepatitis types B and C, excessive alcohol consumption, and various metabolic diseases, and indeed each of these is also strongly associated with the development of HCC. The extent to which it is cirrhosis per se or the factors responsible for the cirrhosis that cause the tumor to develop remains controversial although many authors have considered cirrhosis itself to be a premalignant condition.6Johnson PJ Williams R Cirrhosis and" @default.
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• W2162912407 title "Assessment of Genetic Changes in Hepatocellular Carcinoma by Comparative Genomic Hybridization Analysis" @default.
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