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Alternative Genetic Pathways in Parathyroid Tumorigenesis¹

Departments of Molecular Medicine Endocrine Tumor Unit (F.F., S.K., B.T.T., F.K.W., C.L.), Clinical Pathology (A.H.), and Surgery (L.O.F., K.S.) Karolinska Hospital, SE-171 76 Stockholm, Sweden; Molecular Genetics Unit, Kolling Institute of Medical Research, Royal North Shore Hospital (T.D.), Sydney 0265, Australia; the Department of Surgery, Huddinge Hospital (M.E.), SE-14186 Huddinge, Sweden; the Department of Clinical Biochemistry, King’s College School of Medicine and Dentistry (W.S.W.), London SE59PJ, United Kingdom; and the Department of Surgery, University of Michigan Hospital (N.W.T.), Ann Arbor, Michigan 48109

Address all correspondence and requests for reprints to: Dr. Filip Farnebo, Department of Molecular Medicine, Endocrine Tumor Unit, Karolinska Hospital CMM L8:01, SE-171 76 Stockholm, Sweden.

In this study 44 parathyroid tumors from 26 sporadic cases, 10 cases previously given irradiation to the neck, and 8 familial cases were screened for sequence copy number alterations by comparative genomic hybridization. In the sporadic adenomas, commonly occurring minimal regions of loss could be defined to chromosome 11 (38%), 15q15-qter (27%), and 1p34-pter (19%), whereas gains preferentially involved 19p13.2-pter (15%) and 7pter-qter (12%). Multiple aberrations were found in sporadic tumors with a somatic mutation and/or loss of heterozygosity of the MEN1 gene. The irradiation-associated tumors also showed multiple comparative genomic hybridization alterations and frequent losses of 11q (50%), and subsequent analysis of the MEN1 gene demonstrated mutations in 4 of 8 cases (50%). The adenomas from familial cases showed few alterations, and in 3 of these tumors a gain of 19p13.2-pter was seen as the only aberration. In this study numerical copy number alterations were frequently detected in sporadic and irradiation-associated parathyroid adenomas, although these tumors are benign. The majority of these alterations were found in tumors with confirmed involvement of the MEN1 gene locus in agreement with a role of the MEN1 gene in genomic stability. Furthermore, the frequent occurrence of MEN1 mutations (50%) in irradiation-associated parathyroid tumors suggests that inactivation of the MEN1 gene is an important genetic alteration involved in the development of parathyroid tumors in postirradiation patients.

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