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

Abstract

Rearrangements involving the RET gene are common in radiation-associated papillary thyroid cancer (PTC). The RET/PTC1 type of rearrangement is an inversion of chromosome 10 mediated by illegitimate recombination between the RET and the H4 genes, which are 30 megabases apart. Here we ask whether despite the great linear distance between them, RET and H4 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 RET and H4 loci within interphase nuclei. At least one pair of RET and H4 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 RET and H4 may provide a structural basis for generation of RET/PTC1 rearrangement by allowing a single radiation track to produce a double-strand break in each gene at the same site in the nucleus.

Mammary Analogue Secretory Carcinoma of the Parotid Gland as a Secondary Malignancy in a Childhood Survivor of Atypical Teratoid Rhabdoid Tumor

“…It has been shown that RET translocation partners like the H4 gene are in close spatial continuity during interphase. With radiation induced breakage enabling rearrangement between RET and H4, this results in the RET/PTC1 fusion gene seen in R-PTC [14]. A similar mechanism is possible with MASC, where the ETV6-NTRK3 fusion product is the result of similar spatial continuity during interphase.…”

RET rearrangements in post-Chernobyl papillary thyroid carcinomas with a short latency analysed by interphase FISH

“…Cells in which there was only one signal were excluded from analysis to avoid any artefacts owing to section preparation. In an earlier study, it has been demonstrated that in 35% of normal human thyroid cells at least one pair of RET and H4 signals were juxtaposed detected by FISH analysis (Nikiforova et al, 2000). Thus, a significant number of tumour cells with RET/PTC rearrangement might be misclassified, which is dependent on the interphase arrangement of chromosome 10 in the tumour nuclei and the linear distance between RET and the partner gene.…”

“…To avoid this problem, we have used in our study a different FISH approach showing overlapping FISH signals in normal nuclei and split signals only when the RET gene is disturbed. This approach avoids confusion caused by the interphase arrangements of chromosome 10 as described by Nikiforova et al (2000). We also have performed a series of control studies that argue against artefacts (caused by the nuclear arrangement of chromosome 10 or by formalin fixation).…”

The role of nuclear organization in cancer

“…Furthermore, the frequency of observed recurrent gene fusions arising from translocations in cancer cells correlates with the frequency of side-by-side pairing of the relevant genes in normal control cells. These include BCR and ABL (fused in chronic myeloid leukaemia); PML and RARA (acute promyelocytic leukaemia); MYC and IGH, IGK or IGL (B cell leukaemia/lymphoma); IGH and CCND1, BCL2 or BCL6 (B cell leukaemia/lymphoma) [43][44][45][46][47][48].…”