Proximity of Chromosomal Loci That Participate in Radiation-Induced Rearrangements in Human Cells

<jats:p> Rearrangements involving the <jats:italic>RET</jats:italic> gene are common in radiation-associated papillary thyroid cancer (PTC). The <jats:italic>RET</jats:italic> /PTC1 type of rearrangement is an inversion of chromosome 10 mediated by illegitimate recombination between the <jats:italic>RET</jats:italic> and the <jats:italic>H4</jats:italic> genes, which are 30 megabases apart. Here we ask whether despite the great linear distance between them, <jats:italic>RET</jats:italic> and <jats:italic>H4</jats:italic> recombination might be promoted by their proximity in the nucleus. We used two-color fluorescence in situ hybridization and three-dimensional microscopy to map the positions of the <jats:italic>RET</jats:italic> and <jats:italic>H4</jats:italic> loci within interphase nuclei. At least one pair of <jats:italic>RET</jats:italic> and <jats:italic>H4</jats:italic> was juxtaposed in 35% of normal human thyroid cells and in 21% of peripheral blood lymphocytes, but only in 6% of normal mammary epithelial cells. Spatial contiguity of <jats:italic>RET</jats:italic> and <jats:italic>H4</jats:italic> may provide a structural basis for generation of <jats:italic>RET</jats:italic> /PTC1 rearrangement by allowing a single radiation track to produce a double-strand break in each gene at the same site in the nucleus. </jats:p>