| HOME | HELP | FEEDBACK | SUBSCRIPTIONS | ARCHIVE | SEARCH | TABLE OF CONTENTS |
Endocrinological Oncology |
Center for Cell and Molecular Medicine, University of Keele School of Postgraduate Medicine (A.S.B., W.E.F., E.J.B., A.J.T., J.C.B., R.N.C.), Stoke-on Trent, United Kingdom ST4 7QB
Address all correspondence and requests for reprints to: Dr. W. E. Farrell, Center for Cell and Molecular Medicine, University of Keele School of Postgraduate Medicine, Stoke-on Trent, United Kingdom ST4 7QB.
 |
Abstract |
|---|
 Top Abstract IntroductionSubjects and MethodsResultsDiscussionReferences |
|---|
There is a significantly higher frequency of LOH in invasive tumors (10.8% of all loci examined) compared to noninvasive tumors (2.4%; P < 0.001). Of the 11 loci investigated, 75% of the allelic deletions identified in invasive tumors were found at 4 loci: 11q13, 13q12–14, 10q, and 1p. Twenty of 47 invasive tumors had evidence of at least 1 allelic deletion, whereas 14 of 20 had more than 1. Of the 6 tumors with only 1 deletion, 5 involved the 11q13 locus, suggesting that this is an early change in the transition from noninvasive to invasive adenoma. Comparison of invasive and noninvasive tumors demonstrates a significantly higher frequency of deletions affecting 11q13 (P < 0.001), 13q12–14 (P < 0.05), and 10q26 (P < 0.05) in invasive tumors. In addition, allelic deletion correlates with increasingly invasive behavior (modified Hardy classification), as 73% of grade 4 tumors compared to 33% of grade 3 and 9.5% of grade 1 and 2 tumors demonstrated LOH at any locus. Furthermore, in some tumors we identified a breakpoint between markers intragenic and extragenic to the retinoblastoma gene (Rb1) on chromosome 13q, suggesting that tumor suppressor genes other than or in addition to Rb1 may be involved in pituitary tumorigenesis. This was further supported by the presence of Rb protein in two of four tumors where the genetic loss extended to include the intragenic marker D13S153.
Early identification of tumors with likely invasive potential by means of genetic analysis (LOH) may provide useful information on potential tumor behavior and aid tumor management in a manner that is not possible using routine histological methods. A large prospective study is required in patients without radiological evidence of invasion to assess the value of LOH in predicting outcome and for planning treatment.
|
Introduction |
|---|
|
TopAbstractIntroductionSubjects and MethodsResultsDiscussionReferences |
|---|
We now show a significant concentration of LOH in tumors with radiological evidence of invasion compared to noninvasive tumors, in which LOH is minimal. Screening of a total of 11 genetic loci from archival pituitary tumors demonstrated that allelic deletion in the invasive tumors is clustered at four loci: 11q13 (multiple endocrine neoplasm type 1), 13q12–14, 10q26, and 1p.
|
Subjects and Methods |
|---|
|
TopAbstractIntroductionSubjects and MethodsResultsDiscussionReferences |
|---|
Paired samples of normal and tumor tissue were obtained from patients who had undergone surgery for either hormone-secreting or nonfunctional pituitary tumors. Clinical and hormonal characterization was performed by standard endocrinological criteria, and tumor subtype was confirmed by routine immunohistochemistry. Tumor samples were collected retrospectively and randomly from several centers in the United Kingdom and abroad after standard histological assessment. Normal tissue was blood, where available, other normal tissue from the same slide as the tumor, or, in a small number of cases, paraffin-embedded material from other organs taken either for other surgical purposes or postmortem.
Tumors were defined as invasive on the basis of sphenoid sinus invasion on computed tomography and/or cavernous sinus invasion on magnetic resonance imaging reports and graded using criteria modified from Hardy’s classification (11). Grade 4 tumors demonstrated central nervous system/extracranial spread on computed tomography/magnetic resonance imaging scan with or without distant metastases, which were often confirmed at autopsy. Grade 3 tumors were locally invasive, with evidence of bony destruction and tumor within the sphenoid and/or cavernous sinus. Grades 2 and 1 consisted of macroadenomas (>1 cm diameter) with or without suprasellar extension and microadenomas (<1 cm diameter), respectively. Grades 3 and 4 tumors were considered invasive. All centers contributing material used the above-mentioned grading scale. A large proportion of tumors obtained from patients outside our own center were grade 4, i.e. metastatic. To remove any possibility of bias in the interpretation of allelic deletion, assignment to invasive/noninvasive cohorts was performed after genetic analysis.
Based on these criteria, 47 patients had invasive tumors, with 11 classified as grade 4 and 36 as grade 3. This group consisted of 35 men and 12 women with a median age of 45.9 yr (range, 13–79). Twenty-seven subjects had nonfunctional tumors, 7 subjects had prolactinomas, 5 patients were acromegalic, and 4 patients had Cushing’s disease. Of the remainder, there was 1 TSH-secreting adenoma, 1 FSH-secreting adenoma, 1 stem cell adenoma, and 1 gonadotropin-secreting adenoma.
Forty-two patients had noninvasive tumors, of which 35 were classified in grade 2 and 7 in grade 1. The median age was 47.7 yr (range, 15–79), with 19 men and 23 women; 27 members of this group had nonfunctional tumors, 6 were acromegalic, 6 had Cushing’s disease, and 3 had prolactinomas.
Of the total of 89 tumors in this series, 13 have been previously reported (2); 6 of these are included in the invasive and 7 in the noninvasive cohort.
Fifteen postmortem pituitary samples confirmed to be normal by routine microscopy (see above) before DNA extraction were included as controls. Of these, nine were from women and six were from men with a median age of 78 yr (range, 27–88). Constitutive DNA was extracted from samples of spleen removed simultaneously and stored at -70 C.
Approval for this study was obtained from the North Staffordshire District ethics committee, and informed consent was obtained from patients or relatives.
Tissue and DNA preparation
Ten 5-µm sections were taken from the original fixed and paraffin-embedded block. Hematoxylin and eosin staining of one slide allowed identification of tumor material, which was carefully removed from the remaining slides. This procedure allowed the clear distinction of tumor from any surrounding nontumorous tissue, thereby minimizing the possibility of contamination and providing a microscopically homogeneous sample. DNA was extracted by prolonged proteinase K (0.2 mg/mL) digestion (up to 120 h) in 50 mmol/L Tris-Cl (pH 8.5), 1 mmol/L ethylenediamine tetraacetate, and 0.5% Tween-20. After brief centrifugation, the supernatant was removed to a fresh tube and heated to 95 C for 10 min.
Constitutive DNA for comparison was extracted from leukocytes or other tissue using commercially available reagents (Nucleon I, Scotlab, Strathclyde, Scotland) or normal paraffin-embedded tissue, as described above.
Location of microsatellite markers and PCR amplification
PCR amplification was carried out using oligonucleotide primers
specific for highly polymorphic microsatellite repeat sequences
situated at the site of known tumor suppressor gene loci. Nucleotide
sequences and chromosomal locations are shown in Table 1
. Nested primers were used in some cases to improve
sensitivity and specificity (12).
|
Detection of LOH
Constitutive and tumor DNA products were run adjacently and separated on 8–10% nondenaturing polyacrylamide gels, fixed in 10% methanol-10% acetic acid, and then incubated in 0.1% aqueous silver nitrate for 15 min. After two brief washes in distilled water, products were visualized by development in an aqueous solution of 1.5% sodium hydroxide and 0.1% formaldehyde.
Allele loss is identified by a reduction in intensity of greater than 80% or the absence of one of the expected PCR products. This method has previously been shown to identify LOH in fixed archival material and gives identical results as Southern blot restriction fragment length polymorphism analysis from fresh or frozen tissue in direct comparison from the same tumor (2). Results were independently reviewed by three observers without knowledge of tumor grade, and LOH was recorded only if the reduction in intensity was clear and agreed upon by all three observers. All samples in which LOH was identified were subject to repeat amplification with identical results on at least two occasions.
Immunohistochemical staining
Sections were hydrated and microwaved in citrate buffer, pH 6.0, for 25 min at full power in a 650-watt microwave. They were immunostained essentially as previously described (7), using a labeled streptavidin-biotin-peroxidase technique with a mouse monoclonal antibody, NCL-RB1 (Novacastra Labs, Newcastle upon Tyne, UK), as primary antibody and 3',3'-diaminobenzidine as chromogen. Negative controls included omission of primary antibody and staining of tissue from a proven retinoblastoma. A breast carcinoma was used as a positive control. Tumors were scored positive if nuclear staining was present and negative if no nuclear staining was present in the tumor, but positivity was present in normal cells.
Statistical analysis
Differences in the frequency of allelic deletions between groups were assessed using Fisher’s exact test. Statistical significance was assigned to P < 0.05, whereas borderline significance was given to values of less than 0.1 and actual P values were quoted. The odds ratios (OR) and 95% confidence intervals were calculated using Instat (Graph Pad software, San Francisco, CA). This provides an indication of the probability of a tumor demonstrating LOH at a given locus in invasive compared to noninvasive tumors or, alternatively, the probability of a tumor having a 13q12–14 deletion in the presence of LOH affecting 11q13.
|
Results |
|---|
|
TopAbstractIntroductionSubjects and MethodsResultsDiscussionReferences |
|---|
Twenty of the 47 (42.6%) tumors studied in this group had
evidence of LOH involving at least 1 locus; of these, 6 had evidence of
only 1 deletion, of which 5 involved 11q13. Of the total of 14 tumors
with 11q13 deletions, 5 also demonstrated LOH involving 13q12–14
(D13S155). Using Fisher’s exact test, there was a significant
association between LOH at these two loci (P < 0.05;
OR = 5.6; confidence interval = 1.2–27.4), the remaining 70% of
tumors (14 of 20) had sustained at least 2 deletions. The overall
frequency of deletions for this cohort at all 11 loci studied in
informative cases was 10.8% (50 of 463). However, the majority of
losses (37 of 50; 74%) were confined to 4 loci: 11q13, 13q12–14,
10q26, and 1p31–35. Thus, LOH in these tumors is not a general
phenomenon, but exhibits relative specificity for these sites. 11q13 is
most commonly affected with a frequency of 31.1%. (14 of 45),
13q12–14 was demonstrably involved in 25% of the tumors (11 of 44),
10q26 in 14.9% (7 of 47), and 1p31–35 in 11.1% (5 of 45). The
remaining loci were affected in less than 10% of the cases; in
particular, there was evidence of LOH in only 4.8% of informative
cases (2 of 42) at the p53 locus. Removal of the 13 samples previously
studied (6 invasive and 7 noninvasive) did not change the conclusions
and had a marginal, but insignificant, effect on calculated
P values (see below). Examples of LOH using these techniques
are shown in Fig. 1.
|
From this group of 42 tumors, only 4 of 42 (9.5%) demonstrated LOH at any of the sites examined in the invasive cohort. There were 10 deletions in total in these 4 tumors, with 6 occurring in 1, 2 in another, and 1 only in the third and fourth tumors.
Overall, the frequency of any LOH in the noninvasive tumors was 2.4% (10 of 415) at the 11 loci studied, significantly less than that in the invasive cohort (10.8%; P < 0.0001; OR = 4.4; CI = 2.2–8.8). Removal of the previously reported tumors (2) resulted in a calculated P < 0.0003.
When we compared the noninvasive tumors (grades 1 and 2) with the
invasive (grades 3 and 4) tumors, we found that LOH correlates with
increasingly invasive behavior. For this comparison we further divided
the invasive cohort into those without (grade 3) and those with intra-
or extracranial spread (grade 4). Figure 2 shows that in
comparison to noninvasive tumors, in which 9.5% (4 of 42) showed LOH
at any locus, this figure increased to 33% of the grade 3 tumors (12
of 36; P < 0.001) and to 73% of the grade 4 tumors (8
of 11; P < 0.05).
|
. There was a significantly higher
frequency of deletions affecting 11q13 (P < 0.001;
OR = 17.6; confidence interval = 2.2–141.5), 13q12–14
(P < 0.05; OR = 4.2; confidence interval =
1.1–16.4), and 10q26 (P < 0.05; OR = 0.8–58.1) in
invasive tumors. There was no significant difference in the frequency
of deletions affecting any of the other loci studied.
|
and 4).
|
). Two tumors (no.
228 and 261) that showed retention of D13S153 were
immunohistochemically negative for Rb protein. No evidence of LOH was
found in 15 postmortem pituitary samples using markers for 11q13,
13q12–14, 10q26, 1p31–35, and 17q21, indicating that background LOH
is negligible (0 of 75 loci). |
Discussion |
|---|
|
TopAbstractIntroductionSubjects and MethodsResultsDiscussionReferences |
|---|
The frequency of LOH in the invasive tumors is higher than that in previous reported studies (2, 4, 5, 6), which did not specifically differentiate invasive from noninvasive tumors. This together with minimization of false negative results, due to normal tissue contamination, by the use of tumor DNA extracted exclusively from homogeneous tumor material may explain the difference between this study and its predecessors.
It is interesting that in those invasive tumors with LOH affecting only one locus, five of the six were lesions affecting 11q13. The probability that this occurred by chance is small, because these deletions make up only 28% of the total number of allele losses in our series. This suggests that LOH at this site is an important step in the transition from noninvasive to invasive adenoma.
Functional inactivation of the retinoblastoma tumor suppressor gene (Rb1) is an important pathogenetic factor in the development of several human malignancies, for example osteosarcoma and non-small cell lung carcinoma (16). Direct evidence for a pathogenic role for Rb1 is provided in Rb knock-out transgenic mice, which develop neurointermediate lobe pituitary tumors (17). However, three studies have failed to find any evidence of LOH in human pituitary tumors, using intragenic markers for Rb1 (4, 5, 6). Immunocytochemistry has also confirmed the presence of Rb1 protein in clinically unselected adenomas and Western blot analysis (18) showed normal amounts of Rb protein compared to postmortem pituitary. LOH using intragenic markers for Rb1 has been found in invasive adenomas and carcinomas (3), but this study also identified Rb1 protein by immunocytochemistry, suggesting that other tumor suppressor genes on 13q may be involved in the pathogenesis of aggressive pituitary adenomas (3). Our study initially used a microsatellite marker (D13S155) that lies between Rb1 and the recently characterized hereditary breast cancer gene (BRCA2) that maps to chromosome 13q12–13 (19). The finding of 25% LOH in invasive pituitary adenomas at D13S155, with 5 of 11 of these tumors and 2 of 3 noninvasive tumors retaining the Rb1 intragenic marker (D13S153), supports the view that a tumor suppressor gene(s) on 13q12–13 other than and centromeric to Rb1 is also involved in pituitary tumorigenesis. This view is further supported by the findings of Rb protein by immunocytochemistry in those tumors with D13S155 deletions. In addition, as reported by others (3), we found no correlation between loss of an Rb intragenic marker (D13S153) and immunohistochemical detection of Rb protein. Our failure to detect RB protein in some tumors may reflect deletion not detected by the microsatellite marker D13S153 or more subtle mutations, to an expressed protein, that is no longer recognized by the antibody.
Of the five pituitary adenomas reported to date with multiple allele losses, four have sustained deletions affecting the long arm of chromosome 10, at 10q26 (2, 10). We have also shown LOH in invasive pituitary tumors affecting the same locus. It is interesting that these deletions do not commonly affect the entire long arm of chromosome 10, as LOH affecting D10S225 (10q11.2) is not usually involved. LOH affecting this region has also been identified in other tumors, such as glial neoplasms (15) and thyroid carcinomas (20). It is noteworthy that in glial tumors, deletions affecting 10q occurred exclusively in high grade gliomas of aggressive phenotype (15). Our own data also suggest that deletions involving 10q occur more frequently in invasive than in noninvasive lesions.
Our data have shown that LOH involving 11q13, 13q, and 10q26 occurs significantly more frequently in invasive pituitary tumors. Although this suggests that tumor suppressor gene inactivation is involved in tumor progression rather than initiation, it remains possible that other tumor suppressor genes are involved at an earlier stage.
Prediction of the biological behavior of pituitary tumors remains difficult on clinical grounds, and radiological and histological criteria are not particularly helpful in this regard. Early identification of which tumors may become invasive may not only provide prognostic information, but may also guide management in a manner not previously possible. We suggest that routine genetic analysis using the markers identified here as being frequently lost in invasive tumors might provide useful information for therapeutic decision making. For example, if a large macroadenoma has been incompletely removed at surgery, the decision as to whether to irradiate that particular tumor is not necessarily automatic, as many such residual tumors are slow growing. If allelic loss at the loci identified in this study was found in the tumor, this would suggest more rapid regrowth and indicate the need for immediate radiotherapy to reduce the chance of recurrence. A long term prospective study is underway to examine this possibility.
|
Acknowledgments |
|---|
|
Footnotes |
|---|
2 Supported by a Sheldon Research Fellowship awarded by the West
Midlands Regional Health Authority.
3 Present address: Department of Pathology, Glasgow Royal Infirmary,
University National Health Service Trust, Castle Street, Glasgow,
United Kingdom.
4 Supported by the BUPA Medical Foundation Ltd.
5 Present address: Royal Free Hospital School of Medicine,
Department of Obstetrics and Gynecology, University of London, Pond
Street, London, United Kingdom NW3 2QG.
6 Present address: Medical Research Council Molecular Medicine Group,
Royal Postgraduate Medical School, Hammersmith Hospital, London, United
Kingdom.
Received August 22, 1996.
Revised October 31, 1996.
Accepted November 11, 1996.
|
References |
|---|
|
TopAbstractIntroductionSubjects and MethodsResultsDiscussionReferences |
|---|
This article has been cited by other articles:
 |
|
 |
|
  X. Zhu, X. Mao, R. Hurren, A. D. Schimmer, S. Ezzat, and S. L. Asa Deoxyribonucleic Acid Methyltransferase 3B Promotes Epigenetic Silencing through Histone 3 Chromatin Modifications in Pituitary Cells J. Clin. Endocrinol. Metab., September 1, 2008; 93(9): 3610 - 3617. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 X. Zhu, S. L. Asa, and S. Ezzat Fibroblast Growth Factor 2 and Estrogen Control the Balance of Histone 3 Modifications Targeting MAGE-A3 in Pituitary Neoplasia Clin. Cancer Res., April 1, 2008; 14(7): 1984 - 1996. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 A. Matoso, Z. Zhou, R. Hayama, A. Flesken-Nikitin, and A. Yu. Nikitin Cell lineage-specific interactions between Men1 and Rb in neuroendocrine neoplasia Carcinogenesis, March 1, 2008; 29(3): 620 - 628. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
S. Melmed Aryl Hydrocarbon Receptor Interacting Protein and Pituitary Tumorigenesis: Another Interesting Protein J. Clin. Endocrinol. Metab., May 1, 2007; 92(5): 1617 - 1619. [Full Text] [PDF]
|
|
|
|
 |
|
 X. Zhu, K. Lee, S. L. Asa, and S. Ezzat Epigenetic Silencing through DNA and Histone Methylation of Fibroblast Growth Factor Receptor 2 in Neoplastic Pituitary Cells Am. J. Pathol., May 1, 2007; 170(5): 1618 - 1628. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 A. Gurlek, N. Karavitaki, O. Ansorge, and J. A H Wass What are the markers of aggressiveness in prolactinomas? Changes in cell biology, extracellular matrix components, angiogenesis and genetics Eur. J. Endocrinol., February 1, 2007; 156(2): 143 - 153. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 C. Onofri, M. Theodoropoulou, M. Losa, E. Uhl, M. Lange, E. Arzt, G. K Stalla, and U. Renner Localization of vascular endothelial growth factor (VEGF) receptors in normal and adenomatous pituitaries: detection of a non-endothelial function of VEGF in pituitary tumours. J. Endocrinol., October 1, 2006; 191(1): 249 - 261. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 I. Donangelo, S. Gutman, E. Horvath, K. Kovacs, K. Wawrowsky, M. Mount, and S. Melmed Pituitary Tumor Transforming Gene Overexpression Facilitates Pituitary Tumor Development Endocrinology, October 1, 2006; 147(10): 4781 - 4791. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 W E Farrell Pituitary tumours: findings from whole genome analyses. Endocr. Relat. Cancer, September 1, 2006; 13(3): 707 - 716. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
D. Giacomini, M. Paez-Pereda, M. Theodoropoulou, M. Labeur, D. Refojo, J. Gerez, A. Chervin, S. Berner, M. Losa, M. Buchfelder, et al. Bone Morphogenetic Protein-4 Inhibits Corticotroph Tumor Cells: Involvement in the Retinoic Acid Inhibitory Action Endocrinology, January 1, 2006; 147(1): 247 - 256. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
G. A. Kaltsas, P. Nomikos, G. Kontogeorgos, M. Buchfelder, and A. B. Grossman Diagnosis and Management of Pituitary Carcinomas J. Clin. Endocrinol. Metab., May 1, 2005; 90(5): 3089 - 3099. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 A. Bahar, D. J. Simpson, S. J. Cutty, J. E. Bicknell, P. R. Hoban, S. Holley, M. Mourtada-Maarabouni, G. T. Williams, R. N. Clayton, and W. E. Farrell Isolation and Characterization of a Novel Pituitary Tumor Apoptosis Gene Mol. Endocrinol., July 1, 2004; 18(7): 1827 - 1839. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
D. J. Simpson, A. M. McNicol, D. C. Murray, A. Bahar, H. E. Turner, J. A. H. Wass, M. M. Esiri, R. N. Clayton, and W. E. Farrell Molecular Pathology Shows p16 Methylation in Nonadenomatous Pituitaries from Patients with Cushing's Disease Clin. Cancer Res., March 1, 2004; 10(5): 1780 - 1788. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 F Sandrini, L S Kirschner, T Bei, C Farmakidis, J Yasufuku-Takano, K Takano, T R Prezant, S J Marx, W E Farrell, R N Clayton, et al. PRKAR1A, one of the Carney complex genes, and its locus (17q22-24) are rarely altered in pituitary tumours outside the Carney complex J. Med. Genet., December 1, 2002; 39(12): e78 - 78. [Full Text] [PDF]
|
|
|
|
|
|
D.J. Simpson, A.A. Fryer, A.B. Grossman, J.A.H. Wass, M. Pfeifer, J.M. Kros, R.N. Clayton, and W.E. Farrell Cyclin D1 (CCND1) genotype is associated with tumour grade in sporadic pituitary adenomas Carcinogenesis, November 1, 2001; 22(11): 1801 - 1807. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
D. J. Simpson, S. J. Frost, J. E. Bicknell, J. C. Broome, A. M. McNicol, R. N. Clayton, and W. E. Farrell Aberrant expression of G1/S regulators is a frequent event in sporadic pituitary adenomas Carcinogenesis, August 1, 2001; 22(8): 1149 - 1154. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 U. Pagotto, T. Arzberger, M. Theodoropoulou, Y. Grübler, C. Pantaloni, W. Saeger, M. Losa, L. Journot, G. K. Stalla, and D. Spengler The Expression of the Antiproliferative Gene ZAC Is Lost or Highly Reduced in Nonfunctioning Pituitary Adenomas Cancer Res., December 1, 2000; 60(24): 6794 - 6799. [Abstract] [Full Text]
|
|
|
|
|
|
R. N. Clayton, M. Pfeifer, A. B. Atkinson, P. Belchetz, J. A. H. Wass, E. Kyrodimou, M. Vanderpump, D. Simpson, J. Bicknell, and W. E. Farrell Different Patterns of Allelic Loss (Loss of Heterozygosity) in Recurrent Human Pituitary Tumors Provide Evidence for Multiclonal Origins Clin. Cancer Res., October 1, 2000; 6(10): 3973 - 3982. [Abstract] [Full Text]
|
|
|
|
|
|
H. E. Turner, Zs. Nagy, M. M. Esiri, A. L. Harris, and J. A. H. Wass Role of Matrix Metalloproteinase 9 in Pituitary Tumor Behavior J. Clin. Endocrinol. Metab., August 1, 2000; 85(8): 2931 - 2935. [Abstract] [Full Text]
|
|
|
|
|
|
D. J. Simpson, N. A. Hibberts, A. M. McNicol, R. N. Clayton, and W. E. Farrell Loss of pRb Expression in Pituitary Adenomas Is Associated with Methylation of the RB1 CpG Island Cancer Res., March 1, 2000; 60(5): 1211 - 1216. [Abstract] [Full Text]
|
|
|
|
|
|
S. J. Frost, D. J. Simpson, R. N. Clayton, and W. E. Farrell Transfection of an Inducible p16/CDKN2A Construct Mediates Reversible Growth Inhibition and G1 Arrest in the AtT20 Pituitary Tumor Cell Line Mol. Endocrinol., November 1, 1999; 13(11): 1801 - 1810. [Abstract] [Full Text]
|
|
|
|
|
|
N. A. Hibberts, D. J. Simpson, J. E. Bicknell, J. C. Broome, P. R. Hoban, R. N. Clayton, and W. E. Farrell Analysis of Cyclin D1 (CCND1) Allelic Imbalance and Overexpression in Sporadic Human Pituitary Tumors Clin. Cancer Res., August 1, 1999; 5(8): 2133 - 2139. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
D. J. Simpson, J. Magnay, J. E. Bicknell, A. L. Barkan, A. M. McNicol, R. N. Clayton, and W. E. Farrell Chromosome 13q Deletion Mapping in Pituitary Tumors: Infrequent Loss of the Retinoblastoma Susceptibility Gene (RB1) Locus Despite Loss of RB1 Protein Product in Somatotrophinomas Cancer Res., April 1, 1999; 59(7): 1562 - 1566. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 A. Yu. Nikitin, M. I. Juarez-Perez, S. Li, L. Huang, and W.-H. Lee RB-mediated suppression of spontaneous multiple neuroendocrine neoplasia and lung metastases in Rb+/- mice PNAS, March 30, 1999; 96(7): 3916 - 3921. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
X. Zhang, G. A. Horwitz, A. P. Heaney, M. Nakashima, T. R. Prezant, M. D. Bronstein, and S. Melmed Pituitary Tumor Transforming Gene (PTTG) Expression in Pituitary Adenomas J. Clin. Endocrinol. Metab., February 1, 1999; 84(2): 761 - 767. [Abstract] [Full Text]
|
|
|
|
|
|
M. R. Gadelha, T. R. Prezant, K. N. Une, R. P. Glick, S. F. Moskal II, M. Vaisman, S. Melmed, R. D. Kineman, and L. A. Frohman Loss of Heterozygosity on Chromosome 11q13 in Two Families with Acromegaly/Gigantism Is Independent of Mutations of the Multiple Endocrine Neoplasia Type I Gene J. Clin. Endocrinol. Metab., January 1, 1999; 84(1): 249 - 256. [Abstract] [Full Text]
|
|
|
|
|
|
N. A. T. M. Huizenga, P. de Lange, J. W. Koper, R. N. Clayton, W. E. Farrell, A. J. van der Lely, A. O. Brinkmann, F. H. de Jong, and S. W. J. Lamberts Human Adrenocorticotropin-Secreting Pituitary Adenomas Show Frequent Loss of Heterozygosity at the Glucocorticoid Receptor Gene Locus J. Clin. Endocrinol. Metab., March 1, 1998; 83(3): 917 - 921. [Abstract] [Full Text]
|
|
|
|
|
|
L. S. Ward, G. Brenta, M. Medvedovic, and J. A. Fagin Studies of Allelic Loss in Thyroid Tumors Reveal Major Differences in Chromosomal Instability between Papillary and Follicular Carcinomas J. Clin. Endocrinol. Metab., February 1, 1998; 83(2): 525 - 530. [Abstract] [Full Text]
|
|
| |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| HOME | HELP | FEEDBACK | SUBSCRIPTIONS | ARCHIVE | SEARCH | TABLE OF CONTENTS |
| Endocrinology | Endocrine Reviews | J. Clin. End. & Metab. |
| Molecular Endocrinology | Recent Prog. Horm. Res. | All Endocrine Journals |
