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Somatic Deletions and Mutations in the Cowden Disease Gene, PTEN, in Sporadic Thyroid Tumors¹

Translational Research Laboratory, Human Cancer Genetics Unit, Department of Adult Oncology, Dana-Farber Cancer Institute, Department of Medicine, Harvard Medical School, Boston, Massachusetts 02115-6084 [P. L. M. D., D. J. M., Z. Z., C. E.]; Departments of Molecular Medicine and Surgery, Karolinska Hospital, Stockholm S104 01, Sweden [J. Z., T. F., G. W., C. L.]; Department of Pathology, University of Zürich, Zürich CH-8091, Switzerland [P. K.]; Department of Pathology, Columbia University Cancer Center, New York, New York 10021 [R. P.]; Division of Molecular Oncology, Institut Bergonié, 33076 Bordeaux, France [M. L.]; and Cancer Research Campaign Human Cancer Genetics Research Group, University of Cambridge, Cambridge CB2 2QQ, United Kingdom [C. E.]

The majority of familial medullary thyroid neoplasms are associated with germ-line mutations of the RET proto-oncogene, yet very little is known about the mechanisms involved in the pathogenesis of familial and sporadic nonmedullary thyroid tumors. A subset of thyroid tumors have loss of heterozygosity of chromosome 10q22–23, a region harboring the gene responsible for Cowden disease, an autosomal dominant hamartoma syndrome associated with thyroid and breast tumors. PTEN/MMAC1/TEP1 codes for a dual-specificity phosphatase and is likely a tumor suppressor gene. We sought to determine the PTEN status in a series of epithelial thyroid neoplasms. We studied 95 sporadic thyroid tumors, of which 39 were papillary thyroid carcinomas (PTCs), 12 were follicular carcinomas, 9 were anaplastic carcinomas, 5 were Hürthle cell carcinomas, 21 were nonfunctioning follicular adenomas, and 9 were Hürthle cell adenomas. Direct sequencing of PCR-amplified products was performed for all nine exons of PTEN. Two polymorphic markers, one located in intron 8 and another, a dinucleotide repeat marker, AFMa086wg9, located within intron 2, were analyzed in paired blood-tumor DNA samples to assess hemizygous deletions of PTEN. We found a somatic frameshift mutation in one PTC, which was expected to generate a premature stop codon 2 amino acids downstream. Twenty-six % of informative benign tumors (four follicular adenomas and three Hürthle cell adenomas) and only 3 of 49 (6.1%) informative malignant tumors (one PTC, one follicular carcinoma, and one anaplastic carcinoma) showed evidence of hemizygous deletion of PTEN (P = 0.046). We conclude that a subset of thyroid tumors have somatic deletions of the PTEN gene, predominantly the benign forms, and that small intragenic mutations of PTEN are infrequent in thyroid tumors. We speculate that other mechanisms of PTEN inactivation, rather than small intragenic mutations, might occur in the hemizygously deleted samples and act as the "Knudson second hit." Alternatively, other tumor suppressor genes mapping to chromosome 10q22–23 could be the actual targets for such deletions and thus represent the various hits in the pathway of multistep carcinogenesis.

¹ This work was supported by the American Cancer Society Grant RPG-97-064-01-VM, a Young Scientist Award from the Markey Charitable Trust, the Barr Investigatorship, and the Lawrence and Susan Marx Investigatorship (to C. E.).

² To whom requests for reprints should be addressed, at Dana-Farber Cancer Institute, 44 Binney Street, Boston, MA 02115-6084. Phone: (617) 632-5632; Fax: (617) 532-4280; E-mail: charis_eng@macmailgw.dfci.harvard.edu.

Received 8/ 7/97. Accepted 9/15/97.

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