Eighteen new polymorphic markers in the multiple endocrine neoplasia type 1 (MEN1) region

Manickam, Pachiappan; Guru, Siradanahalli C.; Debelenko, Larisa V.; Agarwal, Sunita K.; Olufemi, Shodimu-Emmanuel; Weisemann, Jane M.; Boguski, Mark S.; Crabtree, Judy S.; Wang, Y; Roe, Bruce A.; Lubensky, Irina A.; Zhuang, Zhengping; Kester, Mary Beth; Burns, A. Lee; Spiegel, Allen M.; Marx, Stephen J.; Liotta, Lance A.; Emmert-Buck, M. R.; Collins, Francis S.; Chandrasekharappa, Settara C.

doi:10.1007/s004390050595

Cited by 51 publications

(28 citation statements)

References 17 publications

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“…The discovery of homozygous genotypes at these two markers in UACC 903 assisted in identifying a loss of 11q22-25 material in this melanoma cell line 11q23 melanoma tumor suppressor gene GP Robertson et al Figure 3 Retention of chromosome 11 fragments in nine melanoma hybrids and identi®cation of an 11q22-25 deletion in UACC 903. Eighty-three chromosome 11 markers (some in marker groups (MG1-15)) and 16 genes (underlined, including the neo selectable marker) are listed from pter to qter (Vanagaite et al, 1995;Dib et al, 1996;Baysal et al, 1997;James et al, 1994;Arai et al, 1996;Li et al, 1997;Kawana et al, 1997;Manickam et al, 1997;unpublished results); designations for hybrids and UACC 903 (903) are provided at the top. The approximate location of a number of genes/markers is indicated to the left on an ideogram of chromosome 11.…”

Section: Microsatellite Marker Analyses On Tumors From Nude Micementioning

confidence: 99%

Functional localization of a melanoma tumor suppressor gene to a small (≤2 Mb) region on 11q23

et al. 1999

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We have previously demonstrated the existence of a melanoma tumor suppressor gene(s) on the long arm of chromosome 11 through suppression of tumorigenicity assays. Although loss of heterozygosity studies also support this ®nding, only a large critical region (44 cM) has been identi®ed to date on 11q22-25. To further localize a tumor suppressor gene(s) within this region, we have now generated and characterized nine melanoma microcell hybrids, each retaining an introduced fragment of 11q. Of the nine hybrids, four were suppressed for tumor formation in nude mice, while ®ve formed tumors at the same rate as the parental melanoma cell line (UACC 903). Molecular analysis of the hybrids with 118 microsatellite markers narrowed the location of a putative suppressor gene to a small (42 Mb) candidate region on 11q23 between the markers D11S1786 and D11S2077 and within the larger region frequently deleted in melanoma tumors and cell lines. While multiple tumor suppressor genes are likely to reside on 11q22-25, the presence of this region in all four suppressed hybrids supports the simplest model that a single locus is responsible for the suppressed phenotype observed in UACC 903.

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Section: Microsatellite Marker Analyses On Tumors From Nude Micementioning

confidence: 99%

Functional localization of a melanoma tumor suppressor gene to a small (≤2 Mb) region on 11q23

et al. 1999

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“…Our results may point to the involvement of another TSG in this region in pituitary tumours and perhaps in other sporadic endocrine tumour types with evidence of LOH on 11q13. The recently described microsatellite markers in the MEN1 region and other markers on this chromosomal arm (European Consortium on MEN1, 1997b;Manickam et al, 1997) will substantially aid the identification of potentially novel genes and their protein products with tumour suppressor activity in sporadic tumours.…”

Section: Discussionmentioning

confidence: 99%

Sequence analysis and transcript expression of the MEN1 gene in sporadic pituitary tumours

Farrell¹,

Simpson²,

Bicknell³

et al. 1999

Br J Cancer

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The majority of pituitary tumours are monoclonal in origin and arise sporadically or occasionally as part of multiple endocrine neoplasia type 1 (MEN1). Whilst a multi-step aetiology involving both oncogenes and tumour suppressor genes has been proposed for their development, the target(s) of these changes are less clearly defined. Both familial and sporadic pituitary tumours have been shown to harbour allelic deletion on 11q13, which is the location of the recently cloned MEN1 gene. We investigated 23 sporadic pituitary tumours previously shown to harbour allelic deletion on 11q13 with the marker PYGM centromeric and within 50 kb of the MEN1 locus. In addition, the use of intragenic polymorphisms in exon 9 and at D11S4946 , and of telomeric loci at D11S4940 and D11S4936 , revealed that five of 20 tumours had loss of heterozygosity (LOH) telomeric to the menin gene. However, the overall pattern of loss in informative cases was indicative of non-contiguous deletion that brackets the menin gene. Sequence analysis of all MEN1 coding exons and flanking intronic sequence, in tumours and matched patient leucocyte DNA, did not reveal mutation(s) in any of the 23 tumours studied. A benign polymorphism in exon 9 was encountered at the expected frequency, and in seven patients heterozygous for the polymorphism the tumour showed retention of both copies of the menin gene. Reverse transcription polymerase chain reaction analysis of ten evaluable tumours and four normal pituitaries revealed the presence of the menin transcript. Whilst these findings suggest that gene silencing is unlikely to be mechanistic in sporadic pituitary tumorigenesis, they do not exclude changes in the level or stability of the transcript or translation to mature protein. Our study would support and extend very recent reports of a limited role for mutations in the MEN1 gene in sporadic pituitary tumours. Alternatively, these findings may point to an, as yet, unidentified tumour suppressor gene in this region. © 1999 Cancer Research Campaign

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“…LOH analysis In 16 cases the DNA of the PBL was available for LOH analysis. Three highly polymorphic markers at the MEN1 gene locus were used, including the intragenic marker D11S4946 and the flanking markers D11S4941 and D11S4945, as reported by Manickam et al 14) PCR amplification was performed in a 50 µl reaction mixture for 35 cycles consisting of 30 s at 94°C, 30 s at 60°C and 1 min at 72°C. Six microliters of the PCR products was mixed with the same volume of loading buffer (99% deionized formamide, 20 mM EDTA, 0.05% xylene cyanol FF and 0.05% bromophenol blue), denatured for 5 min at 95°C, and loaded onto a 6% polyacrylamide gel containing 7 M urea and 32% formamide.…”

Section: Methodsmentioning

confidence: 99%

Clonal Emergence in Uremic Parathyroid Hyperplasia Is Not Related to MEN1 Gene Abnormality

Shan¹,

Nakamura²,

Murakami³

et al. 1999

Japanese Journal of Cancer Research

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It is difficult to differentiate between parathyroid neoplasia and hyperplasia. In an attempt to elucidate the clonality of uremic parathyroid hyperplasia and the molecular genetic abnormalities accounting for clonal emergence, we analyzed 20 cases of uremic parathyroid hyperplasia. Clonalities were determined using the X-chromosome-linked human androgen receptor (HUMARA) gene and the phosphoglycerate kinase (PGK) gene, and multiple endocrine neoplasia type 1 (MEN1) gene abnormality was analyzed by studying loss of heterozygosity (LOH) in 11q13 and somatic mutations in the MEN1 gene. As a positive control, a case of MEN1 with Zollinger-Ellison syndrome was analyzed simultaneously. Our analysis revealed that a majority (75%) of the uremic parathyroid hyperplasia tissues, including an autograft with recurrent hyperparathyroidism, was of monoclonal origin. Clonality did not correlate with serum carboxyl-terminal parathyroid hormone (C-PTH) level, calcium level, hemodialytic duration, gland weight or pathological features. Neither LOH in 11q13 nor somatic mutation in the MEN1 gene was detected. For the MEN1 case, a germline mutation (W198X) was detected in exon 3. We concluded that a majority of the uremic parathyroid hyperplasia cases was in fact monoclonal neoplasia. MEN1 gene abnormality played a minor role, if any, in the clonal emergence in uremic parathyroid hyperplasia.Key words: Parathyroid -Uremic parathyroid hyperplasia -Clonality -MEN1 gene Uremic parathyroid hyperplasia is characterized by hypersecretion of parathyroid hormone (PTH) and enlargement of more than one gland. Because of these features, uremic parathyroid hyperplasia is traditionally interpreted as reactive hyperplasia of the parenchymal cells.1, 2) Parathyroid tumors may occur in uremic parathyroid hyperplasia but are considered rare. Recently this concept has been challenged by molecular analysis and clinical longterm follow-up. Molecular analysis has demonstrated that some uremic parathyroid hyperplasia specimens are of monoclonal origin and should therefore be interpreted as neoplastic. 3,4) Clinical studies showed that about 3% and 7% of patients receiving a subtotal parathyroidectomy developed recurrent hyperparathyroidism 5 and 7 years later, respectively. A much higher recurrence rate was observed in autografts, with a frequency of 10, 20 and 30% occurring 3, 5 and 7 years, respectively, after total parathyroidectomy and autotransplantation. 5)In these cases, pathological observation of the autografts often revealed a distinct nodular proliferation of the parenchymal cells with larger and more irregular nuclei. Occasionally, apparent mitotic activity and nuclear pleomorphism were noted. A striking finding by Klempa et al. was the presence of small nests of parathyroid tissue next to or at some distance from the autografts. 6) These observations and evidence are suggestive of a neoplastic nature of uremic parathyroid hyperplasia. However, little is known about the molecular abnormalities accounting for this neoplastic proliferation. In...

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Eighteen new polymorphic markers in the multiple endocrine neoplasia type 1 (MEN1) region

Cited by 51 publications

References 17 publications

Functional localization of a melanoma tumor suppressor gene to a small (≤2 Mb) region on 11q23

Functional localization of a melanoma tumor suppressor gene to a small (≤2 Mb) region on 11q23

Sequence analysis and transcript expression of the MEN1 gene in sporadic pituitary tumours

Clonal Emergence in Uremic Parathyroid Hyperplasia Is Not Related to MEN1 Gene Abnormality

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