1. ¹IPATIMUP-Institute of Molecular Pathology and Immunology of the University of Porto, Rua Dr Roberto Frias s/n, 4200-465 Porto, Portugal
2. ²Department of Surgery, Hospital São João, Porto, Portugal
3. ³Department of Pathology, Medical Faculty of Porto, Porto, Portugal
4. ⁴Department of Pathology, Portuguese Oncology Institute, Porto, Portugal
5. ⁵Department of Endocrinology, Portuguese Oncology Institute, Porto, Portugal
6. ⁶Pathology Service, 'Dr A Onãtivia' Hospital, Salta, Argentina
7. ⁷Strangeways Research Laboratory, University of Cambridge, Cambridge, UK
8. ⁸Department of Pathology, Hospital São João, Porto, Portugal

Correspondence: Dr M Sobrinho-Simões, IPATIMUP-Institute of Molecular Pathology and Immunology of the University of Porto, Rua Dr Roberto Frias s/n, 4200-465 Porto, Portugal. E-mail: ssimoes@ipatimup.pt

Received 23 November 2004; Revised 18 February 2005; Accepted 28 February 2005; Published online 19 April 2005.

Abstract

Oxyphil or Hürthle cell tumours of the thyroid are characterised by their consistent excessive number of mitochondria. A recently discovered gene, GRIM-19 has been found to fulfil two roles within the cell: as a member of the interferon- and retinoic acid-induced pathway of cell death, and as part of the mitochondrial Complex I assembly. In addition, a gene predisposing to thyroid tumours with cell oxyphilia (TCO) has been mapped to chromosome 19p13.2 in one family. A cluster of genes involved in mitochondrial metabolism occurs in this region; one of these is GRIM-19. We have searched for GRIM-19 mutations in a series of 52 thyroid tumours. Somatic missense mutations in GRIM-19 were detected in three of 20 sporadic Hürthle cell carcinomas. A germline mutation was detected in a Hürthle cell papillary carcinoma arising in a thyroid with multiple Hürthle cell nodules. No mutations were detected in any of the 20 non-Hürthle cell carcinomas tested, nor in any of 96 blood donor samples. In one of the sporadic Hürthle cell papillary carcinomas positive for GRIM-19 mutation, we have also detected a ret/PTC-1 rearrangement. No GRIM-19 mutations were detected in any of the six cases of known familial Hürthle cell tumour tested, so that our results do not support the identification of GRIM-19 as the TCO gene. The GRIM-19 mutations we have detected are the first nuclear gene mutations specific to Hürthle cell tumours to be reported to date; we propose that such mutations can be involved in the genesis of sporadic or familial Hürthle cell tumours through the dual function of GRIM-19 in mitochondrial metabolism and cell death.