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RET Oligonucleotide Microarray for the Detection of RET Mutations in Multiple Endocrine Neoplasia Type 2 Syndromes¹

Familial Cancer Clinic, National Cancer Center, Gyeonggi 411-764, Korea [J-G. P., J-S. L.]; Korean Hereditary Tumor Registry, Laboratory of Cell Biology, Cancer Research Center and Cancer Research Institute, Seoul National University College of Medicine, Seoul, Korea 110-744 [I-J. K., H. C. K., J-H. P., J-L. K., H-J. K., K-A. Y., H-Y. Y., J-G. P.]; Departments of Surgery [S. C. H., S. K. O., Y-K. Y.] and Internal Medicine [B. Y. C., S. Y. K., D-J. P.], Seoul National University College of Medicine, Seoul, Korea 110-744; Department of Medicine, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Korea 135-230 [M-S. L.]; and Department of Internal Medicine, The Catholic University College of Medicine, Seoul, Korea 137-070 [K-W. L.]

Multiple endocrine neoplasia type 2 (MEN2) syndromes are inherited in an autosomal dominant fashion with high penetrance. There are three subtypes, namely, MEN2A (multiple endocrine neoplasia type 2A), MEN2B (multiple endocrine neoplasia type 2B), and familial medullary thyroid carcinoma. The variations in the RET gene play an important role in the MEN2 syndromes. In this work, we have developed a RET oligonucleotide microarray of 67 oligonucleotides to quickly detect RET mutations in MEN2 syndromes. The predominant RET mutations are missense mutations and are restricted to nine codons (codons 609, 611, 618, 620, 630, 634, 768, 804, and 918) in MEN2 syndromes. Missense mutations at codons 609, 611, 618, 620, and 634 have been identified in 98% of MEN2A families and in 85% of familial medullary thyroid carcinoma families. More than 95% of MEN2B patients also had a predominant mutation type at codon 918 (Met Thr). RET oligonucleotide microarray can detect RET missense mutations at these nine codons. Theoretically, a total of 55 missense mutation types can occur at eight codons (codons 609, 611, 618, 620, 630, 634, 768, and 804). RET oligonucleotide microarray is designed to detect all of these 55 missense mutation types at these eight codons and one predominant type at codon 918. Fifty-six oligonucleotides were designed for the 56 mutation types at nine codons, and 11 oligonucleotides were designed for the wild types and positive controls. We found RET mutations in all eight of the Korean MEN2A families (a total of 75 members; 27 affected members, 19 gene carriers, and 29 unaffected members) using the developed RET oligonucleotide microarray and an automatic sequencing. Because we found only five mutation types from eight MEN2A families, the international collaborations are required to see whether the RET oligonucleotide microarray may be used as a genetic diagnostic tool. Taken together, the RET oligonucleotide microarray can function as a fast and reliable genetic diagnostic device, which simplifies the process of detecting RET mutations.

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