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The Journal of Clinical Endocrinology & Metabolism Vol. 82, No. 9 3141-3147
Copyright © 1997 by The Endocrine Society

Original Studies

Infrequent Mutations of p27Kip1 Gene and Trisomy 12 in a Subset of Human Pituitary Adenomas1

Chisato Tanaka, Katsuhiko Yoshimoto, Peng Yang, Takehiko Kimura, Shozo Yamada, Maki Moritani, Toshiaki Sano and Mitsuo Itakura

Otsuka Department of Clinical and Molecular Nutrition (C.T., K.Y., M.M., M.I.), First Department of Pathology (P.Y., T.S.) and First Department of Internal Medicine (T.K.), School of Medicine, The University of Tokushima, 3–18-15, Kuramoto-cho, Tokushima-city, 770 Japan, Department of Neurosurgery (S.Y.), Toranomon Hospital, 2–2-2, Toranomon, Minato-ku, Tokyo, 105 Japan

Address all correspondence and requests for reprints to: Mitsuo Itakura, M.D., Ph.D., Otsuka Department of Clinical and Molecular Nutrition, School of Medicine, The University of Tokushima, 3–18-15, Kuramoto-cho, Tokushima-city, 770 Japan. E-mail: itakura{at}nutr.med.tokushima-u.ac.jp


   Abstract
Top
 Abstract
Introduction
 Materials and Methods
 Results
 Discussion
 References
 
To study the etiologic roles of genes on chromosome 12 for the pituitary tumorigenesis of adenomas, mutations of the p27Kip1 gene and allelic ratios of 18 microsatellite markers on the entire chromosome 12 were studied in 33 pituitary adenomas. The p27Kip1 gene on chromosome 12p12-p13 encoding an inhibitor of complexes between cyclins and cyclin-dependent kinases is supposed to function as the tumor suppressor gene. Among 31 sporadic and 2 familial pituitary adenomas, PCR-single strand conformation polymorphism analysis detected three polymorphic changes but no tumor-specific mutations of the p27Kip1 gene. Genotyping of 18 microsatellite markers on the entire chromosome 12 detected the uniformly decreased allelic ratios ranging from 54–66% in 8 of 33 pituitary adenomas (24%), although no loss of heterozygosity was detected. Fluorescence in situ hybridization confirmed trisomy 12 in all 5 available samples out of these 8 samples. Based on these, we conclude that not mutations of the p27Kip1 gene, but trisomy 12 may be etiologically important in a subgroup of pituitary adenomas.


   Introduction
Top
 Abstract
 Introduction
Materials and Methods
 Results
 Discussion
 References
 
THE MOLECULAR basis of tumorigenesis of pituitary adenomas remains largely unknown. p27Kip1 functions as G1/S check point control by inhibiting G1 cyclin-cyclin dependent kinases (CDKs) complexes of cyclin E-cdk2 and cyclin D-cdk4/6 (1, 2), and its loss was associated with tumor progression in T-cell leukemia/lymphoma (3) or breast cancer (4). Knock-out mice of the p27Kip1 gene on chromosome 12p12-p13 (5, 6) caused neoplastic nodular hyperplasia of the pituitary intermediate lobe (7, 8, 9). These findings suggest that p27Kip1 functions as the tumor suppressor gene especially in the pituitary gland. To determine the role of p27Kip1, we screened mutations of the p27Kip1 gene in pituitary adenomas with PCR-single strand conformation polymorphism (SSCP) analysis and determined DNA sequences of aberrantly shifted bands in PCR-SSCP analysis.

Although decreased allelic ratios caused by loss of heterozygosity (LOH) or aneuploidy have been frequently observed in various cancers (10, 11, 12), trisomy in adenomas has been limited to thyroid (13), colorectal (14, 15), and pituitary adenomas (16, 17, 18). To understand the etiologic role of LOH or aneuploidy of chromosome 12 for the tumorigenesis, we calculated allelic ratios of 18 polymorphic microsatellite markers on the entire chromosome 12 in 33 pituitary adenomas by comparing those in pituitary adenomas and leukocytes. Trisomy 12 suggested by the uniformly decreased allelic ratios was further examined with fluorescence in situ hybridization (FISH) using the chromosome 12 {alpha}-satellite probe.


   Materials and Methods
Top
 Abstract
 Introduction
 Materials and Methods
Results
 Discussion
 References
 
Tissue samples and extraction of DNA from tissues

Pituitary adenomas were obtained from 33 patients at transsphenoidal surgery. Peripheral blood samples were collected from these patients. The clinical features of 31 patients with sporadic pituitary adenomas and 2 patients with familial acrogigantism are summarized in Table 1Go. Adenomas were graded by Hardy’s classification (19), which graded the tumor sizes from grades I to IV and the degree of tumor extension from 0 to C. In addition, the presence of cavernous sinus invasion was marked in Table 1Go. DNA was isolated from frozen tumor sections obtained at surgery and leukocytes, as previously described (20).


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  		Table 1. Clinical features of pituitary adenomas

 
PCR-SSCP

PCR amplification was performed using primers listed in Table 2Go. The p27Kip1 gene encoding 198 amino acids is composed of 2 exons of about 600 bp in total (5). Among PCR primers, 1AF is located in the 5'-noncoding sequence, 1CR, 2F, and 2R are located in an intron, and 1AR, 1BF, 1BR, and 1CF are located in the exon 1. PCR proceeded in a Program Temp Control System PC-700 (ASTEC, Fukuoka, Japan) with 10 ng of genomic DNA in a total volume of 5 µl containing 1.5 µCi of [{alpha}-32P] dCTP (3,000 Ci/mmol; 10 mCi/ml). After an initial denaturation step at 95 C for 10 min, 30 cycles of PCR were performed with each cycle consisting of 95 C for 1 min, 64 C for 1 min, and 72 C for 1 min. Gel electrophoresis and analysis of paired PCR products from tumor and leukocyte DNA were performed as described (21). Two 8% polyacrylamide gels, containing 0 or 5% glycerol, were used for all samples.


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  		Table 2. PCR primers used to amplify the coding region of the p27Kip1 and product sizes

 
DNA sequencing

Aberrantly shifted bands detected with PCR-SSCP analysis and at least one control sample were excised from polyacrylamide gels in each electrophoresis, and eluted in distilled water at 55 C for more than 30 min. DNA sequences of at least five cloned PCR products were determined as described (21) in sense and antisense directions with fluorescence-based dideoxy cycle sequencing.

Analysis of allelic ratios

Allelic ratios in adenoma DNA relative to leukocyte DNA were examined in regard to 18 microsatellite markers on chromosome 12: telomere of the short arm-D12S341, D12S94, D12S89, D12S364, D12S320, D12S308, D12S310, D12S363, D12S269, D12S87, D12S85, D12S355, D12S1660, D12S346, D12S1583, D12S86, D12S1658, and D12S357-telomere of the long arm (22) (Table 3Go). The primer sequences and genetic distances between markers were based on Dib et al. (22).


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  		Table 3. Pituitary adenomas showing uniformly decreased allelic ratios of 18 microsatellite markers on chromosome 12

 
Allelic ratios were assessed with the reported methods (23) with minor modifications. In brief, microsatellite markers were PCR-amplified from 33 paired normal and tumor DNA samples. One of each primer pair was labeled with 6-FAM fluorescent dye (Perkin Elmer, Foster City, CA). PCR was performed as described above except for the annealing temperature at 55 C for 25 cycles with 10 ng of human DNA. Gel electrophoresis, data collection, and analysis were carried out as described (24). Each fluorescent peak was assessed by the peak height. The ratio of alleles 1 and 2 was calculated for leukocyte DNA as the representative normal tissue and the tumor DNA. Calculation was made by T1:T2/N1:N2, where T1 and N1 were the peak height values of the smaller allele product peak for the adenoma DNA and the normal leukocyte DNA, respectively, and T2 and N2 were the peak height values of the taller allele product from the adenoma DNA and the normal leukocyte DNA, respectively.

FISH

Tissue sections of 6 µm in thickness were cut from paraffin blocks and mounted onto poly-L-lysine-coated glass slides. After heating the slides at 65 C for 4 h, they were deparaffinized in xylene for 10 min, 100% ethanol for 5 min twice, and air-dried. After proteinase digestion at 45 C for 20 min (Tissue Kit, Oncor, Gaithersburg, MD), DNA probe was directly added onto the tissue sections, which were denatured simultaneously with the probe at 90 C for 12 min, hybridized at 37 C for 16 h, and washed in 1 x SSC at 72 C for 5 min. The biotin-labeled {alpha}-satellite probe for chromosome 12 (D12Z3, Oncor) was used. After the in situ hybridization, tissue sections were counterstained with propidium iodide at 0.6 µg/ml (Oncor). The signals produced by the hybridized probe was detected with fluorescein-conjugated avidin under confocal fluorescent microscopy, and the number of signals per nucleus was counted. Based on the consistent results of three or two signals per nucleus in more than 80% of examined nuclei, diagnosis of trisomy or disomy was made.


   Results
Top
 Abstract
 Introduction
 Materials and Methods
 Results
Discussion
 References
 
Four overlapping PCR products covering the entire coding region of the p27Kip1 gene were used to screen mutations in the p27Kip1 gene located on 12p12-p13 with PCR-SSCP. Three aberrantly shifted bands in the exon 1 of the p27Kip1 gene detected with SSCP analysis were observed in 9 pituitary adenomas (Fig. 1Go). No aberrantly shifted bands were detected in the exon 2 in any of all 33 examined pituitary tumors. PCR-SSCP of DNA from 9 pituitary adenomas and their leukocytes detected the comparable SSCP patterns showing that variant shifted bands are common to adenoma and leukocyte DNA (data not shown). As summarized in Table 4Go, one missense mutation was observed at codon 109 of the p27Kip1 gene in sample 26 (Fig. 1BGo, lane 26), resulting in an amino acid change from valine to glycine. Furthermore, two silent mutations were observed at codon 55 (GCG to GCA) in samples 9, 12, 14, 20, 22, 32, and 33 (Fig. 1AGo, lanes 9, 32, and 33) and at codon 115 (GCG to GCA) in sample 5 (Fig. 1CGo, lane 5), both of which did not change coding amino acids.



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  		Figure 1. PCR-SSCP analysis of the p27Kip1 gene in pituitary adenomas. Genomic DNAs from pituitary adenomas were amplified by PCR using primers for the p27Kip1 gene. A, Results of p27Kip1 exon 1A region in 9 representative pituitary adenomas. Variant bands were observed in samples 9, 32, and 33. B, Results of p27Kip1 exon 1B region in 3 representative pituitary adenomas. A variant band was observed in sample 26. C, Results of p27Kip1 exon 1C region in four representative pituitary adenomas. A variant band was observed in sample 5.

 

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  		Table 4. Polymorphic changes of the p27Kip1 gene

 
To determine the presence of decreased allelic ratios due to LOH or aneuploidy of chromosome 12, especially trisomy 12, we calculated allelic ratios of 18 microsatellite markers by comparing the PCR-amplified allelic patterns of 33 pituitary adenomas with those of their leukocytes. Representative examples on the microsatellite analysis of DNA from pituitary adenomas and their corresponding leukocytes were shown in Fig. 2Go. The decrease in the fluorescence intensity of one allele in tumor DNA compared with that in matched patients’ leukocyte DNA was detected in 8 out of 33 pituitary adenomas (Table 3Go).



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  		Figure 2. Representative examples of decreased allelic ratios at the markers of D12S341, D12S364, D12S310, D12S87, D12S1660, D12S1583, and D12S1658 in pituitary adenomas. Results of samples 8, 14, and 17 were shown in panels A, B, and C, respectively. DNAs from leukocytes (WBC) and a pituitary adenoma (tumor) were analyzed for each sample. Arrowheads denote smaller allele product peaks in adenoma DNA compared with leukocyte DNA. The corresponding allelic ratio value (%) was shown below each set of profiles.

 
To assess the distribution of allelic ratios, the numbers of informative observation were plotted against the allelic ratios observed for 18 microsatellite markers on chromosome 12 in 33 samples (Fig. 3Go). Based on the bimodal distribution, adenoma DNA with the allelic ratio of less than 70% was regarded as having the decreased allelic ratio at that locus, whereas the allelic ratio between 71 and 100% was regarded as retaining both alleles at that locus. Based on this criteria, we detected uniformly decreased allelic ratios of 18 microsatellite markers on chromosome 12 in 8 of 33 pituitary adenomas.



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  		Figure 3. Distribution of allelic ratios on chromosome 12 in 33 pituitary adenomas. The data set of 286 informative observations was obtained from the analysis of 33 tumors with 18 microsatellite markers. The number of observations per category was indicated above each bar.

 
Trisomy 12 suggested by the decreased allelic ratios of 54–66% in regard to 18 microsatellite markers (Table 3Go) was examined with FISH using the {alpha}-satellite probe for chromosome 12. Intact and independent nuclei were examined with confocal fluorescent microscopy. Three centromere signals of chromosome 12 were detected in more than 80% of examined nuclei in all 5 available samples including sample numbers 4, 8, 14, 15, and 28 out of 8 samples, which showed the decreased allelic ratios (Fig. 4AGo). Out of 8 samples with the decreased allelic ratios, paraffin-embedded tissue of 3 samples including sample numbers 16, 17, and 19 were not available for FISH analysis. On the other hand, only 2 centromere signals were detected in more than 80% of examined nuclei of 5 control samples including sample numbers 2, 5, 9, 11, and 30 (Fig. 4BGo), which retained both alleles with the allelic ratios of more than 90% for 18 microsatellite markers.



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  		Figure 4. FISH with the {alpha}-satellite probe for the centromere of chromosome 12. A, One typical interphase nucleus from sample 4 shows trisomy 12 with three nuclear hybridization signals. B, One typical interphase nucleus from sample 9 shows disomy 12 with two nuclear hybridization signals.

 
Eight pituitary adenomas showing trisomy 12 included 2 somatotroph adenomas, 4 prolactinomas, 1 thyrotroph adenoma, and 1 nonfunctioning adenoma (Table 1Go). Trisomy 12 was detected in 4 out of 6 prolactinomas. Among 8 pituitary adenomas showing trisomy 12, 6 were men and 2 were women, whereas the approximately equal numbers of both sexes, i.e. 18 men and 15 women, were analyzed. In adenomas of grade IV, trisomy 12 was detected in 67% (2/3), whereas it was not detected in microadenomas of grade I (0/4). Out of 11 adenomas of stage A with suprasellar extension, 3 showed trisomy 12. Among 7 adenomas of stage B with obliteration of the third ventricle recesses or 2 adenomas of stage C with gross displacement of the third ventricle, none showed trisomy 12. Among 7 adenomas with cavernous sinus invasion, 2 showed trisomy 12. No obvious correlation was thus observed between trisomy 12 and grade of tumor size, stage of extension, microscopic grade of dysplasia, or the patients’ age.


   Discussion
Top
 Abstract
 Introduction
 Materials and Methods
 Results
 Discussion
References
 
The tumor-suppressor function of the p27Kip1 gene, especially in the pituitary gland, was suggested by p27Kip1 knock-out mice that developed neoplastic nodular hyperplasia of the intermediate lobe of the pituitary gland by 12 weeks of age (7, 8, 9). In this study, we screened the mutations of the p27Kip1 gene in 33 human anterior pituitary adenomas including 31 sporadic and 2 familial pituitary adenomas. We found 3 variants of the p27Kip1 gene in the DNA samples from 9 pituitary tumors (Table 4Go). The same SSCP patterns in pituitary adenoma DNA and their leukocyte DNA and the final DNA sequencing confirmed that they were polymorphisms. Although two polymorphisms of codons 55 (GCG to GCA, Ala to Ala) and 109 (GTC to GGC, Val to Gly) were reported (5, 6, 25), the polymorphism of codon 115 (GCG to GCA, Ala to Ala) has not been reported. We did not, however, find any tumor-specific somatic mutations of the p27Kip1 gene in any of 33 pituitary adenomas. Because primers were designed to cover the intron-exon boundaries for PCR-SSCP analysis, exons and splice junction mutations should have been detected. Although the sensitivity of SSCP analysis is less than 100%, the detection of three different polymorphic changes in nine pituitary adenomas with our method using two gel conditions for all samples is expected to attain the high sensitivity of our SSCP technique as reported previously (26).

To our knowledge, only two tumors having p27Kip1 mutations were reported; one was a stop codon mutation at position 76 in adult T-cell leukemia/lymphoma (3), another is a stop codon mutation at position 104 in breast cancer (4). Mutations of the p16INK4A or p15INK4B genes, which were members of a CDK inhibitor family, were not found in pituitary adenomas in our previous study (21). These two studies of ours suggest that mutations of CDK inhibitor genes including p16INK4A, p15INK4B, and p27Kip1 do not contribute to the tumorigenesis of the human pituitary gland.

The unexpected uniformly decreased mean allelic ratios from 54–66% with small standard deviation (SD) values were found in regard to all 18 microsatellite markers encompassing the entire chromosome 12 in 8 out of 33 human pituitary adenomas (24%) (Table 3Go). The uniformly decreased allelic ratios close to 50% strongly suggested trisomy 12 because trisomy should theoretically lead to the decreased allelic ratio of 50%. FISH detected trisomy 12 in 5 available samples out of 8 samples with the uniformly decreased allelic ratios, whereas all 5 control samples with the retained alleles showed disomy 12. The fluorescent PCR microsatellite analysis was shown eligible in this study to detect trisomy in addition to its known capacity to detect LOH (23). Although FISH is a sensitive method to detect trisomy, the usage of the probe to the centromere leaves the possibility of limited trisomy of the target chromosome. The concordant results of the uniformly decreased allelic ratios to 54–66% for 18 microsatellite markers and triple centromere signals of the chromosome 12 in FISH of adenoma preparation without culture in our study proved that trisomy 12 of the entire chromosome occurs at the relatively high incidence of 8 out of 33 pituitary adenomas (24%).

In adenomas, trisomy is limited to thyroid, colorectal, and pituitary adenomas (13, 14, 15). In colorectal adenomas, trisomy 7 was observed in 37% (13/35), whereas in much higher percentage of 80% (12/15) in colorectal carcinoma (15). The increased incidence of trisomy 7 from 37% in colorectal adenomas to 80% in colorectal carcinomas is compatible with the interpretation that trisomy 7 is etiologic for the tumorigenesis of colorectal adenomas and cancers. In colorectal adenomas, trisomy of chromosomes 7, 13, 18, and 20 was reported, respectively, in 15% (5/34), 15% (5/34), 6% (2/34), and 18% (6/34) (14). In the thyroid, trisomy 22 was found in 8% (3/38) and combined trisomies between chromosomes 5, 7, 9, 12, and 16 were found in 5% (2/38) of follicular thyroid adenomas (13). Combined trisomies 7 and 12 were found in 20% (1/5) of follicular thyroid adenomas (27). Cytogenetic analysis of pituitary adenomas detected 58 chromosomes with multiple trisomies 3, 5, 7, 11, 12, 13, 17, and 19 in one GH-producing adenoma (16), trisomy 9 in one nonsecreting and one PRL-producing pituitary adenoma (17), both after the short-term culture, and trisomy 8 and 12 in one nonsecretary adenoma out of 12 pituitary adenomas without culture (18). These numerical aberrations of chromosome, including relatively frequent trisomy, can either be etiologic for the tumorigenesis of adenomas through changing the gene doses, or one of the consequences of genetic instability in adenomas. Because K-ras, int 1, CDK2, tel, and mdm2 are mapped on chromosome 12, the amplification of these genes by trisomy 12 can be etiologic for the tumorigenesis of pituitary tumors.

The incidence of trisomy 12 at 24% (8/33) in our study is much higher than the reported incidence of 8% (1/12) in pituitary adenomas (18). Because both studies analyzed the samples without culture, the higher incidence of trisomy in our study may be 1) due to the calculation of allelic ratios combined with FISH used in our study compared with FISH only used in the other study (18), and 2) due to the racial difference.

Although the small number of samples in our study made it impossible to point out the relationship between trisomy 12 and clinical features, trisomy 12 detected in 4 out of 6 prolactinomas suggested the etiologic importance of trisomy 12 in prolactinomas. Among 8 pituitary adenomas showing trisomy 12, 6 were men and 2 were women, whereas the approximately equal numbers of both sexes, i.e. 18 men and 15 women, were analyzed. Except for these, no obvious correlation was found between trisomy 12 and clinicopathological parameters.

Based on these, we conclude that the uniformly decreased allelic ratios on chromosome 12 from 54–66% for 18 microsatellite markers in 8 out of 33 pituitary adenomas are caused by trisomy 12, that trisomy 12 may be etiologic for the tumorigenesis of the pituitary adenomas, especially for prolactinoma, and that the unexamined genes on chromosome 12 rather than the loss of the p27Kip1 gene may play an important role through altered gene doses for the tumorigenesis of human pituitary adenomas.


   Acknowledgments
 
We thank Dr. Hiroyuki Iwahana, Takashi Yamaoka, and Setsuko Ii for continuous support.


   Footnotes
 
1 This work was supported in part by a grant from Otsuka Pharmaceutical Factory, Inc., for Otsuka Department of Clinical and Molecular Nutrition, School of Medicine, The University of Tokushima. Back

Received March 11, 1997.

Revised May 20, 1997.

Accepted May 30, 1997.


   References
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 Abstract
 Introduction
 Materials and Methods
 Results
 Discussion
 References
 

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