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The Journal of Clinical Endocrinology & Metabolism Vol. 83, No. 5 1801-1805
Copyright © 1998 by The Endocrine Society

Original Studies

Comparative Genomic Hybridization Analysis of Nonfunctioning Pituitary Tumors1

Michal Daniely, Ayala Aviram, Eric F. Adams, Michael Buchfelder, Gad Barkai, Rodulf Fahlbusch, Boleslaw Goldman and Eitan Friedman

The Institute of Genetics (M.D., A.A., G.B., B.G., E.F.) and the Oncogenetics Unit (E.F.) Chaim Sheba Medical Center, Tel-Hashomer, Israel; and the Department of Neurosurgery, Kopfklinikum (E.F.A., M.B., R.F.), Erlangen, Germany

Address all correspondence and requests for reprints to: Eitan Friedman, M.D., Ph.D., The Suzanne Levy Gertner Oncogenetics Laboratory, Institute of Genetics, Chaim Sheba Medical Center, Tel-Hashomer 52621, Israel. E-mail: feitan@post.tau.ac.il, or eitan211{at}netvision.net.il


   Abstract
Top
 Abstract
Introduction
 Materials and Methods
 Results
 Discussion
 References
 
Clinically nonfunctioning pituitary adenomas constitute about one third of pituitary neoplasms and are considered monoclonal tumors. The molecular mechanisms of tumorigenesis in these neoplasms are poorly understood, as evidenced by the paucity of reported somatic genetic alterations. Furthermore, the somatic mutations detected to date were primarily ascribed to candidate genes or chromosomal regions: gsp, ras, p53 mutations, and allelic losses of 11q and 13q. To gain insight into which chromosomal regions bear genes involved in nonfunctioning pituitary tumorigenesis, we examined 23 such tumors by comparative genomic hybridization. Four tumors showed no genetic abnormality, and the rest (17 of 23, 74%) exhibited at least one chromosomal region of abnormality. Gains and losses affected all chromosomes (except for chromosome 14). Notably, 8 of 23 tumors (34.7%) displayed sex chromosome and chromosome 18 aberrations (amplifications or deletions). Nonrandom DNA amplification of subchromosomal regions on 4q, 5q (5q13->5q23), 9p (9p21->9pter), 13q (13q21->13q32), and 17q were detected in 10–30% of the tumors. Noteworthy, no tumor displayed deletion of 11q, the MEN1 gene locus. These findings suggest that genes localized to previously undescribed chromosomal regions play a role in the tumorigenesis of nonfunctioning pituitary adenomas.


   Introduction
Top
 Abstract
 Introduction
Materials and Methods
 Results
 Discussion
 References
 
CLINICALLY nonfunctioning pituitary tumors represent 30–40% of all pituitary adenomas, and their presence is not heralded by a distinct endocrine hypersecretion syndrome (1). The majority of pituitary neoplasms, including nonfunctioning adenomas, have been shown to be monoclonal (2, 3), but the exact pathogenic mechanism(s) underlying their development is largely unknown. Tumor monoclonality clearly indicates that a somatic mutation occurred in a single progenitor cell, probably conferring growth advantage to this cell and possibly enhancing its secretory capability (2, 3). A handful of genetic alterations have been demonstrated in various benign pituitary tumors: allelic loss involving primarily the long arm of chromosome 11, possibly in the MEN1 gene locus, in prolactinomas and somatotropinomas (4, 5), Ras point mutation in one prolactinoma (6), and gsp mutations in GH-secreting (7, 8) and nonfunctioning (9) pituitary tumors. However, the majority of pituitary neoplasms tested do not have mutations in several prominent candidate genes, such as p53, Rb, and ras (10; reviewed in 11).

To the best of our knowledge, the only genetic alterations described in nonfunctioning pituitary tumors were gsp mutations (9) and allelic loss at 11q13 (12). By and large, the genetic alterations that were sought, and frequently not found, in pituitary neoplasms were in candidate genes (such as p53, ras, and retinoblastoma) or candidate chromosomal regions [11q (at the MEN1 gene locus) (13) and 13q (at the retinoblastoma locus (14)]. The difficulty in ascertaining which chromosomes harbor genes that are involved in pituitary tumorigenesis is partially attributed to the technical difficulty in obtaining tumor-specific karyotypes. Comparative genomic hybridization (CGH), provides an opportunity to scan the entire human genome and localize genetic alterations of medium size to a specific chromosomal region in a single experiment (15). It has been estimated that an amplicon as small as 100 kilobases can be detected by CGH, whereas the detection limits of deletions are about 1–2 megabases (16). In this study, we applied CGH to 23 nonfunctioning pituitary tumors to define which chromosomal regions are putatively involved in pituitary tumor devel-opment.


   Materials and Methods
Top
 Abstract
 Introduction
 Materials and Methods
Results
 Discussion
 References
 
Tumor processing and DNA isolation

High mol wt DNA was isolated from the resected pituitary tumor at the same time when primary pituitary cell cultures were set up, as previously described in detail (17). DNA isolation from the tumor (i.e. test DNA) was performed by standard techniques. Reference DNA was extracted from peripheral blood of karyotypically normal males, using standard protocols.

Pathological features, immunocytochemistry, and hormone assays

All tumors were examined by a neuropathologist using separate formalin-fixed, paraffin-embedded, hematoxylin-eosin-stained sections. All immuncytochemical studies were performed using a standard peroxidase-antiperoxidase method (18) with rabbit antibodies against PRL, GH, ACTH, TSH, LH, and FSH (Dako, Munich Germany). Cryostat sections of 5–10 µm were prepared and fixed in cold acetone for 15 min. Endogenous peroxidase activity was blocked with 3% H2O2 in phosphate-buffered saline for 5 min, followed by staining with rabbit antiserum. Sections were developed with 0.03% 3,3-diaminobenzidine tetrahydrochloride containing 0.01% H2O2 in Tris buffer.

Preoperative serum levels of hormones were determined by the ELISA method, using commercially available kits. The kits for GH and PRL were purchased from ELIAS (Freiburg, Germany), and those for LH, FSH, TSH and ACTH were obtained from Ares-Serono (Geneva, Switzerland).

Genomic DNA probes and labeling procedure

One microgram from each test and reference DNA was directly labeled with spectrum-Green-deoxy-UTP and spectrum-Red-deoxy-UTP (Vysis, Downers Grove, IL), respectively, by nick translation using the Vysis kit, according to the manufacturer’s recommendations. Fragment lengths after nick translation ranged from 500-2000 bp, as measured after separation on 1.5% agarose gels (19).

CGH

CGH was performed as previously described (20) with minor modifications. High quality metaphase spreads were prepared from a karyotypically normal male according to standard protocols. Slides were prepared at least 1 day before hybridization, and were kept at room temperature for a maximal period of 2 weeks. Slides were denatured in 70% formamide and 2 x standard saline citrate (SSC) at 70 C for 2 min and dehydrated in a series of immersions in ice-cold ethanol. One microgram each of spectrum-Green-labeled test DNA and spectrum-Red-labeled reference DNA, and 40 µg unlabeled Cot-1 DNA (Life Technologies, Gaithersburg, MD) were mixed, ethanol precipitated, and resuspended in 14 µL hybridization buffer (50% formamide and 10% dextran sulfate in 2 x SSC). This probe mixture was denatured for 5 min in 75 C, preannealed for 30 min at 37 C, and hybridized on slides containing denatured chromosomes using a glass coverslip sealed with rubber cement. Hybridization took place in a moist chamber at 37 C for 72 h. Slides were washed in 0.4 x SSC at 75 C for 2 min, followed by 0.1% Nonidet P-40 in 2 x SSC for 2 min at room temperature. Target chromosomes were counterstained with 4,6-diamino-2-phenylindole (DAPI; Sigma Chemical Co., St. Louis, MO) and mounted with Vectashield (Vector Laboratories, Burlingame, CA).

Digital image analysis

CGH results were analyzed using an epifluorescence microscope (Zeiss Axioscope, Jena, Germany) equipped with a 100-watt mercury lamp and a cooled charge-coupled device camera (Photometrics, Tucson, AZ) controlled by a Cytovision image analysis system (Applied Imaging International, Tyne and Wear, UK). Analysis was performed as previously described (21). Briefly, 10–15 metaphases were chosen for image analysis with high fluorescence intensity and uniform hybridization. Gray level images were captured separately for each fluorochrome (DAPI, spectrum-Green, and spectrum-Red). Karyotyping performed based on DAPI banding by inverting the DAPI image. Green and red fluorescence intensities were determined along each chromosome medial axis at 1-pixel intervals. Green to red fluorescence intensity ratio profiles were calculated after background correction and normalization of the green to red ratio for each metaphase to 1.0. Mean ratio profiles for each chromosome were determined after data from all analyzed metaphases were combined. Trisomies or partial chromosome gains were defined as having a green/red ratio greater than 1.25. Monosomies or partial chromosome losses were defined as having a green/red ratio less than 0.75 (22).


   Results
Top
 Abstract
 Introduction
 Materials and Methods
 Results
Discussion
 References
 
Clinical and immunohistochemical data

Each patient’s age and sex, the tumor size [as determined by Wilson’s staging and grading system (23)], peripheral blood hormone profile of patients, and results of immunohistochemical analyses and immunocytochemical analyses are summarized in Table 1Go. There were 12 men and 11 women, with an age range of 33–78 yr. None of the 23 patients with tumors clinically classified as nonfunctioning had detectable hormonal hypersecretion in the serum, but in 18 tumors there was immunohistochemical evidence or in vitro culture evidence of the presence of gonadotropins (Table 1Go). Tumor diameters ranged from 13–45 mm, and invasion of the pituitary tumors into the surrounding anatomical structures was evident in 6 cases. Three patients (no. 920, 925, and 936) underwent reoperation within 6 months after transsphnoidal resection because of local tumor recurrence.


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  		Table 1. Clinical, hormonal, and immunohistochemical data

 
CGH analysis

The results of CGH analysis are summarized in an ideogram (Fig. 1Go) and in Table 2Go, and examples of chromosomal gains and losses are shown in Fig. 2Go. There were five tumors in which no genetic abnormality was detected by this analysis (no. 907, 911, 936, 946, and 964). At the other extreme, there were five tumors (no. 910, 914, 926, 967, and 980) that displayed chromosomal aberrations involving seven or more chromosomes. Interestingly, one of the tumors with no detectable genetic abnormality (no. 936) required reoperation for local recurrence, whereas none of the tumors displaying multiple aberrations required such a procedure. Noteworthy, the tumors displaying multiple genetic aberrations had unique patterns of abnormalities: four tumors in this group displayed a gain of the long arm of chromosome 4 not exhibited by any other tumor sample. In addition, multiple gains of entire chromosomes were noted specifically in this group of tumors; three of five tumors had overrepresentation of at least three different chromosomes. This phenomenon was not detected in any of the other tumor samples (Fig. 1Go).



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  		Figure 1. Combined CGH data for all tumors in an ideogram.

 

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  		Table 2. Summary of CGH results

 


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  		Figure 2. a, An example of a tumor displaying gain of the entire chromosome 13. b, An example of a tumor showing loss of the long arm of chromosome 5.

 
Chromosome imbalances most frequently involved chromosome 18 (8 of 23, 34.7%): gain of the short arm in 2 tumors, gain of the long arm in 3 tumors, loss of the entire chromosome in 2 tumors, and loss of the short arm in 2 other tumors. Chromosome X was also frequently involved (8 of 23, 34.7%), only in the form of chromosomal gains. In 6 tumors (26%), imbalances (gains as well as losses) were localized to chromosome 17, in 4 tumors involving the entire chromosome. Gains of chromosomes 4q, primarily around 4q13->4q31.1, 5q at 5q13->5q23, and 13q at 13q21->13q32, were found in five samples each (21.7%). Gain of chromosome 9p (9p12->9pter) was found in four samples (17.4%), and gains in chromosomes 1q, 8p, and 16q were each found in three samples (13%). These latter amplifications were consistently localized to a well defined, relatively small, subchromosomal region. No tumor displayed loss of the long arm of chromosome 11 (the MEN1 gene locus) (13), and only one had loss of an entire copy of chromosome 13 (the Rb gene locus) (14). In addition, one tumor displayed amplification of 20q at band 13.3, distal to the chromosomal region harboring the gene for the {alpha}-subunit of the stimulatory GTP-binding protein, Gs{alpha} (24).


   Discussion
Top
 Abstract
 Introduction
 Materials and Methods
 Results
 Discussion
References
 
In this study, CGH analysis of 23 nonfunctioning pituitary tumors revealed genetic abnormalities in the majority of neoplasms (17 of 23, 74%). These data provide further support for the monoclonal origin of the majority of nonfunctioning pituitary adenomas. Only a handful of cytogenetic studies analyzing pituitary tumors were reported. In a recent study (25), 38% of the pituitaries analyzed displayed a karotypically detectable chromosomal abnormality, whereas the rest of the tumors were chromosomally balanced. The most common findings in that series were trisomies 5 and 12, with no other specific alterations observed. In another study, trisomy 12 was detected in 5 of 33 (15%) pituitary adenomas (26). The discrepancy between the rates of genetic alterations in our series (74%) and those in the series of Bettio and co-workers (38%) can be explained by the higher sensitivity in the detection of copy number abnormalities using the GCH technique.

Two types of genetic alterations can be detected by CGH: amplifications and deletions. DNA amplification is a well recognized genetic abnormality in tumors, traditionally revealed by Southern blot analysis. The amplified DNA presumably contains direct acting oncogenes that are overexpressed, resulting in uncontrolled cellular proliferation and tumor development (27). The amplifications of 4q, 5q, 8p, 9p, 13q 16q, and 17 detected in nonfunctioning pituitary tumors seem to be nonrandom, affecting four or more tumors, or the specific amplicon is localized to a relatively small, subchromosomal region. Some of these chromosomal regions are amplified in a variety of other tumors, as determined by CGH: 5q amplification in hereditary renal cell carcinoma (28) 13q in uveal melanomas (29), and 17q in breast cancer (19). The long arm of chromosome 17 contains several known genes that have been implicated in tumorigenesis; c-erbB-2 plays a significant role in the pathogenesis of breast cancer (30), ovarian cancer (31), and neuroblastoma (32), but apparently not in pituitary tumors (33). A region on the long arm of chromosome 5 is duplicated in renal cell carcinomas (34), and the distal region of chromosome 9p was reported in primitive neuroectodermal tumors (35).

Chromosomal losses and deletions are indicative of the involvement of tumor suppressor genes in tumorigenesis (36). Despite the relative insensitivity of CGH in detecting losses, nonrandom deletions affecting several chromosomal loci were identified in prostate cancer (37). Furthermore, in that study there was a 76% concordance between the CGH results and allelic loss genotype determined by a PCR-based method. Thus, the chromosomal loss of 18q seen in our series might reflect bona fide allelic loss of chromosome 18, targeting the DCC gene (38) or other tumor suppressor genes that are apparently involved in prostate cancer (37).

Genetic alteration involving the X chromosome in a substantial number of tumors (34.7%) in our series is interesting, as it harbors no obvious candidate genes, and its involvement in tumorigenesis has been reported sporadically and anecdotally (37). Unexpectedly, 11q was not deleted in any tumor, and only one tumor displayed allelic loss of chromosome 13. These regions contain the MEN1 (13) and retinoblastoma (14) genes, respectively, which have been implicated in pituitary tumorigenesis (11). Indeed, somatic mutations of the recently cloned MEN1 gene (menin) (39) have been detected in a subset of pituitary tumors, as direct evidence of their involvement in pituitary neoplasia (40). It is possible that genetic changes exist in these regions that are below the CGH resolution and play a role in the development of pituitary tumors. Alternatively, our findings might indicate the infrequent involvement of these genes in the tumorigenesis of nonfunctioning pituitary tumors. By the same token, other genes localizing to chromosomal regions displaying amplification or losses are acting as oncogenes or tumor suppressor genes, respectively, and are probably involved in pituitary tumor development.

The possibility that the genetic alterations detected by CGH in this series are secondary events, subclonal expansions of the monoclonal tumor, needs to be considered. However, this seems unlikely because all analyzed tumors were benign, and only a fraction of them recurred. Secondary genetic events are primarily observed in malignant invasive tumors with a rapid proliferation rate. Furthermore, the nonrandom distribution coupled with the subchromosomal localization of the genetic alterations strongly support the idea that these abnormalities are relevant to and associated with the neoplastic process.

In summary, nonrandom genetic alterations affecting previously undescribed chromosomal regions in pituitary tumorigenesis are detected by CGH. This finding further supports the monoclonal origin of these neoplasms and points out that genes other than the currently appreciated candidate genes may be involved in pituitary neoplasia.


   Footnotes
 
1 This work was performed in partial fulfillment of the Ph.D. degree of M.D. from the Department of Human Genetics, Sackler School of Medicine, Tel-Aviv University. Back

Received December 17, 1997.

Revised January 28, 1998.

Accepted February 4, 1998.


   References
Top
 Abstract
 Introduction
 Materials and Methods
 Results
 Discussion
 References
 

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