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Journal of Clinical Endocrinology & Metabolism , doi:10.1210/jc.2005-1478
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The Journal of Clinical Endocrinology & Metabolism Vol. 90, No. 12 6580-6587
Copyright © 2005 by The Endocrine Society

Tumor Deletion Mapping on Chromosome 11q13 in Eight Families with Isolated Familial Somatotropinoma and in 15 Sporadic Somatotropinomas

Beatriz S. Soares, Kuniki Eguchi and Lawrence A. Frohman

Section of Endocrinology and Metabolism, Department of Medicine, University of Illinois at Chicago, Chicago, Illinois 60612

Address all correspondence and requests for reprints to: Lawrence A. Frohman, M.D., Section of Endocrinology and Metabolism (MC 640), University of Illinois at Chicago, 1819 West Polk Street, Chicago, Illinois 60612. E-mail: frohman{at}uic.edu.


   Abstract
Top
 Abstract
Introduction
 Subjects and Methods
 Results
 Discussion
 References
 
Context: Isolated familial somatotropinoma (IFS) is a rare endocrine disease defined as the occurrence of at least two cases of acromegaly or gigantism in a family that does not exhibit features of Carney complex or multiple endocrine neoplasia type 1. Analysis of the multigenerational expression in families suggests that IFS is inherited as an autosomal dominant disease with incomplete penetrance. The association between the disease and loss of heterozygosity on chromosome 11q13 as well as its linkage to this region has been well established, but the IFS gene still remains unknown.

Objective: The aim of this report was to narrow the previously described chromosomal region (9.7 cM) to which the gene was previously localized and to evaluate potential candidates.

Design and Setting: Using haplotyping and allelotyping techniques, we studied eight new families (total of 14 tumors) with IFS and 15 sporadic somatotropinomas. Eighteen polymorphic markers spanning an approximately 9-Mb region on chromosome 11q12.2–11q13.3 were used.

Main Outcome and Results: Loss of heterozygosity was found in all families and in 40% of sporadic tumors. Although multiple and frequently discontinuous, the presence of allelic loss limited by retentions at their boundaries suggests a new interval of approximately 2.21 Mb on chromosome 11q13.3. Three potential candidate genes (DOC-1R, LOC 399919, and LOC 440049) in this region were sequenced, although no mutations were found.

Conclusions: Identification of the IFS gene is still necessary because it will not only provide insight into the molecular basis of IFS but may also elucidate the pathogenesis of sporadic somatotropinomas.


   Introduction
Top
 Abstract
 Introduction
Subjects and Methods
 Results
 Discussion
 References
 
THE GREAT MAJORITY of somatotropinomas are sporadic, although a few occur with a familial aggregation, either as a component of multiple endocrine neoplasia type 1 (MEN-1) or Carney complex (CNC) or when unassociated with other tumors, such as isolated familial somatotropinoma (IFS) (1). IFS is defined as the occurrence of at least two cases of acromegaly or gigantism in a family that does not exhibit features of CNC or MEN-1.

Since the availability of a reliable biochemical diagnosis of GH excess, 46 IFS families have been reported with 108 affected members (2). Although the clinical manifestations of IFS are similar to those in patients with sporadic GH-secreting adenomas, the median age at diagnosis is earlier compared with patients with sporadic acromegaly, especially when only a single generation is affected. Because the majority of families contain only two affected members (2), the existence of two independent sporadic somatotropinomas in some kindreds is theoretically possible. However, the very low prevalence of acromegaly in the general population (3) makes this extremely unlikely.

Loss of heterozygosity (LOH) at chromosome 11q13 has been reported in both sporadic and familial somatotropinomas. An allelic loss has been observed in 18–40% of sporadic somatotroph tumors (4, 5, 6), but a mutation of the MEN-1 gene, which is located in the region of allelic loss, is present in only a small number of tumors (7, 8, 9). In contrast, pituitary tumors from most IFS families have exhibited LOH on chromosome 11q13 (10, 11, 12, 13), suggesting that a tumor suppressor gene is involved in the pathogenesis of the disease. Linkage of IFS to chromosome 11q13 has been established using meiotic recombination analysis (14) and genome-wide allelotyping in the only two families of sufficient size to perform such studies (13, 15). Although linkage to chromosome 2 was suggested in one family (14), subsequent studies in several different families appeared to exclude this possibility (15). The IFS candidate gene was initially mapped to an approximately 8.6-Mb interval, flanked by microsatellite markers D11S1335 and INT-2 (14). Subsequent to the publication of a high-resolution map of the human genome (16), this interval was recalculated to a region of approximately 10 Mb (17).

Since that time, several candidate genes located in that region have been examined for genetic alterations. MEN-1 was the first to be studied (18) but, subsequent to its cloning (19), was excluded as the IFS gene by several groups, based on the absence of somatic or germline mutations in its coding region or the exon-intron boundaries (10, 11, 20, 21, 22, 23, 24, 25, 26, 27). Similarly, many other genes involved in somatotroph proliferation and GH secretion such as GHRH-R, gsp, and GNAI2 were also excluded as candidates (11, 25, 27, 28, 29, 30). The PRKAR1A gene (associated with the CNC) was also excluded through haplotyping and allelotyping analyses using an intragenic marker (12). Two genes included in the 11q13 region, FEN1, involved with DNA repair, and REQ, an apoptosis-related gene have also been excluded as candidates in patients with IFS (12, 13).

In the present study, we performed allelotype and haplotype analyses on eight additional families with IFS and 15 sporadic somatotropinomas in an effort to restrict the region of the tumor suppressor gene. The region was mapped using 18 polymorphic microsatellite markers, and the results suggest a more limited candidate region of 2.21 Mb. In addition, three different candidate genes located in this region were analyzed by direct sequencing.


   Subjects and Methods
Top
 Abstract
 Introduction
 Subjects and Methods
Results
 Discussion
 References
 
Subjects

Tumor and leukocyte DNA was obtained from eight previously unreported IFS families (three from the United States, two from Japan, one from Serbia, one from Sweden, and one from the United Kingdom), all of whom had biochemical evidence of acromegaly and radiological evidence of a pituitary adenoma. The pedigrees are shown in Fig. 1Go. None of the affected subjects or their family members exhibited clinical or laboratory evidence of other endocrine tumors, based on history, physical exam, and/or biochemical studies. Tumor and leukocyte DNA from 15 sporadic GH-secreting tumors was obtained from patients at Felicio Rocho Hospital, Belo Horizonte, Minas Gerais, Brazil, and the University of Illinois Medical Center. Patients with sporadic tumors had no history of other endocrine tumors. The study was approved by the institutional review boards of the University of Illinois at Chicago, Felicio Rocho Hospital, and the other institutions, and informed consent was obtained from the subjects.



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  		FIG. 1. Pedigrees of the eight families with IFS. Generations available for study are indicated by Roman numerals. Subjects in the second generation are shown in age-descending order. Affected subjects are shown in black symbols. The numbers shown below the symbols indicate the age at diagnosis in affected individuals (shown in bold) and of time of study in unaffected individuals. The question marks denote those individuals in whom age is unknown, and the asterisk indicates an affected individual who was not available to be studied.

 
Haplotyping and allelotyping analyses

Studies were performed on DNA from peripheral blood samples and paraffin-embedded pituitary adenoma tissue from IFS patients. Tumor DNA from patients with sporadic GH-secreting tumors was primarily obtained as fresh tissue or as paraffin blocks. DNA was extracted from leukocytes with the Wizard genomic DNA purification kit (Promega Corp., Madison, WI) and from tumors using the DNeasy tissue kit (QIAGEN, Inc., Valencia, CA). Eighteen polymorphic microsatellite markers from chromosome region 11q12.2–11q13.3 were analyzed: D11S1765, D11S4076, D11S480, D11S1883, D11S4941, D11S4908, AFMA 190YD5, D11S2072, D11S1889, D11S4155, D11S1296, D11S1917, D11S4087, D11S1337, D11S4178, D11S4113, D11S4095, and D11S4136 (centromeric to telomeric). The location and order of markers are as described in the UCSC database (http://www.genome.ucsc.edu, May 2004) (31). Primer sequences were obtained from the UniSTS database (http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=unists). One nucleotide of each reverse primer was labeled with a 6-carboxyfluorescein on the 5' end (Operon Biotechnologies, Inc., Huntsville, AL).

PCRs were performed in a total volume of 25 µl using the 2X PCR Master Mix Fermentas kit (Fermentas Inc., Hanover, MD) and included 12.5 µl 2X Master Mix, 0.05–0.5 µM of each primer, approximately 20–40 pg DNA as template, and distilled water. A hot start was performed at 95 C for 10 min, followed 40 subsequent cycles at 95 C for 1 min, 52–62 C (primer dependent) for 1 min, and 72 C for 1 min and a final extension at 72 C for 10 min. Aliquots of the amplified product were electrophoresed in a 1.5% agarose gel to confirm product size. Fragment analyses were performed using an ABI Prism 3100 genetic analyzer with GeneMapper 3.5 software (Applied Biosystems, Foster City, CA). For allelotype analyses, LOH was defined as a greater than 50% decrease in the height or area of tumor DNA as compared with peripheral (leukocyte) DNA.

Homozygosity mapping of deletion analysis (HOMOD)

HOMOD analyses were performed as described by Goldberg et al. (32) using heterozygosity scores from the GDB Human Genome Database (http://www.gdb.org). Using this method, the probability of five consecutive closely spaced microsatellite markers all exhibiting homozygosity is equal to the product of their individual heterozygosity scores. Such a DNA segment could represent a constitutional deletion and hide an allelic loss because tumor tissue would not be analyzed in such instances.

Direct sequencing

DNA from four subjects (family C, II-1 and II-2; family D, II-4; and family G, I-2) was extracted as described above. Primers were selected to span all coding regions of the DOC-1R (derived oral cancer-related 1) gene and two hypothetical proteins (LOC 399919 and LOC 440049). DOC-1R is a gene related to a tumor suppressor gene associated with oral cancer, with the same embryological origin as the pituitary (33). LOC 399919 and LOC 440049, neither of which has a described function, are located in a region that became of interest based on allelotyping results. They are both located near the boundaries of PRAD-1, an oncogene associated with parathyroid tumorigenesis (34, 35). The Primer 3 program (http://frodo.wi.mit.edu/cgi-bin/primer3/primer3_www.cgi) was used for design of the primers (synthesized by Operon Biotechnologies). Primer sequences are available on request. After PCR amplification, the product was purified using the QIAquick PCR purification kit (QIAGEN) and sequenced using the ABI Prism BigDye Terminator cycle sequencing ready reaction kit (Applied Biosystems) on an ABI Prism 3100 genetic analyzer.


   Results
Top
 Abstract
 Introduction
 Subjects and Methods
 Results
Discussion
 References
 
Haplotyping

Haplotypes from seven members of family A and nine members from family D were constructed using markers located at chromosome 11q12.2–11q13.3. In family A, the two affected sons shared the identical haplotype based on the presence of the disease in a paternal second cousin (Fig. 2Go). The DNA from this subject was unavailable for the study. Two unaffected individuals are at risk based on their haplotypes. However, because of relatively late onset of acromegaly in one sibling, their disease status must remain uncertain. No meiotic recombination events were observed in this family.



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  		FIG. 2. Haplotype analyses of families A and D. Black symbols represent affected individuals. Vertical numbers denote allele size (1, smallest; 4, largest) for the polymorphic microsatellite markers. The haplotype cosegregating with the disease is shown in bold, asterisks denote noninformative markers, and the open rectangles denote meiotic recombinations.

 
In family D, the two affected siblings shared the identical paternal haplotype, indicating that the germline mutation was transmitted by the father. Two unaffected siblings also shared this haplotype although they were phenotypically normal and their disease status is uncertain. (Fig. 2Go) Meiotic recombinations were detected at markers D11S2072 and D11S1889 in non-disease-associated haplotypes in two unaffected siblings.

Haplotyping of the other families gave results that were consistent with the inheritance pattern described, but no recombination events were observed in any of the subjects.

Allelotyping

The patterns of allelic loss in tumors from the eight families are shown in Fig. 3AGo. LOH was considered to be present only when tumor tissue exhibited loss of the normal allele. Partial loss of 11q13 was observed in all families, although not in an entirely consistent manner. The most noteworthy region was between markers D11S4155 and D11S4136 (approximately 2.21 Mb). In family C, the tumors showed an extensive LOH flanked by retentions at both borders of this region. In families C (C-II-2), D (D-II-3), and F (F-I-2), the germline DNA contained a stretch of homozygosity encompassing five consecutive markers in this region, resulting in P values of 0.009, 0.005, and 0.012, respectively, by HOMOD analysis. These regions were therefore considered to contain a constitutional LOH.



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  		FIG. 3. Tumor deletion mapping of familial (A) and sporadic (B) somatotropinomas using polymorphic microsatellite markers from chromosome 11q12.2–11q13.3. UniSTS boundaries are 60.55 Mb (centromeric) to 69.39 Mb (telomeric). Blanks indicate that the analysis was not performed. The locations of the individual markers are shown in Fig. 5Go.

 
Figure 4Go shows the allelotyping results from two subjects with marker D11S1917. Retention of both alleles is clearly shown in subject G-II-1 (Fig. 4AGo), as is the nearly complete loss of the smaller allele in subject D-II-3 (Fig. 4BGo).



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  		FIG. 4. Allelotyping results using marker D11S1917 in two families. A, Allelic retention in subject II-1 (family G); B, LOH in subject II-4 (family D). The x-axis indicates the allele size and the y-axis the relative allele height. The arrow indicates the allelic deletion. The double peaks for each allele are one nucleotide different in size and reflect the deadenylated PCR-amplified products.

 
Figure 5Go shows a composite deletion map of the tumors in the eight families incorporating HOMOD analysis. Eleven of the 14 tumors exhibited LOH or a stretch of homozygosity between microsatellites D11S4155 and D11S4136.



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  		FIG. 5. Composite tumor deletion map of chromosome 11q13. Microsatellite marker positions are based on UniSTS location map (Build 34.1). The locations of the sequenced genes are shown in italics beneath the marker bar. Subjects are listed at the left. LOH is shown by the black bars, retention by the white bars, and germline homozygosity by the gray bars. Regions of homozygosity meeting the HOMOD criteria are shown as LOH. The proposed 2.21-Mb region for the candidate gene is shown by the rectangle with a dotted line boundary.

 
The allelic losses in the sporadic somatotropinomas were multiple and discontinuous, with areas of LOH interspersed with areas of retention of heterozygosity. Thirteen markers were used to map the region, and LOH was observed in at least one marker in 40% of the tumors. The number of markers exhibiting LOH in individual tumors reflected the number examined and their ability to undergo amplification. Three tumors (S6, S8, and S13) showed two or more regions of allelic loss, with tumor S6 exhibiting the largest region (1.86 Mb). Microsatellite instability was present in 33% of the tumors (Fig. 3BGo).

DOC-1R, LOC 399919, and LOC 440049 sequencing

Four affected subjects from different families were selected for the sequencing studies. Three PCR products spanning the entire coding region of the DOC-1R gene were screened for mutations by direct sequencing. The LOC399919 sequence was determined using two sets of primers and LOC440049 by a single pair of primers. No mutations were found in any of the sequences.


   Discussion
Top
 Abstract
 Introduction
 Subjects and Methods
 Results
 Discussion
References
 
IFS has now been clearly established as a discrete clinical entity distinguishable from both the MEN-1 syndrome and CNC. In addition to the earlier onset of the disease in patients with IFS compared with MEN-1, somatotropinomas constitute only a minority of pituitary tumors in the MEN-1 syndrome (36) with an incidence similar to that in sporadic pituitary tumors. IFS can also be distinguished from the CNC on both a clinical basis (where none of the associated findings of CNC has been observed) and a genetic basis, but the identification of the specific genetic defect still remains to be determined.

In this report, we have described tumor deletion mapping in eight IFS families that resulted in a LOH region of interest between makers D11S4155 and D11S 4136, representing an interval of approximately 2.21 Mb. This allelic loss is not present in all families, but there are several possible explanations for this apparent discrepancy.

The technique of identifying tumor-suppressor genes by mapping regions of allelic loss has well recognized limitations. Factors such as intratumor heterogeneity, contamination by normal cells, karyotypic complexity, homozygous deletions, and changes in gene dosage can interfere with interpretation of the allele loss studies (37). In the present study, efforts were made to minimize these artifacts by using adequate amounts of template DNA for PCR amplification, quantifying allele intensities using both area and height measurements, performing replicate PCR analyses to ensure reproducibility, and demonstrating retention of markers flanking the regions of LOH.

In addition, we used the technique of HOMOD analysis (32), which employs probability statistics to define regions of genomic allelic loss when five or more highly polymorphic microsatellite markers occur in an extended region of homozygosity. Individuals from two families (D and F), in whom LOH was not apparent in this region of interest, exhibited a stretch of homozygosity in this region that is consistent with a constitutive allelic deletion in their genomic DNA. One recognized limitation in the HOMOD analysis is the variance in heterozygosity indices of the markers in different population groups based on their racial diversity. Therefore, the HOMOD probability in family F, which is Japanese, could vary from the value described.

Allelotyping studies were also performed in a group of sporadic somatotropinomas in an effort to further restrict the chromosomal region of interest in IFS. Previous reports have indicated that 18–40% of sporadic tumors exhibit LOH on chromosome 11q13 (4, 5, 6). In the present study, LOH was observed in 40% of sporadic tumors. The frequency of allelic loss was related to the number of microsatellite markers that were successfully amplified. The larger number of markers used in this region as compared with previous reports may explain the greater frequency of LOH observed. Although several tumors exhibited multiple areas of allelic loss and/or microsatellite instability, the pattern of loss was not useful in further restricting the chromosomal region of LOH in IFS families. Yet, the observation that four of the sporadic tumors had LOH in the newly restricted interval raises the possibility that this region contains a locus that is also relevant in some sporadic tumors.

Three subjects (from two families) did not show LOH or a stretch of homozygosity within the interval of 2.21 Mb, flanked by markers D11s4155 and D11s4136, and those individuals did not have another distinct region of allelic loss on chromosome 11q13 either. As described in many familial diseases, not all affected subjects have a germline mutation (38, 39), raising the possibility that other mechanisms are involved in tumorigenesis in IFS in these individuals.

The proposed interval is contained within the region of 11q13 first described in 2000 (14). It is also located within one of the two possible regions recently described in a family with IFS in which a meiotic recombination was identified in twin sisters, one of whom exhibited a somatotropinoma (17). This region contains approximately 50 genes and 9000 expressed sequence tags (http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=unists).

Several candidates of potential interest were examined in this region. The first was DOC-1R (derived oral cancer-related 1), which is related to a tumor suppressor gene associated with oral cancer. DOC-1R was chosen because of the similar embryological origin of pituitary and buccal cavity. In addition, two hypothetical proteins flanking the CCND1 gene, associated with parathyroid gland tumors, were sequenced. Although potentially attractive as candidates for an IFS gene, no mutations were found in tumor or germline DNA in any of the families.

In summary, the present study has extended our previous observations by reducing the size of the region containing a tumor-suppressive gene associated with IFS to an approximately 2.21-Mb interval on chromosome 11q13 through the use of deletion mapping. It has also raised the possibility that this region may contain a tumor suppressor gene related to sporadic somatotropinomas. Future studies in additional families will be required to identify the specific gene involved with the pathogenesis of IFS and to determine whether it also contributes to the development of nonfamilial GH-secreting tumors.


   Acknowledgments
 
We thank Drs. Eleni Dimaraki and Ariel Barkan (University of Michigan), Drs. Anne Klibanski and Karen Miller (Massachusetts General Hospital, Boston), Drs. Marta Korbonits and Ashley Grossman (St. Bartholomew’s Hospital, London), Dr. Vera Popovic (Institute of Endocrinology, Belgrade), Dr. Hakan Widell, (Boras, Sweden), and Dr. Katsuhiko Yoshimoto (University of Tokushima) for providing the material studied in this project and/or referring subjects to the authors for study; Dr. Luiz Armando De Marco (Federal University of Minas Gerais, Belo Horizonte, Brazil) for his encouragement and support; Dr. Nancy Cox (University of Chicago) for advice on statistical analysis; and Leslie Kelley (University of Illinois at Chicago) for DNA sequencing assistance.


   Footnotes
 
This work was supported in part by Conselho Nacional de Desenvolvimento Cientifico e Tecnologico (CNPq, Ministry of Science and Technology of Brazil) to B.S.S. and the Bane Foundation to L.A.F.

Present address for B.S.S.: Department of Pharmacology, Federal University of Minas Gerais, Belo Horizonte, Brazil.

Present address for K.E.: Department of Neurosurgery, Hiroshima University, Hiroshima, Japan.

First Published Online September 27, 2005

Abbreviations: CNC, Carney complex; HOMOD, homozygosity mapping of deletion analysis; IFS, isolated familial somatotropinoma; LOH, loss of heterozygosity; MEN-1, multiple endocrine neoplasia type 1.

Received July 5, 2005.

Accepted September 19, 2005.


   References
Top
 Abstract
 Introduction
 Subjects and Methods
 Results
 Discussion
 References
 

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