Definitive functional evidence for a tumor suppressor gene on human chromosome 7q31.1 neighboring the Fra7G site

Zenklusen, Jean C.; Hodges, Leslie C.; LaCava, Margaret; Green, Eric D.; Conti, Claudio J.

doi:10.1038/sj.onc.1203488

Cited by 38 publications

(23 citation statements)

References 24 publications

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“…The common deleted region to all cases with 7q loss in this group of tumours was 7q31. The second most common aphidicolin-inducible fragile site of the human genome (Fra7G) has been located in this region, and loss of heterozygosity (LOH) studies indicate this chromosomal region as a frequent site of allele loss in a variety of tumours (Zenklusen et al, 2000). In the thyroid gland, it was proposed (Trovato et al, 1999) that 7q31 was the site of at least one suppressor gene involved in follicular tumorigenesis.…”

Section: Discussionmentioning

confidence: 99%

Chromosomal imbalances associated with anaplastic transformation of follicular thyroid carcinomas

Rodrigues¹,

Roque²,

Rosa-Santos

et al. 2004

Br J Cancer

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The genetic alterations that underlie the progression of follicular thyroid carcinoma towards anaplasia are still largely uncharacterised. We compared the Comparative Genomic Hybridization (CGH) profiles of 20 follicular (FTCs), 12 poorly differentiated (PDTCs) and seven anaplastic thyroid carcinomas (ATCs), in order to identify the chromosomal imbalances potentially associated with cancer progression. We found: (i) when considering that a 'direct' transformation of FTC towards anaplasia occurs, the defined significantly important alterations were the increase of gains at 3q (Po0.05) and 20q (Po0.01), and the increase of losses at 7q (Po0.05) and Xp (Po0.01); (ii) regarding poorly differentiated carcinomas as an intermediate independent entity in the anaplastic transformation of follicular cancers, evidenced as important alterations towards anaplasia, were the proportional decrease in copy sequences at 7p, 7q, 12q and 13q resulting from the significant decrease of DNA gains at 7p and 12q (Po0.05), and the significant increase of losses at 7q and 13q (Po0.05). These results unveil the chromosomal regions where genes of interest in thyroid anaplastic transformation are to be located, and demonstrate that different gene dosage copy sequence imbalances are associated to the 'direct' pathway of transformation of follicular into anaplastic cancers and to the progressive FTC-PDTC-ATC pathway.

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Section: Discussionmentioning

confidence: 99%

Chromosomal imbalances associated with anaplastic transformation of follicular thyroid carcinomas

Rodrigues¹,

Roque²,

Rosa-Santos

et al. 2004

Br J Cancer

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“…Deletions involving this region have been observed in virtually every major tumor type, with loss of heterozygosity (LOH) found in up to 80% of breast (Bieche et al, 1992;Zenklusen et al, 1994a), prostate (Zenklusen et al, 1994c;Latil et al, 1995;Takahashi et al, 1995), pancreatic (Achille et al, 1996), colon (Zenklusen et al, 1995a), ovarian (Zenklusen et al, 1995b), and thyroid cancers (Zhang et al, 1998), with lower frequencies in renal cancers (Shridhar et al, 1997) and squamous cell carcinomas of the head and neck (Zenklusen et al, 1995a). Functional studies using microcell-mediated transfer of chromosome 7 have shown that introduction of a normal copy of chromosome 7 can restore senescence to human fibroblasts (Ogata et al, 1993) and suppress tumorigenicity of a murine squamous cell carcinoma cell line and the human prostate carcinoma cell line, PC-3 (Zenklusen et al, 1994b;Zenklusen et al, 2000). Furthermore, deletion mapping of PC-3/hchr7 tumors obtained after reversion to the malignant phenotype revealed a common region of loss at 7q31.1, therefore providing compelling evidence for a TSG in this region (Zenklusen et al, 2000).…”

Section: Introductionmentioning

confidence: 99%

“…Functional studies using microcell-mediated transfer of chromosome 7 have shown that introduction of a normal copy of chromosome 7 can restore senescence to human fibroblasts (Ogata et al, 1993) and suppress tumorigenicity of a murine squamous cell carcinoma cell line and the human prostate carcinoma cell line, PC-3 (Zenklusen et al, 1994b;Zenklusen et al, 2000). Furthermore, deletion mapping of PC-3/hchr7 tumors obtained after reversion to the malignant phenotype revealed a common region of loss at 7q31.1, therefore providing compelling evidence for a TSG in this region (Zenklusen et al, 2000). The gene Suppressor of Tumorigenicity 7 (ST7), also known as RAY1/HELG (Hughes et al, 2001;Vincent et al, 2000), has emerged as the leading contender for the 7q31.1 TSG (Zenklusen et al, 2001).…”

Section: Introductionmentioning

confidence: 99%

ST7-mediated suppression of tumorigenicity of prostate cancer cells is characterized by remodeling of the extracellular matrix

et al. 2006

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Multiple lines of evidence have provided compelling evidence for the existence of a tumor suppressor gene (TSG) on chromosome 7q31.1. ST7 may be the target of this genetic instability but its designation as a TSG is controversial. In this study, we show that, functionally, ST7 behaves as a tumor suppressor in human cancer. ST7 suppressed growth of PC-3 prostate cancer cells inoculated subcutaneously into severe combined immunodeficient mice, and increased the latency of tumor detection from 13 days in control tumors to 23 days. Re-expression of ST7 was also associated with suppression of colony formation under anchorage-independent conditions in MDA-MB-231 breast cancer cells and ST7 mRNA expression was downregulated in 44% of primary breast cancers. Expression profiling of PC-3 cells revealed that ST7 predominantly induces changes in genes involved in re-modeling the extracellular matrix such as SPARC, IGFBP5 and several matrix metalloproteinases. These data indicate that ST7 may mediate tumor suppression through modification of the tumor microenvironment.

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“…This is in agreement with the hypothesis that this chromosomal region might contain a putative tumorsuppressor gene that could be discovered either in early or in advanced stages of the disease. 12,33,35 As for chromosome 11 (Table IV), losses have been shown in a series of malignant human tumors. 5,8,14 Yet, to our knowledge, except for a small number of cases described by Dahiya et al this is the first report of a consistent LOH in a specific region of chromosome 11 in transitional zone prostate carcinomas.…”

Section: Loss Of Heterozygositymentioning

confidence: 99%

Molecular disorders in transitionalvs. peripheral zone prostate adenocarcinoma

et al. 2001

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Loss of heterozygosity (LOH) and microsatellite instability (MSI) have been shown to be mechanisms for tumor-suppressor gene inactivation in human oncogenesis. In our study, we examined LOH and MSI using 16 polymorphic markers of DNA for chromosomes 1, 3, 7, 8, 10 and 11. Microdissected tumor samples were isolated from 32 patients, representing 11 foci of incidentally discovered prostate cancer of the transitional zone (TZ), 12 prostate cancer of the peripheral zone (PZ) and 10 of high-grade PIN. We found loss of heterozygosity in the TZ group in 91% of informative cases (10/11) with al least 1 marker compared to 58% of cases (7/12) in PZ group and 70% of cases (7/10) in the HGPIN group. Chromosome 7 showed the highest rate of allelic loss in all 3 categories, with loss of 43% of loci in PIN, 37% in TZ tumors and 31% in PZ tumors. At chromosome 11, LOH was detected in 26% of loci in the TZ group, in 7% of loci in the PZ group and in 13% of loci in the PIN group. On chromosome 8, the PZ and HGPIN group showed allelic loss in 22% and 21% of loci, respectively, compared to 10% detected in the TZ group. The TZ group showed a significant higher rate of allelic instability compared to that observed in tumor samples from the peripheral zone: 73% of cases (8/11) showed genetic alterations (RER؉ phenotype) in at least 4 loci analyzed compared to 8% and 10% in the PZ and HGPIN groups, respectively (p ‫؍‬ 0.0006). These data suggest that transitional zone carcinoma and peripheral zone carcinoma display distinct and specific genetic alterations in different chromosomes. This diversity may help explain biologic and clinical differences between carcinomas arising in these distinct zones of the prostate. Also our results strongly suggest that the RER؉ mutator phenotype could be linked to early development of transitional zone prostate carcinoma.

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Definitive functional evidence for a tumor suppressor gene on human chromosome 7q31.1 neighboring the Fra7G site

Cited by 38 publications

References 24 publications

Chromosomal imbalances associated with anaplastic transformation of follicular thyroid carcinomas

Chromosomal imbalances associated with anaplastic transformation of follicular thyroid carcinomas

ST7-mediated suppression of tumorigenicity of prostate cancer cells is characterized by remodeling of the extracellular matrix

Molecular disorders in transitionalvs. peripheral zone prostate adenocarcinoma

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