This Article Full Text Full Text (PDF) Supplemental Data Submit a related Letter to the Editor Alert me when this article is cited Alert me when eLetters are posted Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Request Copyright Permission Citing Articles Citing Articles via Google Scholar Google Scholar Articles by Cavaco, B. M. Articles by Leite, V. Search for Related Content PubMed PubMed Citation Articles by Cavaco, B. M. Articles by Leite, V. Related Collections Thyroid Endocrine Oncology

Mapping a New Familial Thyroid Epithelial Neoplasia Susceptibility Locus to Chromosome 8p23.1-p22 by High-Density Single-Nucleotide Polymorphism Genome-Wide Linkage Analysis

Centro de Investigação de Patobiologia Molecular (B.M.C., P.F.B., V.L.) and Serviço de Endocrinologia (L.G.S., V.L.), Instituto Português de Oncologia de Lisboa Francisco Gentil, 1099-023 Lisboa, Portugal; Faculdade de Ciências Médicas da Universidade Nova de Lisboa (L.G.S., V.L.), 1169-056 Lisboa, Portugal; and Instituto de Medicina Molecular (B.M.C.), Faculdade de Medicina de Lisboa, 1600-190 Lisboa, Portugal

Address all correspondence and requests for reprints to: Branca M. Cavaco, Ph.D., Centro de Investigação de Patobiologia Molecular (CIPM), Instituto Português de Oncologia de Lisboa Francisco Gentil, 1099-023 Lisbon, Portugal. E-mail: bcavaco{at}ipolisboa.min-saude.pt.

Context: Familial nonmedullary thyroid carcinoma (FNMTC) accounts for approximately 5% of all thyroid tumors. Genetic mapping studies have identified four different chromosomal regions predisposing to FNMTC: fPTC/PRN (1p13.2-1q22), NMTC1 (2q21), MNG1 (14q32), and TCO (19p13.2).

Objective: Our objective was to map the gene predisposing to familial thyroid epithelial neoplasia in a large Portuguese family.

Methods and Results: The clinical screening of a Portuguese family identified 11 members affected with benign thyroid lesions and five affected with thyroid carcinomas. Linkage analysis excluded the involvement of the fPTC/PRN, NMTC1, MNG1, and TCO loci. To map the gene predisposing to thyroid epithelial neoplasia in this family, a genome-wide linkage analysis was conducted, using DNA samples from 17 family members and high-density single-nucleotide polymorphism arrays. A genome-wide significant evidence of linkage, to a single region on chromosome 8p23.1-p22 was obtained, with a maximum parametric haplotype-based LOD score of 4.41 ( = 0.00). Linkage analysis with microsatellite markers confirmed linkage to 8q23.1-p22, and recombination events delimited the minimal region to a 7.46-Mb span. Seventeen suggestive candidate genes located in the minimal region were excluded as susceptibility genes by mutational analysis. Allelic losses in the 8p23.1-p22 region were absent in seven thyroid tumors from family members, suggesting that the inactivation of a putative tumor suppressor gene may have occurred through other mechanisms.

Conclusions: Our results present evidence for the existence of a novel familial thyroid epithelial neoplasia susceptibility locus on chromosome 8p23.1-p22, providing the basis for the identification of a gene for this disease.