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Recurrent Allelic Deletions at Mouse Chromosomes 4 and 14 in Myc-Induced Liver Tumors

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Recurrent Allelic Deletions at Mouse Chromosomes 4 and 14 in Myc-Induced Liver Tumors Oncogene (2002) 21, 1518 ± 1526 ã 2002 Nature Publishing Group All rights reserved 0950 ± 9232/02 $25.00 www.nature.com/onc Recurrent allelic deletions at mouse chromosomes 4 and 14 in Myc-induced liver tumors Yuanfei Wu1, Claire-Ange lique Renard1, FrancËoise Apiou3, Michel Huerre2, Pierre Tiollais1, Bernard Dutrillaux3 and Marie Annick Buendia*,1 1Unite de Recombinaison et Expression GeÂneÂtique (Inserm U163), Institut Pasteur, 28 rue du Dr. Roux, 75015 Paris, France; 2Unite d'Histopathologie, Institut Pasteur, 28 rue du Dr. Roux, 75015 Paris, France; 3CNRS UMR 147, Institut Curie, 26 rue d'Ulm, Paris, France Transgenic mice expressing the c-Myc oncogene driven by Introduction woodchuck hepatitis virus (WHV) regulatory sequences develop hepatocellular carcinoma with a high frequency. To Hepatocellular carcinoma (HCC) is among the com- investigate genetic lesions that cooperate with Myc in liver monest cancers worldwide, with an increasing annual carcinogenesis, we conducted a genome-wide scan for loss of incidence in many countries (Bosch, 1997; El-Serag and heterozygosity (LOH) and mutational analysis of b-catenin Mason, 1999). In more than 80% of cases, HCC in 37 hepatocellular adenomas and carcinomas from development has been linked to chronic infection with C57BL/6 x castaneus F1 transgenic mice. In a subset of hepatitis B and C viruses. Other risk factors include these tumors, chromosome imbalances were examined by alcohol-related cirrhosis and dietary exposure to comparative genomic hybridization (CGH). Allelotyping a¯atoxin B1 (Schafer and Sorell, 1999). Allelotype with 99 microsatellite markers spanning all autosomes studies of human HCC have demonstrated recurrent revealed allelic imbalances at one or more chromosomes in loss of heterozygosity (LOH) at multiple chromosome 83.8% of cases. The overall fractional allelic loss was rather loci, mostly on chromosome arms 1p, 4q, 6q, 8p, 9p, low, with a mean index of 0.066. However, signi®cant LOH 13q, 16p, 16q and 17p (Boige et al., 1997; Nagai et al., rates involved chromosomes 4 (21.6% of tumors), 14, 9 and 1997). Comparative genomic hybridization (CGH) 1 (11 to 16%). Interstitial LOH on chromosome 4 was con®rmed these losses and revealed frequent chromo- mapped at band C4 ± C7 that contains the INK4a/ARF and some gains involving 1q, 8q, 6p and 17q arms INK4b loci, and on chromosome 14 at band B ± D including (Marchio et al., 1997). Among known tumor suppres- the RB locus. In man, the homologous chromosomal regions sor genes (TSGs), LOH has been reported for TP53 at 9p21, 13q14 and 8p21 ± 23 are frequently deleted in liver 17p13, RB at 13q14, axin at 16p13 and mannose-6- cancer. LOH at chromosomes 1 and 14, and b-catenin phosphate/IGF-II receptor at 6q27 (De Souza et al., mutations (12.5% of cases) were seen only in HCCs. All 1995; Murakami et al., 1991; Satoh et al., 2000). TSGs tumors examined were found to be aneuploid. CGH analysis localized in other frequently deleted regions remain of 10 representative cases revealed recurrent gains at presently unknown. Few oncogenes, namely c-Myc and chromosomes 16 and 19, but losses or deletions involving b-catenin, are known to be activated in HCC (reviewed mostly chromosomes 4 and 14 generally prevailed over in Buendia, 2000). Recent studies support the notion gains. Thus, Myc activation in the liver might select for that distinct pathways might be dierentially activated inactivation of tumor suppressor genes on regions of in HCCs of various etiological origins (Laurent-Puig et chromosomes 4 and 14 in a context of low genomic al., 2001). A hot-spot mutation at codon 249 of TP53 instability. Myc transgenic mice provide a useful model is considered as a hallmark of a¯atoxin B1 contamina- for better de®ning crosstalks between oncogene and tumor tion (Bressac et al., 1991). Higher LOH and p53 suppressor pathways in liver tumorigenesis. mutation rates, and lower incidence of b-catenin Oncogene (2002) 21, 1518 ± 1526. DOI: 10.1038/sj/ mutations have been evidenced in hepatitis B virus- onc/1205208 related tumors (Hsu et al., 2000; Legoix et al., 1999; Marchio et al., 2000; Sheu et al., 1999). Keywords: hepatocellular carcinoma; c-Myc; LOH; Tumor-prone transgenic mice oer powerful tools CGH; INK4A/ARF for investigating the molecular mechanisms of onco- genesis. Animals with uniform genetic background are maintained in controlled environment, providing a stable and theoretically unlimited resource for analys- *Correspondence: MA Buendia, Unite de Recombinaison et ing tumors induced by the same initial oncogenic event. Expression Ge ne tique, De partement des Retrovirus, Institut Transgenic models of hepatocarcinogenesis have de- Pasteur, 28 rue du Dr. Roux, 75724 Paris Cedex 15, France; monstrated the high oncogenic impact of c-Myc E-mail: [email protected] Received 10 October 2001; revised 12 November 2001; accepted 28 activation on liver cells. In previous studies, we have November 2001 shown that liver expression of a woodchuck c-myc Allelotype of Myc-induced liver tumors YWuet al 1519 transgene controlled by hepatitis virus sequences in Genome-wide screen of LOH in liver tumors WHV/c-myc transgenic mice induces hepatocellular adenomas and HCCs within 8 ± 12 months, with a We initially genotyped 81 tumor samples collected from high (near 100%) penetrance (Etiemble et al., 1994). In 30 mouse livers by microsatellite marker analysis, using this model, c-Myc is transiently overexpressed in the 99 markers distributed along all 19 autosomes and X liver after birth, and it is re-expressed together with chromosome. Dierent tumor samples from a given IGF-II at tumor onset (Liu et al., 1997). Activation of mouse that showed identical LOH patterns were the Wnt pathway has been implicated in a subset of considered as the same tumor, while they were regarded these tumors by the ®nding of frequent b-catenin as independent tumors when presenting dierent LOH mutations (de La Coste et al., 1998), but other patterns. Finally, 37 independent tumors (27 HCCs and secondary genetic events that cooperate with Myc 10 adenomas) were included in this study. Among HCCs, remain poorly de®ned. 24 were well dierentiated, and three were moderately or In this study, we performed a genome-wide screen of poorly dierentiated. LOH was assessed with at least LOH in 37 tumors (27 HCCs and 10 adenomas) of three widely spaced markers per chromosome, spanning C57BL/6 x Mus Musculus Castaneus F1 hybrids de- a total distance of 1075 cM and covering 75% of the rived from WHV/c-myc transgenic mice. In 10 selected mouse genome. Because some regions of mouse chromo- tumors, we further analysed DNA ploidy by ¯ow somes 1, 4, 8 and 14 are homologous to frequently cytometry and chromosome imbalances by CGH. In altered chromosomal loci in human HCC (Boige et al., addition, we compared the pro®les of genetic altera- 1997; Nagai et al., 1997), these chromosomes were tions in tumors carrying mutated or wild-type b- analysed with a higher density of markers. We also catenin alleles. Our data, showing nonrandom losses positioned markers nearby 10 known TSGs, including on regions of chromosomes 4 and 14 that are the metastasis-suppressing gene KAI1/CD82, Wilms' homologous to frequently involved regions in human tumor (WT1), cyclin-dependent kinase inhibitors HCCs, imply that TSGs located on these chromosomes INK4a/ARF and INK4b, Modi®er of Min-1 (Mom-1), are selectively inactivated in Myc-related liver tumori- breast cancer susceptibility BRCA2, ataxiatelangiecta- genesis. sia-mutated (ATM), mutL homologue (MLH1), TP53, retinoblastoma (RB), adenomatous polyposis coli (APC), dual speci®city phosphatase PTEN (MMAC1/ TEP1) and Myc-antagonist (Mxi1) genes. Based on Results reconstruction experiments, LOH was judged by reduc- tion of allelic intensity of more than twofold, as Liver tumorigenesis in hybrid C57BL/6 x Cast/ei illustrated in Figure 1. All makers detected one or two transgenic mice alleles with the same size in tumor and matched non- We have shown previously that liver-speci®c expres- tumor samples. Therefore, in the absence of replication sion of c-Myc in WHV/c-myc transgenic mice is error on short repeat sequences, these tumors did not associated with the invariable development of liver exhibit microsatellite instability (MIN). tumors (hepatocellular adenomas and HCCs) at 8 ± LOH was detected at one or more chromosomal loci in 12 months of age (Etiemble et al., 1994). The 30/37 tumors (81%). The number of chromosomes with transgenic founder 93-7 (hybrid C57Bl/6 x SJL/J LOH varied from 0 ± 4 per tumor (average: 1.3) (Figure 2). background) and progeny were serially backcrossed The fractional allelic loss or FAL (fraction of chromo- to the C57BL/6 strain for 18 generations. The resulting animals developed liver tumors in all cases within 6 ± 24 months (mean latency period: 12 months). For the present study, male and female transgenic mice were crossed with Cast/ei mice to produce F1 ospring harboring a high rate of polymorphism in microsatellite marker loci. The onset of liver tumors was markedly delayed in F1 animals compared to pure-strain C57BL/6 mice, with 80% of the F1 transgenic cohort harboring liver tumors between 12 ± 24 months (average: 16.5 months). At autopsy, most animals carried several tumor masses, with average three macroscopic nodules, often localized in the right liver lobe. At histopathological examination, the tumors consisted mainly of well-dierentiated, trabecular-type HCCs Figure 1 Examples of microsatellite analysis of liver and tumor with frequent necrosis, or hepatocellular adenomas. DNAs. PCR products were separated on agarose gels and stained These tumors were indistinguishable from those of with ethidium bromide. (a) Liver DNA from a normal F1 hybrid the parental C57Bl/6 mice (Etiemble et al., 1994), (NF1) was ampli®ed with D4Mit52 primers and PCR products were compared to those from Cast/ei and C57B1/6 DNAs mixed and adjacent liver similarly carried dysplastic lesions in dierent ratios.
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