Mapping of a minimal deleted region in human hepatocellular carcinoma to 1p36.13–p36.23 and mutational analysis of the RIZ (PRDM2) gene localized to the region

Fang, Wei; Piao, Zhe; Simón, Daniela; Sheu, Jin‐Chuan; Shi, Hongbo

doi:10.1002/1098-2264(200007)28:3<269::aid-gcc4>3.3.co;2-b

Cited by 29 publications

(40 citation statements)

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“…The apparent selection for RIZ2 expression in breast cancers may have favoured the strategy of RIZ1 gene silencing rather than altering RIZ1 peptide sequences. This is similar to previous findings of lack of RIZ1 mutations in HCC where RIZ2 expression is uniformly present (Jiang et al, 1999;Fang et al, 2000). These observations suggest that decreasing RIZ1 expression may represent the more common way of inactivating RIZ1, at least in breast cancer and HCC.…”

Section: Discussionsupporting

confidence: 91%

“…One candidate in this region is the retinoblastoma protein-interacting zinc finger gene RIZ(PRDM2), which was isolated in a functional screening for Rb-binding proteins (Buyse et al, 1995), also independently isolated as a DNA-binding protein MTB-Zf (Muraosa et al, 1996), a GATA3 transcription factor binding protein G3B (Shapiro et al, 1995), and a coactivator of oestrogen receptor (ER) (Abbondanza et al, 2000). The gene maps within the minimal deleted region on 1p36 in liver, breast and familial colon cancers (Chadwick et al, 2000;Fang et al, 2000).…”

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confidence: 99%

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Preferential loss of a polymorphic RIZ allele in human hepatocellular carcinoma

et al. 2001

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SummaryThe RIZ (PRDM2) locus commonly undergoes loss of heterozygosity (LOH) and maps within the minimal deleted region on 1p36 in hepatocellular carcinoma (HCC). Although peptide-altering mutations of RIZ are rare in HCC, the RIZ1 product is commonly lost in HCC and has tumour suppressive activities. Here, we analysed RIZ gene mutations and LOH in HCC, breast cancer, familial melanoma, colon cancer, and stomach cancer. We found 7 polymorphisms but no mutations. By analysing the Pro704-deletion polymorphism, we detected LOH of RIZ in 31 of 79 (39%) informative HCC cases, 11 of 47 (23%) colon cancer cases, 8 of 43 (19%) breast cancer cases, 8 of 66 (12%) stomach cancer cases. Importantly, loss of the Pro704 + allele was found in 74% of the 31 LOH positive HCC cases (P < 0.01), indicating a preferential loss and hence a stronger tumour suppressor role for this allele compared to the P704 Ϫ allele. In addition, the Pro704 + allele was found to be more common in Asians (0.61) than Caucasians (0.42) (P = 0.0000), suggesting an interesting link between gene polymorphisms and potential differences in tumour incidence between racial groups.

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Section: Discussionsupporting

confidence: 91%

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confidence: 99%

Preferential loss of a polymorphic RIZ allele in human hepatocellular carcinoma

et al. 2001

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“…In HNPCC tumors, there was a gradual decline of the LOH rate from WIAF-481 to RIZ 3Ј to RIZ 5Ј. Three intragenic polymorphisms of RIZ were analyzed for LOH, including a codon Pro-704 deletion at exon 8, an intron 4 CA repeat (18), and a SNP flanking exon 4 (GAT to GAC 18 bases 3Ј of the coding exon 4 sequence). The LOH rates for these RIZ markers were 21% (3͞14), 9% (1͞11), and 0% (0͞8), respectively.…”

Section: Resultsmentioning

confidence: 99%

Candidate tumor suppressor RIZ is frequently involved in colorectal carcinogenesis

Chadwick

Jiang

Bennington

et al. 2000

Proc. Natl. Acad. Sci. U.S.A.

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The distal portion of chromosome 1p is one of the most commonly affected regions in human cancer. In this study of hereditary and sporadic colorectal cancer, a region of frequent deletion was identified at 32.2 centimorgans from 1ptel. Deletion breakpoints clustered in the vicinity of or inside the gene RIZ, which encodes a retinoblastoma protein-interacting zinc finger protein. Sequence analysis revealed frequent frameshift mutations of the RIZ gene. The mutations consisted of 1-or 2-bp deletions of a coding (A)8 or (A) 9 tract and were confined to microsatellite-unstable colorectal tumors, being present in 9 of 24 (37.5%) primary tumors and in 6 of 11 (54.5%) cell lines; in 2 cell lines the mutation was homozygous͞hemizygous. The mutations apparently were selected clonally in tumorigenesis, because similar poly(A) tracts in other genes were not affected. Two alternative products of the gene exist, RIZ1, which contains a PR (PRDI-BF1-RIZ1) domain implicated in tumor suppressor function, and RIZ2, which is lacking this motif. Furthermore, the C-terminal region, which contains the poly(A) tracts, includes a PR-binding motif, possibly mediating interactions with other proteins or with RIZ itself (oligomerization). Four of eleven microsatellite-unstable colorectal cancer cell lines, three of which had frameshifts, showed reduced or absent mRNA expression of RIZ1. In a cell line that is homozygous͞hemizygous for the typical frameshift mutation, immunoblotting showed truncated RIZ protein, whereas adenovirus-mediated RIZ1 expression caused G2͞M arrest and apoptosis. We propose that RIZ is a target of the observed 1p alterations, with impairment of the PR domainmediated function through either frameshift mutation or genomic deletion.S poradic cancer arises as a result of a series of somatic mutations and epigenetic changes that silence tumor suppressor genes or activate oncogenes (1). As such, the APC-RAS-P53 pathway in colorectal cancer is well established (2), but many of its components are not fully understood (3). Recently, two pathways, CIN, a chromosomal instability pathway, and MIN, a microsatellite instability pathway, have been proposed. Loss of heterozygosity (LOH) is a hallmark of the CIN pathway, whereas microsatellite instability (MSI) characterizes the MIN pathway (4). In the MIN pathway, mutations or epigenetic silencing of one of the DNA mismatch repair genes lead to widespread accumulation of mutations, followed by clonal selection (5). The MSI(ϩ) phenotype is easily distinguishable by allelic changes of repetitive regions throughout the genome (6).Some genes contain repetitive regions in their coding sequences that are often targets of MSI. Insertion or deletion in these repetitive regions leads to frameshift and protein truncation. In colorectal cancer, the TGFBRII gene (7) and BAX gene (8) are examples of genes mutated in this way and whose loss of function is believed to contribute to tumorigenesis. Other examples include the DNA mismatch repair genes MSH6 and MSH3, and IGFR2 (9). In this paper, w...

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“…Independent evidence, however, has documented LOH at 1p36-p34 not only in HCCs, but also in cirrhotic and dysplastic nodules, indicating the presence of one or more tumor suppressors that are lost prior to the development of tumor (Sun et al, 2001). One gene (designed RIZ), located within 1p36.13-p36.23, appears to be a tumor suppressor that is frequently deleted in HCC (Fang et al, 2000), verifying that commonly deleted regions actually do encode negative regulators of hepatocellular growth. LOH at 6q26-27 often involves loss of the mannose 6-phosphate/IGF2 receptor (DeSouze et al, 1995), which is also an imprinted gene that has been implicated as a tumor suppressor due to its ability to activate TGF-b1 signaling (which triggers apoptosis) and degrade IGF2 (which promotes hepatocellular growth).…”

Section: Early Events In Hepatocarcinogenesismentioning

confidence: 92%

Genetic mechanisms of hepatocarcinogenesis

et al. 2002

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The development of hepatocellular carcinoma (HCC) is a multistep process associated with changes in host gene expression, some of which correlate with the appearance and progression of tumor. Preneoplastic changes in gene expression result from altered DNA methylation, the actions of hepatitis B and C viruses, and point mutations or loss of heterozygosity (LOH) in selected cellular genes. Tumor progression is characterized by LOH involving tumor suppressor genes on many chromosomes and by gene ampli®cation of selected oncogenes. The changes observed in di erent HCC nodules are often distinct, suggesting heterogeneity on the molecular level. These observations suggest that there are multiple, perhaps redundant negative growth regulatory pathways that protect cells against transformation. An understanding of the molecular pathogenesis of HCC may provide new markers for tumor staging, for assessment of the relative risk of tumor formation, and open new opportunities for therapeutic intervention.

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Mapping of a minimal deleted region in human hepatocellular carcinoma to 1p36.13–p36.23 and mutational analysis of the RIZ (PRDM2) gene localized to the region

Cited by 29 publications

References 0 publications

Preferential loss of a polymorphic RIZ allele in human hepatocellular carcinoma

Preferential loss of a polymorphic RIZ allele in human hepatocellular carcinoma

Candidate tumor suppressor RIZ is frequently involved in colorectal carcinogenesis

Genetic mechanisms of hepatocarcinogenesis

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