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Human Molecular Genetics Pages 2285-2290

Identification of MEN1 gene mutations in sporadic carcinoid tumors of the lung
Introduction
Results
Discussion
Materials And Methods
   Tumors and subjects
   DNA analysis
Acknowledgements
References

Identification of MEN1 gene mutations in sporadic carcinoid tumors of the lung

Identification of MEN1 gene mutations in sporadic carcinoid tumors of the lung Larisa V. Debelenko1, Elisabeth Brambilla2, Sunita K. Agarwal3, Jennifer I. Swalwell1, Mary B. Kester3, Irina A. Lubensky1, Zhengping Zhuang1, Siradanahalli C. Guru4, Pachiappan Manickam4, Shodimu-Emmanuel Olufemi4, Settara C. Chandrasekharappa4, Judy S. Crabtree4, Young S. Kim3, Christina Heppner3, A. Lee Burns3, Allen M. Spiegel3, Stephen J. Marx3, Lance A. Liotta1, Francis S. Collins4, William D. Travis5 and Michael R. Emmert-Buck1,*

1Laboratory of Pathology, National Cancer Institute, 3Metabolic Diseases Branch, National Institute for Diabetes, Digestive and Kidney Diseases and 4Laboratory of Gene Transfer, National Human Genome Research Institute, NIH, Bethesda, MD 20892, USA, 2Laboratoire de Pathologie Cellulaire, Groupe de Recherche sur le Cancer Bronchique-CJF, INSERM 97.01, Centre Hospitalier Regional Universitaire de Grenoble, BP 217, 38043 Grenoble Cedex 09, France and 5Department of Pulmonary and Mediastinal Pathology, Armed Forces Institute of Pathology, 6825 N.W. 16th Street, Washington, DC 20306-6000, USA

Received August 4, 1997; Revised and Accepted September 18, 1997

Lung carcinoids occur sporadically and rarely in association with multiple endocrine neoplasia type 1 (MEN1). There are no well defined genetic abnormalities known to occur in these tumors. We studied 11 sporadic lung carcinoids for loss of heterozygosity (LOH) at the locus of the MEN1 gene on chromosome 11q13, and for mutations of the MEN1 gene using dideoxy fingerprinting. Additionally, a lung carcinoid from a MEN1 patient was studied. In four of 11 (36%) sporadic tumors, both copies of the MEN1 gene were inactivated. All four tumors showed the presence of a MEN1 gene mutation and loss of the other allele. Observed mutations included a 1 bp insertion, a 1 bp deletion, a 13 bp deletion and a single nucleotide substitution affecting a donor splice site. Each mutation predicts truncation or potentially complete loss of menin. The remaining seven tumors showed neither the presence of a MEN1 gene mutation nor 11q13 LOH. The tumor from the MEN1 patient showed LOH at chromosome 11q13 and a complex germline MEN1 gene mutation. The data implicate the MEN1 gene in the pathogenesis of sporadic lung carcinoids, representing the first defined genetic alteration in these tumors.

INTRODUCTION

Lung carcinoids derive from endocrine cells associated with lung epithelium and bronchial glands, and are classified as either typical or atypical based on histopathological (size, mitotic index, absence or presence of necroses in the tumor) and clinical (absence or presence of metastases) criteria (1 -4 ). They have a characteristic growth pattern with trabecular, acinar or solid cell arrangement, and express neuroendocrine markers (1 ,5 ). Pulmonary atypical carcinoids frequently behave in a clinically aggressive manner, with a metastatic rate up to 50% (1 -3 ). To date, little is known of the molecular events underlying the development or progression of these tumors.

The classic multiple endocrine neoplasia type 1 (MEN1) spectrum includes tumors of parathyroid glands, anterior pituitary, endocrine pancreas and endocrine duodenum. Less frequently observed neoplasms include neuroendocrine tumors of lung, thymus and stomach as well as some non-endocrine tumors (lipomas, angiofibromas, ependymomas) (6 ). A tumor suppressor role for the MEN1 gene has been suggested based on frequent chromosome 11q13 loss of heterozygosity (LOH) in neoplasms of affected patients (7 -10 ). Allelic deletion (9 -11 ) and, recently, mutation analysis (12 ,13 ) studies have implicated the MEN1 gene as a tumor suppressor in a significant fraction of the sporadic counterparts of typical MEN1 neoplasms (parathyroid tumors, insulinomas and gastrinomas) in accordance with the prediction of Knudson (14 ). Allelic deletions of the MEN1 gene locus have also been reported in lung carcinoid tumors in both MEN1 and non-MEN1 patients, suggesting that the MEN1 gene may be involved in the development of this tumor type (15 ,16 ).

The gene for MEN1 was localized previously to chromosome 11q13 (7 ,17 -19 ), and was recently cloned (20 ). In the present study, we analyzed sporadic lung carcinoid tumors for inactivation of the MEN1 gene. Both allelic deletions of chromosome 11q13 and MEN1 gene mutations were assessed.

Table 1 . Clinical and histopathological characteristics of 12 lung carcinoid cases
No. Age at surgery Other malignancies Family history of MEN1 Tumor size Metastases of lung carcinoids< Mitoses/10 HPF Ki67-positivecells (%)
1 40 None - 1.0 None 3 1
2 46 liposarcoma of spermatic cord - 2.5 none 3 11
3 45 none - 0.7 none 0 4
4 50 none - 2.5 none 1 5
5 56 none - 3.5 none 5 7
6 63 none - 1.8 none 0 5
7 24 none - 3.0 none 0 2
8 39 none - 2.0 none 1 3
9 63 basal cell carcinoma of forearm - 3.0 liver 4 0
10 62 none - 5.0 liver, bones 15 13
11 58 none - 3.0 brain, mediastinum 15 13
12 49 multiple tumors of parathyroid glands + >5.0 mediastinum, cervical lymph node 2 5
HPF, high power field; Nos 1-8, typical carcinoids; Nos 9-12, atypical carcinoids.

Table 2 . Data on allelic deletions of the MEN1 gene locus and mutations of the MEN1 gene in 12 lung carcinoid tumors
No. PYGMa D11S4946 D11S449 MEN1 gene mutation Location of mutation (exon) Mutation classification Consequence of mutation
1 [squ] [squ] [squ] -      
2 [squf] [squf] - + 10 1650insC frameshift
3 [squ] [squ] [squ] -      
4 - [squ] [squ] -      
5 [squf] [squf] [squf] + 3 764+3A -> G alteration of splicing, possible frameshift
6 [squ] [squ] - -      
7 [squ] - - -      
8 [squ] [squ] - -      
9 [squf] - [squf] + 2 134del13 (GACGCTGTTCCCG) frameshift
10 [squf] - [squf] + 10 1461delG frameshift
11 [squ] - [squ] -      
12 [squ] [squf] [squf] + 10 1699delA,* and 1702G -> C* frameshift
Nos 1-8, typical carcinoids; Nos 9-12, atypical carcinoids.
aPolymorphic markers from left to right are listed from centromeric to telomeric direction. Marker D11S4946 is located in the 5' MEN1 gene flanking region, marker PYGM is located 70 kb centromeric to the MEN1 gene and marker D11S449 is located ~500 kb telomeric to the gene.
[squ], retention of constitutional heterozygosity; [squf], LOH; (-), not informative; *germline mutations.

RESULTS

Twelve lung carcinoid tumors were included in the study. Eleven of the tumors were from patients with neither a history of MEN1-associated neoplasms nor a family history of MEN1. One tumor was from a patient with a history of multiple parathyroid tumors and lung carcinoids. A first degree relative (brother) of the patient also had MEN1 endocrinopathy (gastrinoma). The clinical and family history supports the diagnosis of familial MEN1 in this patient (6 ). However, the clinical presentation in the proband does not meet strict criteria of MEN1, since the lung carcinoid (the second endocrine tumor type in this patient) is not considered to be a primary criterion for diagnosis of MEN1 (6 ).

Eight of 12 tumors were classified as typical and four as atypical lung carcinoids based on standard histopathological criteria (1 -4 ).

Clinical and pathological characteristics of the 12 cases are presented in Table 1 . In addition to a characteristic neuroendocrine histological appearance, the tumors were stained positively with at least two of six neuroendocrine markers [chromogranin A, synaptophysin, neuron-specific enolase (NSE), Leu 7,mAb 735 and neural cell adhesion molecule (NCAM) (1 ,5 )]. The degree of proliferation was assessed by the mitotic index of the tumors and the percentage of Ki67-positive cells (Table 1 , and ref. 21 ).

LOH on chromosome 11q13 was detected in four of the 11 sporadically arising tumors using three polymorphic markers located at or near the MEN1 gene on chromosome 11q13 (Fig. 1 , Table 2 ). Dideoxy fingerprinting (ddF) analysis of the MEN1 gene in the 11 tumors revealed altered gel electrophoresis migration patterns in the same four tumors exhibiting 11q13 LOH. Direct sequencing of amplified normal and tumor DNA showed the presence of a MEN1 gene mutation in each tumor (Fig. 2 , Table 2 ). The mutations were observed in exons 2, 3 and 10 (twice), and included a 1 bp insertion, a 1 bp deletion, a 13 bp deletion and an A -> G substitution located adjacent to the splice donor site at the 3' end of exon 3 (GTAT -> GTGT). All four mutations were selectively present in the tumor DNA and not observed in the corresponding normal tissue DNA.


Figure 1. Examples of LOH results in four sporadic tumors. Markers are shown on the bottom of the panel. N, normal tissue DNA; T, tumor DNA. Arrows indicate deleted allele. Marker PYGM migrates as a seven-band complex with a strong middle band and six weaker stutter bands located 1 bp apart. Patient 2 is heterozygous for marker PYGM, with the two overlapping alleles located 1 bp from each other. The arrow points to the location of the most intense band of the upper allele which is missing in the tumor. Stutter bands of the lower allele mask the loss of the upper allele. LOH is scored based on the absence of the top stutter band of the upper allele. A homozygous mutant sequence is seen in tumor 2 (Fig. 2A), additionally confirming LOH. Marker D11S4946 migrates as a seven-band complex, and marker D11S449 migrates as a doublet with a strong main band and a lower stutter band.


Figure 2. Somatic mutations in four sporadic carcinoid tumors. (A) Sequencing gel showing somatic mutation 1650insC in tumor 2. The arrow and the box mark an extra `C' in the tumor DNA. (B) Sequencing gel showing somatic mutation 764+3A -> G in tumor 5. The antisense sequence was obtained with a reverse primer, and the photographic image inverted. The gel shows the presence of two nucleotides in position 764+3. The normal A band is weaker in the tumor sample than the substituted G band (arrow), and may be attributed to contamination of the tumor sample with normal cell DNA. LOH experiments also show normal tissue contamination as is seen for tumor 5 with marker D11S4946 in Figure 1. (C) Sequencing gel showing somatic mutation 134del13 in tumor 9 (arrow). Deleted nucleotides are GACGCTGTTCCCG (empty box). (D) Sequencing gel showing somatic mutation 1461delG (arrow and empty box) in tumor 10.

In each case with a mutation, sequencing was performed twice with independently amplified non-cloned DNA. Additional techniques applied to confirm mutations included restriction digest analysis and single stand conformational polymorphism (SSCP). In tumor 10, the mutant sequence abolishes a BstN1 site (CCAGG), and the digest showed the absence of a normal 162 bp fragment and the presence of a mutant 212 bp fragment in tumor DNA (data not shown). In tumor 5, the mutation neither creates nor abolishes a restriction site for any commercially available enzymes. However, an SSCP analysis of independently amplified DNA confirmed a conformational change (data not shown). Finally, electrophoresis of separately amplified DNA fragments on a 6% polyacrylamide gel demonstrated a 1 bp insertion in tumor 2 (data not shown). The 13 bp deletion in tumor 9 was confirmed by sequencing analysis three separate times.

In the lung carcinoid from the patient with clinical and family features suggestive of MEN1 (Table 1 , tumor 12), a MEN1 gene mutation was seen in both the normal tissue DNA and tumor DNA, consistent with a germline mutation. Deletion of the wild-type allele was seen in the tumor (Fig. 3 A). Comparison of mutant and wild-type MEN1 gene sequence indicated that the mutation was the result of two closely located DNA sequence alterations, 1699delA and a G -> C substitution located two nucleotides in the 3' direction from the single base pair deletion (Fig. 3 B). The altered DNA sequence creates a new AluI site (AGCT). Restriction digest and gel electrophoresis analysis of amplified DNA confirmed the mutant sequence (Fig. 3 C).


Figure 3. Allelic deletion and germline mutation in MEN1 patient 12. (A) LOH results with marker D11S4946.N, normal tissue DNA; T, tumor DNA. The arrow indicates the lost allele. (B) Sequencing gel showing 1699delA (empty box), and 1702G -> C germline substitution. The patient's germline DNA shows a heterozygous sequence with a one nucleotide deletion. The patient's tumor DNA is homozygous due to loss of the wild-type allele, with only the mutated gene sequence present. Both sequence changes are indicated by arrows. (C) Demonstration of the 1702G -> C mutation in germline DNA of MEN1 patient 12 by AluI digestion. A 447 bp fragment in the patient's amplified DNA is seen due to the newly created AluI site (AGCT) in the sequence. The normal wild-type 545 bp fragment is also seen. The 257 and 230 bp bands are expected AluI digestion fragments and are seen in both normal and mutant DNA.

Previously described polymorphisms S545S (AGC/AGT) and D418D (GAC/GAT) (22 ) were also observed.

DISCUSSION

There are no previous reports of frequently occurring mutations in sporadic lung carcinoid tumors. LOH on chromosome 11q13 has been observed in both MEN1-associated (15 ) and sporadic (16 ) lung carcinoids, but it has not been possible to define the precise genetic abnormality in these tumors prior to the identification of the MEN1 gene. LOH studies in lung carcinoids have not identified additional loci with significant levels of allelic loss, including chromosome 3p which has been implicated in small cell lung cancer, a clinically aggressive neuroendocrine tumor of the lung (23 ). The available mutational analysis and immunohistochemistry data on lung carcinoids show infrequent alterations in p53, K-ras-2, c-raf-1, and C-erb-B2 (24 -30 ). RB gene expression is generally retained (31 ), in contrast to small cell lung carcinoma which shows frequent RB gene inactivation (32 -34 ).

The present study directly implicates the MEN1 gene in the development of sporadic lung carcinoid tumors, representing the first defined pathogenetic abnormality for this tumor type. The structure of menin shows no homology with previously identified proteins, thus few clues are available regarding its biochemical function or location of important structural motifs. Each of the four somatic mutations observed in the tumors predicts truncation of the protein, and two of the four mutations involve exon 10, suggesting that loss of the C-terminal portion of the protein is sufficient for functional inactivation. Alternatively, the mutations may lead to decreased RNA and/or protein stability and complete loss of menin in the tumors. The exon 10 mutation 1650insC found in tumor 2 has also been detected as the responsible germline mutation in a MEN1 family (22 ), showing that identical MEN1 gene mutations can occur as germline and somatic events. The DNA sequence in the area of the mutation contains a stretch of seven consecutive cytosines. It is often the case that regions of repetitive DNA are more prone to mutations due to polymerase slippage errors (35 ).

Tumor 9 shows a somatic mutation in exon 2, leaving only the first eight amino acids of the protein intact. This finding argues against a dominant-negative mechanism of mutated menin, consistent with previously described germline mutations observed in MEN1 families which preserve only a small portion of the N-terminus of the protein (20 ).

Tumor 5 contains a splice junction mutation with two possible outcomes. First, an alternative splice junction is created by the new GT sequence, which if it successfully out-competes with normal donor would result in two additional nucleotides (GT) being added to the coding sequence. Alternatively, exon 3 may be entirely omitted from the mRNA due to the change in the existing splice junction consensus sequence. No RNA was available from the tumor to test these hypotheses.

The germline MEN1 gene mutation detected in the patient with an unusual presentation of MEN1 (highly aggressive lung carcinoid tumor) is complex and has not been observed previously in any MEN1 kindred. The two closely located alterations in the gene (1699delA and a G -> C substitution located two nucleotides in the 3' direction from the deletion) presumably occurred simultaneously as a consequence of a complex error in DNA replication. Such germline mutations are not unprecedented. For example, several similar mutations have been detected in patients with cystic fibrosis (36 ).

Of 12 tumors in the study, five cases were characterized by inactivation of both copies of the MEN1 gene, and seven were with both copies of the gene intact. However, it cannot be ruled out that small interstitial deletions including the MEN1 gene are present in tumors 7 and 11,since the marker D11S4946 located in the 5' end flanking region of the gene was not informative (Table 2 ). Additionally, ddF mutation screening was limited to the MEN1 gene coding sequence and splice junctions; thus it is possible that mutations present in the promoter, introns or untranslated regions of the mRNA were not detected.

The five lung carcinoids with MEN1 gene inactivation included three atypical and two typical carcinoids. The two typical carcinoids showed several interesting features (Table 1 , tumors 2 and 5). Both tumors were characterized by a rapid proliferative rate as documented by a higher mitotic index and a stronger Ki67 positivity than in the other six typical carcinoids. According to the recently revised histopathological classification of lung carcinoids (W. Travis et al., in preparation), these two tumors may be placed in the category of atypical lung carcinoids. Interestingly, these two tumors also showed loss of Rb mRNA expression (data not shown), a rather unusual finding, since inactivation of the RB gene is characteristic of aggressive small cell carcinomas, but not generally seen in lung carcinoids (31 -34 ). Thus, the carcinoid tumors displaying MEN1 gene inactivation in our study are characterized by more aggressive histopathological and molecular features compared with the tumors without MEN1 gene alterations.

In summary, the present study implicates the MEN1 gene in the pathogenesis of sporadic lung carcinoid tumors, the first well characterized genetic alteration to be described in these tumors. Further mutational and functional studies of the MEN1 gene in lung carcinoids are warranted and likely to uncover additional insights into the etiology of these lesions.

MATERIALS AND METHODS

Tumors and subjects

Twelve cryopreserved tumors from the files of the Laboratory of Cellular Pathology (Central Hospital of the Regional University of Grenoble, France) were included in the study. Patients were followed at the Hospital of the Regional University of Grenoble for 2-11 years. Tissue samples were collected in accordance with the guidelines of the University of Grenoble (France), and were entered into the study without patient identifiers. The diagnosis of typical or atypical lung carcinoid was based on standard histopathological criteria, which included size of primary tumor, mitotic index (>5 mitoses per 10 high power fields for atypical carcinoids), absence/presence of tumor necroses and absence/presence of metastases. In each case, the histopathological diagnosis was confirmed independently by two pathologists (E.B. and W.D.T.).

DNA analysis

Tissue was frozen in liquid nitrogen immediately after surgical excision and stored at -70°C. Tumor and surrounding normal lung tissue were microdissected from frozen sections using laser capture microdissection (LCM), and DNA was extracted as described previously (37 ).

For LOH analysis, DNA was amplified with three polymorphic markers: PYGM, D11S4946 and D11S449 (38 ,39 ), using random incorporation of [33P]dCTP and PCR conditions described previously (10 ).

For mutational screening, exons 2-10, including corresponding splice junction regions, were amplified with primers designed from intron sequences (www.nhgri.nih.gov/DIR/LGT/MEN1/ table.html or www.niddk.nih.gov). PCR conditions and ddF protocols were the same as described previously (20 ). DNA extracted from normal tissue of four randomly selected tumors and constitutional DNA of two healthy individuals were used for control.

For identification of mutations, the sequencing of primary PCR products was performed with ddF primers using AmpliCycle kit (Perkin Elmer, Branchburg, NJ). To exclude PCR errors, the sequencing reactions were performed twice with non-cloned, independently PCR-amplified DNA. Confirmation for mutations 1702G (C -> G, creating an AluI site) and 1461delG (abolishing a BstN1 site) was achieved by restriction digestion of the PCR products containing exons 9 and 10. Independently amplified and [33P]dCTP-labeled PCR products from tumor 5 were analyzed for conformational changes on non-denaturing MDE gel (FMC BioProducts, Rockland, ME). Radiolabeled amplified DNA from tumor 2 additionally was resolved on 6% polyacrylamide gel for confirmation of a 1 bp insertion.

ACKNOWLEDGEMENTS

C.H. is supported by a grant of the Fritz Thyssen Stiftung (Germany).

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*To whom correspondence should be addressed. Tel: +1 301 496-2912; Fax: +1 301 4800853; Email: mbuck@helix.nih.gov

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