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[Cancer Research 60, 4701-4704, September 1, 2000]
© 2000 American Association for Cancer Research

Advances in Brief

Frequent Frameshift Mutations of RIZ in Sporadic Gastrointestinal and Endometrial Carcinomas with Microsatellite Instability1

Zhe Piao, Wei Fang, Sergei Malkhosyan, Hoguen Kim, Akira Horii, Manuel Perucho and Shi Huang2

The Burnham Institute, La Jolla, California 92037 [Z. P., W. F., S. M., M. P., S. H.]; Department of Pathology, Yonsei University College of Medicine, Seoul, South Korea [Z. P., H. K.]; Department of Molecular Pathology, Tohoku University School of Medicine, Aoba-ku, Sendai, 980-8575, Japan [A. H.]


   ABSTRACT
Top
 ABSTRACT
Introduction
 Materials and Methods
 Results and Discussion
 REFERENCES
 
Many lines of evidence suggest that the retinoblastoma protein interacting zinc finger gene RIZ is a strong candidate for the tumor suppressor locus on 1p36, a region commonly deleted in many human cancers with chromosomal instability. In addition, a role for RIZ in tumors of the microsatellite instability pathway is suggested by frequent frameshift mutations in hereditary non-polyposis colorectal carcinomas. Here we studied RIZ mutations in sporadic cancers with microsatellite instability. Frameshift mutations in the two coding polyadenosine tracks of RIZ were found in 19 (48%) of 40 gastric carcinomas, 6 (33%) of 18 endometrial carcinomas, 14 (26%) of 51 of colorectal carcinomas, and 7 (54%) of 13 cell lines. Eleven tumor tissues showed biallelic inactivation of RIZ. In contrast, no frameshift mutations were found in 70 microsatellite stable tumors. These results suggest an important role for RIZ in sporadic cancers with microsatellite instability.


   Introduction
Top
 ABSTRACT
 Introduction
Materials and Methods
 Results and Discussion
 REFERENCES
 
It is now widely accepted that cancer is the result of an accumulation of mutations in cellular cancer-causing genes. The mutations are thought to be driven by genetic instabilities, which commonly characterize tumor cells. Two major pathways of instabilities have been recognized, CIN3 and MIN (1) . The hallmarks of tumors of the CIN pathway are aneuploidy and LOH. In contrast, tumors of the MIN pathway are usually diploid and show massive instability in simple repeated sequences or microsatellites. In addition, epigenetic events can also facilitate genetic damage, as illustrated by the increased mutagenicity of 5-methylcytosine and the silencing of the MLH1 mismatch repair gene by DNA methylation in colorectal tumors (2) .

MSI-positive (+) tumors are caused by defects in the mismatch repair system (3, 4, 5) . MSI has been detected in HNPCC and HNPCC-associated tumors such as gastric carcinomas and endometrial carcinomas, as well as in many sporadic cases of these tumors (6) . The mechanism of tumorigenesis of MSI(+) tumors is thought to involve frameshift mutations of microsatellite repeats within coding regions of affected target genes the inactivation of which directly contributes to tumor development (7) .

The retinoblastoma protein-interacting zinc finger gene RIZ is a candidate tumor suppressor gene belonging to the PR or SET domain family of chromosomal regulators involved in chromatin-mediated gene activation and silencing (8 , 9) . The PR domain of RIZ is a protein-binding interface and can interact with a motif present in the COOH region of RIZ (9) . The PR/SET domain family plays an important role in human cancers as evidenced by genetic mutations of several family members (10) . RIZ gene normally produces two protein products, RIZ1 and RIZ2, that differ at the NH2-region by the presence or absence of the PR domain (11) . The RIZ1 (PR+) product is considered a strong candidate for the tumor suppressor(s) on 1p36, a region commonly deleted in more than a dozen different types of human cancers (12) . RIZ1 gene expression but not RIZ2 is commonly silenced in all of the human cancers examined including those of breast, liver, colon, and neuroendocrine tissues (13 , 14) . Consistently, RIZ1 has the capacity to induce G2-M cell cycle arrest, apoptosis, or both, and tumor suppression in mice (13 , 14) . These observations suggest a role for RIZ in many tumors of the CIN pathway.

RIZ also appears to play an important role in hereditary tumors of the MIN pathway as suggested by the frequent frameshift mutations in HNPCC tumors (15) . The mutations are located at two polyadenosine tracks within the coding region of RIZ: one (A)8 track at coding nucleotide position 4273–4280 and one (A)9 track at 4462–4471 in exon 8. These mutations generate truncated RIZ1/2 proteins lacking the COOH-terminal PR-binding motif and are expected to have serious deleterious effects on the PR domain-specific function of RIZ1.

Hereditary and sporadic MSI(+) colorectal carcinomas are caused by different tumorigenic events. Genetic defects in MSH2 and MSH3 causes HNPCC, and epigenetic silencing of MLH1 is associated with MSI(+) sporadic colorectal carcinomas (2) . The role of RIZ in sporadic MSI(+) tumors remains to be investigated. Here we describe frequent frameshift mutations of RIZ in sporadic gastrointestinal and endometrial cancers. Importantly, many of these were biallelic or homozygous/hemizygous mutations, which suggests that RIZ inactivation is highly selected during the clonal evolution of these tumors.


   Materials and Methods
Top
 ABSTRACT
 Introduction
 Materials and Methods
Results and Discussion
 REFERENCES
 
Cell Lines and Tumor Samples.
Fourteen cell lines were purchased from American Type Culture Collection. These were derived from colon (HCT116, SW-48, LOVO, LS441N, LS180, LS174T, DLD1, HCT15, HCT8), prostate (DU145), breast (Cal-51), and uterus (AN3CA, SK-UT-1B) cancers. MSI(-) colon cancer cell line SW620 was also included as controls. A total of 179 primary gastrointestinal and endometrial tumors from patients undergoing surgery were analyzed. Among them, 109 tumors were characterized as MSI-High including 40 gastric carcinomas, 18 endometrial cancers, and 51 colorectal cancers. The source of tumor samples has been described previously (16, 17, 18) .

Analysis of MSI.
MSI-High status in primary tumors was defined according to the criteria proposed by Boland et al. (19) .

Mutation Analysis of RIZ.
Frameshift mutations at (A)8 and (A)9 tracks in the RIZ were detected by PCR with Vent DNA polymerase and SSCP analysis, followed by sequencing. The (A)8 track was amplified by PCR with primers RIZA8-F, 5'-GAGCTCAGCAAAATGTCGTC-3', and RIZA9-R, 5'-CAAGTCGGCCTTCTGCTTTG-3'. The (A)9 track was amplified by PCR with primers RIZA9-F, 5'-TCTCACATCTGCCCTTACTG-3', and RIZA9-R, 5'-GTGATGAGTGTCCACCTTTC-3'. PCR was carried out with Vent DNA polymerase as described previously (17) . PCR was performed with primers RIZA8-F and RIZA-9R for SSCP analysis as described (17) . The mutated bands in SSCP gel were sequenced using the Big Dye terminator cycle sequencing kit (Perkin-Elmer Corp.).

Assessment of LOH.
The RIZ Pro704 deletion polymorphism, which has been discovered during sequence analysis of RIZ, was assayed by PCR, then followed by electrophoresis on denaturing gel as described previously (20) . The PCR primers were RP145 (5'-CCC AAG ATA AAC TAA CTC CT-3') and RP105 (5'-ACT CCA TGC TGG TGA GTC-3').


   Results and Discussion
Top
 ABSTRACT
 Introduction
 Materials and Methods
 Results and Discussion
REFERENCES
 
We detected RIZ mutations in 19 (48%) of 40 MSI(+) gastric carcinomas, 6 (33%) of 18 endometrial cancers, 14 (26%) of 51 colorectal carcinomas, and 7 (54%) of 13 MSI(+) cell lines (Fig. 1Citation and Table 1Citation ). Some of the cell lines have also been studied by Chadwick et al. (15) and served as positive control for our studies here. The mutations found in tumor tissues were somatic because the corresponding normal counterparts were wild type. With the exception of a mutation in the (A)8 track in KS19, E75, AC334, and AC590, all of the mutations targeted the (A)9 track. No mutations in the (A)8 or (A)9 track were found in 70 MSI(-) gastric carcinomas, which indicated that these mutations are specific for MSI(+) tumors (46/122 versus 0/70; P = 0.000000 by Fisher’s exact test).



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  		Fig. 1. Frameshift mutations of RIZ at coding (A8) and (A9) tracks in gastric carcinomas and cell lines with MSI. A, LOH analysis of gastric carcinomas using RIZpro704 deletion polymorphism. Case numbers are shown at the top with matched normal (N) and tumor (T) DNA. Tumor KS07 lost lower allele, and tumor KS20 lost upper allele. B, SSCP analysis of PCR products amplified with primers RIZA8-F and RIZA9-R including both (A)8 and (A)9 tracks. Tumor KS07 and KS20 carried a 1-bp deletion at (A)9 track. Tumor KS18 and KS31 carried a 2-bp deletion at (A)9 track. Tumor KS19 had two mutation bands: upper one had a 1-bp deletion at (A)9 track; lower one had a 1-bp deletion at both (A)8 and (A)9 tracks. Tumor KS15 had a homozygous or hemizygous 1-bp deletion at (A)9 track. C, denaturing gel electrophoresis analysis of PCR products amplified with primers RIZA9-F and RIZA9-R using Vent DNA polymerase. The specific MSI and control cell lines are indicated at the top. One-bp deletion was seen in HCT-116, LS441N, LS-180, LS174T, DLD-1, and DU-145. HCT-116 was a homozygous mutation. AN3CA had two mutations: one was 1-bp deletion at (A)9 track, and the other one was 2-bp deletion at (A)9 track. D, SSCP analysis of PCR products with primers RIZA8-F and RIZA9-R including both (A)8 and (A)9 tracks. SSCP results were consistent with those of denaturing gel electrophoresis as shown in C.

 

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  		Table 1 Frameshift mutations of RIZ in gastric carcinomas, endometrial carcinomas, and colorectal cancers and cell lines with MSI

 
Among the 46 cases with RIZ mutations (7 cell lines, 19 gastric carcinomas, 6 endometrial carcinomas, and 14 colorectal carcinomas), 11 cases (KS15, KS19, E4, E68, E75, E505, AC91, AC334, AC469, HCT-116, AN3CA) were biallelic mutations. KS15, E68, E505, AC91, AC469, and HCT-116 showed homozygous/hemizygous mutations (Fig. 1Citation and Table 1Citation ). KS19 and AC334 had a 1-bp deletion at both (A)9 and (A)8 tracks in one allele and a 1-bp deletion at (A)9 track in the other allele, whereas E4 and AN3CA showed a 1-bp deletion at (A)9 track in one allele and a 2-bp deletion at (A)9 track in the other allele. E75 had a 1-bp deletion at (A)8 track in one allele and 2-bp deletion at (A)9 track in the other allele. To determine whether RIZ is also affected by chromosomal deletions in MSI(+) cancers, LOH studies were performed on 25 cases with frameshift mutations for which the matched normal DNAs were available. The RIZpro704 deletion polymorphism, a three-nucleotide deletion at codon Pro704 in exon 8 (20) , allowed us to detect LOH in 2 of 12 informative tumors, KS07 and KS20, which had frameshift mutations in one allele (Table 1)Citation . Therefore, 11 cancers (KS07, KS15, KS19, KS20, E4, E68, E75, E505, AC91, AC334, AC469) and 2 cell lines (HCT-116, AN3CA) had evidence of biallelic inactivation of RIZ. The high frequency of mutation and biallelic inactivation suggest that frameshift mutation of RIZ is clonally selected during tumorigenesis.

All of the frameshift mutations here found in RIZ are predicted to lead to the production of the COOH-terminal domain truncated proteins. The deletion of one adenosine in the (A)8 track at amino acid residue 1436 produces a stop codon two residues from the deletion and a mutant protein lacking COOH-terminal 293 amino acids. It has been demonstrated that the COOH-terminal domain (amino acid 1502–1668 of RIZ1) is a PR domain-binding motif, which may play a role in RIZ1 folding or binding to other proteins or RIZ1 itself (oligomerizaton; 9 ). Thus, deletion of this COOH-terminal protein-binding interface is likely to seriously affect RIZ1 functions.

Our results show that RIZ frameshift mutations are common in sporadic MSI(+) cancers, including gastric, endometrial, and colorectal carcinomas. Importantly, many of these mutations are biallelic or homozygous/hemizygous, which suggests that RIZ fits the Knudson’s two-hit model of tumor suppressor genes (21) . Given the characteristic low frequency of LOH in MSI(+) tumors, it is not surprising that LOH is not commonly found at the RIZ locus in these tumors. Future studies will be required to determine whether other genetic or epigenetic events may be responsible for the inactivation of the remaining wild-type allele. Biallelic inactivation of RIZ was not found in the recent study on HNPCC tumors (15) . This may be related to the genetic differences between hereditary and sporadic cancers but more extensive studies on HNPCC will be required to determine whether heterozygous RIZ mutation is a characteristic of this tumor.

Together with the location on 1p36 and the silencing in many cancers, our finding here suggests that RIZ is a common target of both the CIN and MIN pathways of cancer. In view of the recent report of a role of RIZ in estrogen-receptor signaling (22) , our finding of RIZ mutation in endometrial carcinomas is consistent with an important role in the hormone-dependent growth-control pathways in the endometrium.


   ACKNOWLEDGMENTS
 
We thank Drs. Albert de la Chapelle and Robert Chadwick for communicating results prior to publication.


   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 This work was supported by NIH Grant R01-CA76146 (to S. H.) and by grants (to S. H.) from the Tobacco Related Disease Research Program (TRDRP-7RT0026) and Cancer Research Program of California (CCRP-1 II0023). Back

2 To whom requests for reprints should be addressed, at Program in Oncogenes and Tumor Suppressor Genes, The Burnham Institute, 10901 North Torrey Pines Road, La Jolla, CA 92037. Phone: (619) 646-3120; Fax: (619) 646-3192; E-mail: shuang{at}burnham.org Back

3 The abbreviations used are: CIN, chromosomal instability; MIN, microsatellite instability; LOH, loss of heterozygosity; MSI, microsatellite instability; HNPCC, hereditary non-polyposis colorectal cancer; PR, PRDI-BF1-RIZ1 homology; SET, Suvar 3–9, Enhancer-of-zeste, Trithorax; SSCP, single-strand conformational polymorphism. Back

Received 3/27/00. Accepted 7/18/00.


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 Materials and Methods
 Results and Discussion
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