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The Journal of Clinical Endocrinology & Metabolism Vol. 86, No. 4 1801-1805
Copyright © 2001 by The Endocrine Society

Original Studies

Somatic Mutation and Germline Variants of MINPP1, a Phosphatase Gene Located in Proximity to PTEN on 10q23.3, in Follicular Thyroid Carcinomas1

Oliver Gimm, Hongbo Chi, Patricia L. M. Dahia2, Aurel Perren, Raoul Hinze, Paul Komminoth, Henning Dralle, Paul R. Reynolds and Charis Eng

Clinical Cancer Genetics and Human Cancer Genetics Programs (O.G., P.L.M.D., C.E.), Comprehensive Cancer Center, and Division of Human Genetics, Department of Internal Medicine (C.E.), The Ohio State University, Columbus, Ohio 43210; Department of Orthopedics, University of Rochester Medical School (H.C., P.R.R.), Rochester, New York 14642; Department of Cancer Biology, Dana-Farber Cancer Institute, Harvard Medical School (P.L.M.D.), Boston, Massachusetts 02115; Department of Pathology, University of Zürich (A.P., P.K.), CH 8091 Zürich, Switzerland; Institute of Pathology (R.H.) and Department of General Surgery (H.D.), Martin-Luther-University of Halle-Wittenberg, 06097 Halle/Saale, Germany; and Cancer Research Campaign Human Cancer Genetics Research Group, University of Cambridge (C.E.), Cambridge CB2 2QQ, United Kingdom

Address all correspondence and requests for reprints to: Charis Eng, M.D., Ph.D., Human Cancer Genetics Program, The Ohio State University, 420 West 12th Avenue, Room 690C TMRF, Columbus, Ohio 43210. E-mail: eng-1{at}medctr.osu.edu


   Abstract
Top
 Abstract
Introduction
 Materials and Methods
 Results
 Discussion
 References
 
Various genes have been identified to play a role in the pathogenesis of follicular thyroid tumors. Cowden syndrome is the only known familial syndrome with an increased risk of both follicular thyroid adenoma (FA) and carcinoma (FTC). Germline mutations in the tumor suppressor gene PTEN, which encodes a dual-specificity phosphatase, have been found in up to 80% of patients with Cowden syndrome suggesting a role of PTEN in the pathogenesis of follicular thyroid tumors. Although somatic intragenic mutations in PTEN, which maps to 10q23.3, are rarely found in follicular tumors, loss of heterozygosity (LOH) of markers within 10q22–24 occurs in about 25%. Recently, another phosphatase gene, MINPP1, has been localized to 10q23.3. MINPP1 has the ability to remove 3-phosphate from inositol phosphate substrates, a function that overlaps that of PTEN. Because of this overlapping function with PTEN and the physical location of MINPP1 to a region with frequent LOH in follicular thyroid tumors, we considered it to be an excellent candidate gene that could contribute to the pathogenesis of follicular thyroid tumors. We analyzed DNA from tumor and corresponding normal tissue from 23 patients with FA and 15 patients with FTC for LOH and mutations at the MINPP1 locus. LOH was identified in four malignant and three benign tumors. One of these FTCs with LOH was found to harbor a somatic c.122C > T or S41L mutation. We also found two germline sequence variants, c.809A > G (Q270R) and IVS3 + 34T > A. The c.809A > G variant was found in only one patient with FA but not in patients with FTC or normal controls. More interestingly, IVS3 + 34T > A was found in about 15% of FA cases and normal controls but not in patients with FTC. These results suggest a role for MINPP1 in the pathogenesis of at least a subset of malignant follicular thyroid tumors, and MINPP1 might act as a low penetrance predisposition allele for FTC.


   Introduction
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 Abstract
 Introduction
Materials and Methods
 Results
 Discussion
 References
 
FOLLICULAR THYROID TUMORS are a common finding in iodine-deficient areas. By far, the most common tumors are benign follicular thyroid adenomas; only a minority of the tumors are carcinomas. Until today, it is unknown whether an adenoma-carcinoma sequence exists. Data supporting both theories exist (1, 2, 3).

The only known familial syndrome with an increased risk of both benign and malignant follicular thyroid tumors is Cowden syndrome (4). Germline mutations of PTEN, encoding a dual-specificity phosphatase, are found in up to 80% of patients with Cowden syndrome (5, 6), 60% of patients with Bannayan-Riley-Ruvalcaba syndrome (7), and an unknown proportion of patients with a Proteus-like syndrome (8). Although somatic intragenic PTEN mutations are found in only a minority of sporadic follicular thyroid carcinomas (9, 10), loss of heterozygosity (LOH) of markers within 10q23, especially including marker D10S579, has been found in up to 25% of either benign or malignant follicular tumors (9, 10, 11). In another study, fine structure deletion analysis of 10q22–24 demonstrated regions of loss that suggest that follicular adenomas and carcinomas develop along distinct parallel neoplastic pathways (11).

A new gene, MINPP1 (multiple inositol polyphosphate phosphatase), has recently been localized to 10q23.3 in close proximity to marker D10S579 (12). MINPP1, also known as MIPP, has been shown to encode a conserved domain common to histidine phosphatases (12, 13). This 52-kDa enzyme has the ability to remove 3-phosphate from inositol phosphate substrates, such as Ins(1, 3, 4, 5)P4, a function that overlaps that of PTEN even though the sequence similarity of PTEN and MINPP1 is only about 16%. MINPP1 is the only enzyme known to hydrolyze the abundant metabolites inositol pentakisphosphate and inositol hexakisphosphate. Little is known about human MINPP1. It has been shown, however, to be expressed in a wide variety of tissues, including the human thyroid (Gimm, O., and C. Eng, unpublished data). Because of MINPP1’s overlapping function with PTEN and its physical location within a region of LOH for thyroid tumors, it is an excellent candidate gene that could contribute to thyroid tumorigenesis.

Here, we report the results of mutation analysis of MINPP1 in benign and malignant follicular thyroid tumors from an iodine-deficient area. Our data might tentatively suggest a role of MINPP1 in the tumorigenesis of at least a subset of malignant follicular thyroid tumors.


   Materials and Methods
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 Abstract
 Introduction
 Materials and Methods
Results
 Discussion
 References
 
Patients and specimens

Paraffin blocks from 38 unselected benign (n = 23) and malignant (n = 15) follicular thyroid tumors were ascertained from Germany and Switzerland. Three malignant tumors were classified as Hürthle cell carcinoma. All samples were obtained with informed consent. In all 38 samples, tumor tissue and corresponding normal tissue (either normal thyroid tissue from a different block or from an area not in proximity to the tumor, or adjacent muscle tissue distant to the tumor site) were available for extraction of paired somatic and "germline" genomic DNA. DNA extraction following microdissection was performed using standard protocols (14).

Mutation analysis

PCR amplification using genomic DNA as template was carried out in 1x PCR buffer (Perkin-Elmer Corp., Norwalk, CT) containing 200 µM dNTP (Life Technologies, Inc., Gaithersburg, MD), 1 µM of each primer (see Table 1Go), 2.5U Taq polymerase (QIAGEN, Valencia, CA), 0.9 mM MgCl2, 1x Q-buffer (QIAGEN), and 50–100 ng of tumor DNA template in a 50 µL volume. PCR conditions were 35 cycles of 1 min at 95 C, 1 min at 58 C, and 1 min at 72 C followed by 10 min at 72 C. All exons were at least divided into two (a and b) because of their large sizes. Exon 1 had to be divided into three fragments (a–c).


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  		Table 1. MINPP1 primer sequences and PCR-product sizes

 
Mutation analysis for exon 2 (fragments 2a and 2b), exon 3 (fragments 3a and 3b), and exon 6 (fragments 6a and 6b) was performed with DGGE. Exon 1 and exon 4 of MINPP1 are very GC rich and therefore less suitable for DGGE. Hence, mutation analysis for these two exons was performed using SSCP (fragments 1b, 1c, 4a, and 4b). No optimal SSCP condition could be found for the 5' part of exon 1 (fragment 1a) and hence was subjected to direct semiautomated sequence analysis as previously described (5, 15, 16).

Before DGGE, 10 µl of the resulting PCR product were added to 1 µl of Ficoll-based loading buffer. This mixture was loaded onto 10% polyacrylamide gels carrying a 15–65% urea-formamide gradient and a 2–9% glycerol gradient in 0.5 x TAE. The amplicons were electrophoresed at 60 C and 105 V for 16 h. The fragments were visualized with ultraviolet transillumination after staining with ethidium bromide solution (15 µl in 500 ml dH2O) for 30 min.

Before SSCP, 2 µl of the resulting PCR product were added to 3 µl of formamide buffer and then heated to 95 C for 10 min and subsequently cooled on dry ice. Immediately before SSCP, the samples were quickly thawed and then run through a 10% polyacrylamide/1 x TBE gel. Gels were run either at 100 V for 14 h at room temperature (fragments 1b, 4a, 4b) or at 150 V for 16 h at 4 C (fragment 1c). Subsequent silver staining was performed as previously described (17).

Although DGGE is 100% sensitive and specific in this and other laboratory’s hands (18, 19, 20), SSCP is acknowledged not to have the same high sensitivity and specificity (21). Routine quality control for both SSCP and DGGE in our laboratory takes the form of subjecting a known positive and known negative to electrophoresis along with the test samples. Further, three random SSCP negative samples are subjected to direct sequence analysis.

If variant DGGE/SSCP banding patterns were observed, the remaining PCR aliquot was subjected to purification and semiautomated sequencing using the above primers and dye terminator technology (see above). If sequencing revealed a variant, the corresponding germline DNA was examined in the same manner to determine whether the sequence variant is somatic or germline.

The frequencies of these sequence variants in patients with follicular thyroid tumors and in a race-matched control group were determined using peripheral blood leukocyte DNA. This race-matched control group consisted of patients who were admitted to the Department of General Surgery, Halle, Germany, for nonthyroid-related diseases. Informed consent was given in all cases.

LOH analysis

For every germline-tumor pair, PCR reactions were carried out using 0.6 µM each of forward and reverse primer in 1x PCR buffer (QIAGEN), 4.5 mM MgCl2 (QIAGEN), 1x Q-buffer (QIAGEN), 2.5 U HotStarTaq polymerase (QIAGEN), and 200 µM dNTP (Life Technologies, Inc.) in a final volume of 50 µL. Reactions were subjected to 35 cycles of 94 C for 1 min, 55–60 C for 1 min and 72 C for 1 min followed by 10 min at 72 C. LOH analysis for each germline-tumor pair was performed as previously described using markers flanking MINPP1, D10S541 (telomeric), D10S2491 (telomeric) (5, 22), and D10S1686 (centromeric) as well as the marker D10S579 that lies in close proximity to MINPP1 (12). All forward primers were 5'-labeled with either HEX or 6-FAM fluorescent dye (Research Genetics, Inc., Huntsville, AL).

Statistical analysis

Differences in allele frequencies were calculated using the standard Chi-square test. A P value less than 0.05 was considered significant.


   Results
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 Abstract
 Introduction
 Materials and Methods
 Results
Discussion
 References
 
Mutation analysis of all 5 exons of MINPP1 from 38 follicular thyroid tumors revealed variants in 3 exons (fragments 1a, 2b, and 3b). Sequencing revealed one sequence variant each (Table 2Go). Corresponding germline DNA was examined for the presence of each of these variants.


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  		Table 2. Allele frequency of MINPP1 polymorphic sequence variants in patients with follicular thyroid adenoma and follicular thyroid carcinoma and race-matched controls

 
We detected a sequence variant in one carcinoma, c.122C > T (S41L), in the 5' end of exon 1 (fragment 1a) (Fig. 1AGo). This variant was absent in the corresponding germline (DNA from muscle) (Fig. 1BGo) and most likely represents a somatic missense mutation. Repeat PCR and sequencing confirmed the variant and excluded PCR errors. Thus, somatic S41L was found in 1 out of 15 carcinomas (7%).



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  		Figure 1. Sequence variants in MINPP1 identified by DGGE and/or sequencing. A, Sequence variant c.122C > T (S41L) in one follicular thyroid carcinoma. B, Absence of the sequence variant in the corresponding germline. C, DGGE reveals a variant in exon 2 (fragment 2b) in one follicular adenoma. D, Sequencing identifies the variant c.809A > G (Q270R). E, Example for absence of the variant c.809A > G (Q270R) in blood from one control patient. F, DGGE reveals a variant in exon 3 (fragment 3b) in follicular adenomas. G, Sequencing identifies the variant IVS3 + 34T > A. H, Example for absence of the variant c.809A > G (Q270R) in blood from one control patient. Note: Because the forward primers for the fragments 2b and 3b contain the GC-clamp, the reverse primers have been used for sequencing. Hence, the sequences in D, E, G, and H are reverse.

 
The variants in exon 2 (fragment 2b), c.809A > G (Q270R) (Fig. 1Go, C and D) and fragment 3b, IVS3 + 34T > A (Fig. 1Go, F and G) were also present in the germline (data not shown). The heterozygous c.809A > G variant was seen in a patient with follicular thyroid adenoma and was never seen in patients with follicular thyroid carcinoma or in a race-matched control group (Fig. 1EGo and Table 2Goa).

The germline IVS3 + 34T > A variant was underrepresented in cases with follicular thyroid carcinoma (0%), compared with those with adenoma (15%; P < 0.03, Table 2Gob) or normal controls (14%; P < 0.04, Table 2Gob).

LOH analysis within 10q22–24 was performed for all tumor-germline pairs. We found LOH in seven follicular tumors, four carcinomas (27%), and three adenomas (13%). None of the seven follicular adenomas with IVS3 + 34T > A had LOH. Interestingly, the one carcinoma harboring the somatic mutation S41L showed LOH at D10S579, and the flanking markers D10S2491 and D10S1686 were not informative.


   Discussion
Top
 Abstract
 Introduction
 Materials and Methods
 Results
 Discussion
References
 
In the present study, we detected a somatic S41L mutation in MINPP1 together with loss of the corresponding wild-type allele in one follicular thyroid carcinoma. We also found two previously unreported germline sequence variants in MINPP1; one, an intronic variant, is underrepresented in cases with follicular thyroid carcinomas, compared with those with follicular thyroid adenomas or normal controls.

The somatic mutation c.122C > T in tumor DNA from one patient with follicular thyroid carcinoma changes serine, a neutral and polar amino acid, at position 41, to leucine, which is also neutral but hydrophobic. This region is highly conserved among several species (human, rat, mouse) (12, 13). Hence, one can speculate that this polar for hydrophobic amino acid substitution changes the structure of MINPP1. Postulating that MINPP1 might act as a tumor suppressor, its functional activity might subsequently be lost or at least decreased. However, functional analysis would be necessary to confirm this premature hypothesis. Nonetheless, loss of the corresponding wild-type allele in this sample lends credence that the somatic S41L mutation is pathogenic and both MINPP1 alleles inactivated.

The finding of a rare germline sequence variant in one patient with follicular thyroid adenoma is intriguing. This variant was neither observed in 78 control alleles nor found in 36 patients with Cowden syndrome or Bannayan-Riley-Ruvalcaba syndrome (23). One may speculate that this variant, which leads to substitution of a neutral and polar amino acid for a basic amino acid, affects the function of MINPP1. Whether this hypothetical change of MINPP1 function plays a role in the pathogenesis of follicular thyroid adenomas must remain unresolved at this point. Histological appearance did not show any unusual features. Also, there was no family history of follicular thyroid adenomas, but no germline DNA was available from any relative.

The absence of the relatively frequent intronic polymorphic sequence variant IVS3 + 34T > A in follicular thyroid carcinoma patients is intriguing. Even though our numbers are small, at least one or two follicular thyroid carcinomas harboring this sequence variant should have been detected: power calculations reveal that if only 10% of 30 alleles have this variant, our power to detect this in at least one case would exceed 0.92. We also screened 30 patients with breast cancer for variation in MINPP1 and found about the same frequency (12%) of this polymorphism as found in patients with FA (15%) and controls (14%) (Gimm, O., and C. Eng, unpublished data). Of note, this intronic polymorphism lies on the border of a poly-T/poly-A/poly-T tract. There is some evidence that poly-N tracts may play important roles in RNA splicing and processing (24, 25). Recently,it has become more evident that development of a cancer can result froman interplay of either a few "high penetrance" mutations in key genes or from several, or many, sequence variants presently of unknown significance. For example, overrepresentation of a rare sequence variant of RET has been observed in patients with sporadic medullary thyroid carcinoma (26). Similar observations have been made for polymorphic sequence variants of RET in patients with HSCR (27, 28), Cul2 in sporadic pheochromocytomas (29), and PPARgamma in isolated glioblastoma multiforme cases (30). However, the precise mechanism to explain how the intronic sequence variant could "protect" or at least lower the chance of developing follicular thyroid carcinoma is unknown and open to speculation. Possibly, this intronic change affects a splice-donor or splice-acceptor site or enhances a cryptic splice site, which would subsequently lead to a different protein. Unfortunately, complementary DNA was not available to test this hypothesis. The absence of this polymorphism in patients with follicular thyroid carcinoma may also support the hypothesis that follicular thyroid adenomas and carcinomas do not adhere to an adenoma-carcinoma sequence. Fine-structure deletion mapping of 10q22–24 also suggests that sporadic follicular thyroid adenomas and follicular thyroid carcinomas develop along distinct neoplastic pathways (11).

In conclusion, our observations suggest a role for MINPP1 in the tumorigenesis of malignant follicular thyroid carcinoma. Although it may infrequently contribute to follicular carcinogenesis via the traditional pathway of somatic high penetrance, two-hit (31) mutations, this gene seems to harbor a variant that could act as a common low penetrance susceptibility allele for follicular thyroid carcinoma. Further, the DGGE and SSCP conditions reported here together with the knowledge of the frequency of various sequence variants may help in future mutation analyses of DNA from other cancers with LOH in the 10q23 region in which PTEN does not seem to play a major role, such as head and neck carcinomas, lung cancer, and melanomas (32).


   Footnotes
 
1 This work was supported in part by the Department of Defense U.S. Army Breast Cancer Research Program (DAMD17-00-1-0390 to C.E.) and the National Cancer Institute (P30CA16058 to The Ohio State University Comprehensive Cancer Center). Back

2 Recipient of a postdoctoral fellowship from the Susan G. Komen Breast Cancer Research Foundation (to C.E.). Back

Received December 27, 1999.

Revised November 29, 2000.


   References
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 Abstract
 Introduction
 Materials and Methods
 Results
 Discussion
 References
 

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