Complete sequencing of mitochondrial DNA has been carried out on all tumor biopsies collected at Bellaria hospital (Unit 1). Complete sequence has been obtained for 20 breast carcinomas, 16 gliomas, 21 non-oncocytic thyroid carcinomas and 25 oncocytic thyroid carcinomas. It was possible to obtain more than 98% of the mtDNA sequence from 20 additional oncocytic samples utilizing DNA extracted from formalin fixed tissue. Twelve of the 45 thyroid oncocytomas presented disruptive (nonsense and frameshift) mutations in complex I subunits and 18 presented potentially pathogenic missense mutations. Five breast carcinomas also presented potentially pathogenic mutations and 3 were reclassified as oncocytic after immunohistological analysis. Only 3 samples among the non oncocytic tumors presented disruptive mutations, suggesting a role for complex I in the development of oncocytic tumors. The correlation between occurrence of disruptive mutations and oncocytic phenotype was found to be statistically significant (p<0.05) when oncocytic tumors were compared to non-oncocytic tumors. Systematic screening for mutations in the fourteen genes genes mapping to the region of linkage in affected TCO members has been undertaken. We identify two novel variants respectively in exon 9 and exon 13 of TIMM44, a mitochondrial inner membrane translocase for the import in the mitochondria of nuclear-encoded proteins. These variants were co-segregating with the TCO phenotype, were not present in a large group of controls and were predicted to negatively affect the protein (exon 9 change) or the transcript (exon 13 change). Functional analysis was performed in vitro for both changes and although no dramatic loss of function effects were identified for the mutant alleles, subtler effects might still be present that could alter Timm44 function and thus promote oncocytic tumor development. Thus we suggest that TIMM44 should be considered for further studies in independent samples of affected individuals with TCO.
Functional genomics of thyroid oncocytoma / G. Tallini; G. Romeo; M. Rugolo. - (2005).
Functional genomics of thyroid oncocytoma
TALLINI, GIOVANNI;ROMEO, GIOVANNI;RUGOLO, MICHELA
2005
Abstract
Complete sequencing of mitochondrial DNA has been carried out on all tumor biopsies collected at Bellaria hospital (Unit 1). Complete sequence has been obtained for 20 breast carcinomas, 16 gliomas, 21 non-oncocytic thyroid carcinomas and 25 oncocytic thyroid carcinomas. It was possible to obtain more than 98% of the mtDNA sequence from 20 additional oncocytic samples utilizing DNA extracted from formalin fixed tissue. Twelve of the 45 thyroid oncocytomas presented disruptive (nonsense and frameshift) mutations in complex I subunits and 18 presented potentially pathogenic missense mutations. Five breast carcinomas also presented potentially pathogenic mutations and 3 were reclassified as oncocytic after immunohistological analysis. Only 3 samples among the non oncocytic tumors presented disruptive mutations, suggesting a role for complex I in the development of oncocytic tumors. The correlation between occurrence of disruptive mutations and oncocytic phenotype was found to be statistically significant (p<0.05) when oncocytic tumors were compared to non-oncocytic tumors. Systematic screening for mutations in the fourteen genes genes mapping to the region of linkage in affected TCO members has been undertaken. We identify two novel variants respectively in exon 9 and exon 13 of TIMM44, a mitochondrial inner membrane translocase for the import in the mitochondria of nuclear-encoded proteins. These variants were co-segregating with the TCO phenotype, were not present in a large group of controls and were predicted to negatively affect the protein (exon 9 change) or the transcript (exon 13 change). Functional analysis was performed in vitro for both changes and although no dramatic loss of function effects were identified for the mutant alleles, subtler effects might still be present that could alter Timm44 function and thus promote oncocytic tumor development. Thus we suggest that TIMM44 should be considered for further studies in independent samples of affected individuals with TCO.I documenti in IRIS sono protetti da copyright e tutti i diritti sono riservati, salvo diversa indicazione.
