A 2.8-Mb Clone Contig of the Multiple Endocrine Neoplasia Type 1 (MEN1) Region at 11q13

Guru, Siradanahalli C.; Olufemi, Shodimu-Emmanuel; Manickam, Pachiappan; Cummings, Christiano; Gieser, Linn; Pike, Brian L.; Bittner, Michael; Jiang, Yuan; Chinault, A. Craig; Nowak, Norma J.; Brzozowska, Anna; Crabtree, Judy S.; Wang, Y; Roe, Bruce A.; Weisemann, Jane M.; Boguski, Mark S.; Agarwal, Sunita K.; Burns, A. Lee; Spiegel, Allen M.; Marx, Stephen J.; Flejter, Wendy L.; Jong, Pieter J. de; Collins, Francis S.; Chandrasekharappa, Settara C.

doi:10.1006/geno.1997.4783

Cited by 38 publications

(29 citation statements)

References 42 publications

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“…Nineteen of the markers are localized to the 5.6 Mb interval between markers PYGM and INT2 and the marker D11S533 is localized 8 Mb distal to INT2, thus spanning a total distance of 13.6 Mb for the 20 probes (Courseaux et al, 1996;Wood et al, 1996;Guru et al, 1997). While only two probes were informative in sample 1, multiple probes exhibited polymorphic alleles in all other tumor samples.…”

Section: Deletion Of 11q13 Sequences In Primary Tumorsmentioning

confidence: 99%

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Localization of deletion to a 300 Kb interval of chromosome 11q13 in cervical cancer

et al. 2002

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Previous molecular genetic studies on HeLa cell (a cervical cancer cell line) derived non-tumorigenic and tumorigenic hybrids have localized a tumor suppressor gene to the long arm of chromosome 11. Analysis of cervical cancer cell lines using chromosome 11 specific probes showed deletion and translocation of 11q13 sequences in five out of eight cell lines. Fluorescence in situ hybridization (FISH), using 11q13 specific probes, has shown interstitial deletion of 11q13 sequences in the HeLa cells. In order to determine whether 11q13 deletions occur in primary cervical tumors, we analysed 36 tumors using 20 different microsatellite and RFLP markers. Semi automated fluorescein based allelotyping was performed to identify loss of heterozygosity (LOH) in tumors. The results showed allelic loss in 17 (47%) tumors. Three different regions of loss, one near MEN1, the second near D11S913, and the third near INT2 locus were observed. The smallest region of deletion overlap at the D11S913 locus was localized to a 300 Kb distance between D11S4908 and D11S5023. Fluorescence in situ hybridization (FISH), using 11q13 specific cosmid and BAC (bacterial artificial chromosome) probes, confirmed allelic deletion in the tumors. PCR analysis further identified homozygous deletion of 11q13 sequences in a primary tumor, in HeLa cells and in two HeLa cell derived tumorigenic hybrid cell lines. The homozygous deletion in the cell lines was mapped to a 5.7 kb sequence of 11q13. We hypothesize therefore that a putative cervical cancer tumor suppressor gene exists within the 300 kb of chromosome 11q13.

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Section: Deletion Of 11q13 Sequences In Primary Tumorsmentioning

confidence: 99%

“…Tumors 6 and 15 were also studied with an additional PYGM probe. Two tumors (5 and 16) contained three and the The distances between markers were derived by contig mapping studies (Wood et al, 1996;Courseaux et al, 1996;Guru et al, 1997). A distance of 1.5 Mb separates D11S913 and GSTP1.…”

Section: Confirmation Of 11q13 Loss Using Fishmentioning

confidence: 99%

Localization of deletion to a 300 Kb interval of chromosome 11q13 in cervical cancer

et al. 2002

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“…13,14) The MEN1 gene, transcribed in the direction from the telomere to the centromere, is located at most 200 kb centromeric to D11S4940 and at most 100 kb telomeric to PYGM. 14) D11S4946 is located 0.5 kb upstream from the MEN1 transcription start point. 3,14) Genomic DNA was amplified by PCR with a pair of primers, one of which was labeled with FITC.…”

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confidence: 99%

“…14) D11S4946 is located 0.5 kb upstream from the MEN1 transcription start point. 3,14) Genomic DNA was amplified by PCR with a pair of primers, one of which was labeled with FITC. The primer sequences and PCR conditions were obtained from the Genome Database (http:// gdbwww.gdb.org/).…”

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A Large Germline Deletion of the MEN1 Gene in a Family with Multiple Endocrine Neoplasia Type 1

Kishi¹,

Tsukada²,

Shimizu³

et al. 1998

Japanese Journal of Cancer Research

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Multiple endocrine neoplasia type 1 (MEN1) is a familial cancer syndrome inherited as an autosomal dominant trait. Various heterozygous germline mutations of the responsible gene, MEN1, have been identified within its exons in many, but not all, affected individuals. We here demonstrate, by DNA polymorphism analysis and gene dosage analysis with polymerase chain reaction (PCR), a large heterozygous germline MEN1 deletion in a kindred with MEN1, in whom no mutation could be detected in the PCR-amplified exons. The deletion spanned an at least 7 kb region containing the entire MEN1 gene. These findings indicate that a large germline deletion of the MEN1 gene, which escapes detection in PCR-based sequence analysis, should be considered as a potential cause of MEN1.Key words: Multiple endocrine neoplasia type 1 -MEN1 -Tumor suppressor gene -Gene dosage -DNA testing Multiple endocrine neoplasia type 1 (MEN1) is an autosomal dominant familial cancer syndrome characterized by parathyroid, enteropancreatic and pituitary tumors.1, 2) The responsible gene, MEN1, was recently identified on chromosome 11q13 by positional cloning. 3)A heterozygous MEN1 germline mutation underlies an inherited predisposition to the development of MEN1-related tumors. Although the molecular function of the encoded protein, menin, is unknown, 3) MEN1 is considered to be a tumor suppressor gene because loss of heterozygosity of the MEN1 locus frequently occurs in the MEN1-related tumors. 4)Previous studies have identified various MEN1 germline mutations within its exons in many affected individuals with MEN1.3, 5-8) Although several missense mutations and in-frame deletions have been identified, the detected germline mutations were mostly nonsense or frameshift mutations, which cause truncation of menin and, presumably, loss of function of the gene. These findings are consistent with a tumor suppressor function of this gene.The previous studies also revealed that some individuals affected with MEN1 had no detectable MEN1 germline mutation.3, 5-7) Because these studies analyzed only proteincoding exons that were amplified by polymerase chain reaction (PCR), a mutation in another region of the gene or a large heterozygous deletion could have been missed. Alternatively, some of these mutation-negative individuals could have had a distinct syndrome caused by some other gene(s) that meets the formal definition of MEN1 as suggested previously, 5) or could have had multiple independent tumors by chance in two or more MEN1-related endocrine tissues. Because identification of a MEN1 germline mutation enables presymptomatic recognition or early exclusion of this disease in individuals at risk, it is important to characterize MEN1 germline mutations which escape detection by PCRbased mutation screening.We encountered a case of familial MEN1 with three affected individuals, two of whom (Fig. 1, patients a and c) were previously analyzed and exhibited no detectable MEN1 germline mutation in the protein-coding exons. 7)We analyzed blood cell DNA of the third ...

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“…Nonetheless, mutations of the RB gene itself are infrequent in human pituitary adenomas (Cryns et al, 1993;Levy et al, 1994;Pearce et al, 1996). The MEN1 gene was recently cloned and is associated with endocrine tumors of the parathyroid, pancreas, and pituitary (Guru et al, 1997). The incidence of LOH at 11q13 in sporadic parathyroid and pancreatic endocrine tumors was 26-38% and 19-44%, respectively (Pearce et al, 1996).…”

Section: Discussionmentioning

confidence: 99%

Clinical significance of molecular genetic changes in sporadic invasive pituitary adenomas

Nam

Song²,

Park³

et al. 2001

Exp Mol Med

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AbstactSeveral molecular and genetic changes have been found in pituitary adenomas. We looked for correlations between these changes and the degree of invasiveness of the tumors. The invasiveness of 11 pituitary adenomas was graded by Hardy classification. We examined the retinoblastoma gene (RB1.20 on chromosome 13q) and the region around the MEN1 locus (chromosome 11q13.1-5) for loss of heterozygosity. Also examined are p53 mutations using single strain conformation polymorphism, p53 protein overexpression using immuno cytochemistry, homozygous deletions of p15 and p16 by polymerase chain reaction, and cellular proliferative activity using MIB-1 antibody. Six tumors (54.5%) had an LOH at either RB1.20 or the MEN1 locus. LOHs were found more frequently in Grade 4 and stage E tumors (72% and 67%) than in Grade 3 and stage D tumors (25% and 40%). However, no mutation or overexpression of p53 was found. No homozygous deletions of p15 or p16 were identified. The cell proliferative index ranged from 0 to 3%. LOH at 11q13 and 13q may be valuable in predicting the invasiveness of pituitary adenomas.

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A 2.8-Mb Clone Contig of the Multiple Endocrine Neoplasia Type 1 (MEN1) Region at 11q13

Cited by 38 publications

References 42 publications

Localization of deletion to a 300 Kb interval of chromosome 11q13 in cervical cancer

Localization of deletion to a 300 Kb interval of chromosome 11q13 in cervical cancer

A Large Germline Deletion of the MEN1 Gene in a Family with Multiple Endocrine Neoplasia Type 1

Clinical significance of molecular genetic changes in sporadic invasive pituitary adenomas

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