8q24 prostate, breast, and colon cancer risk loci show tissue-specific long-range interaction with MYC

Abstract

The 8q24 gene desert contains risk loci for multiple epithelial cancers, including colon, breast, and prostate. Recent evidence suggests these risk loci contain enhancers. In this study, data are presented showing that each risk locus bears epigenetic marks consistent with enhancer elements and forms a long-range chromatin loop with the MYC proto-oncogene located several hundred kilobases telomeric and that these interactions are tissue-specific. We therefore propose that the 8q24 risk loci operate through a common mechanism-as tissue-specific enhancers of MYC.

Fig. 1.

Epigenetic annotation of cancer risk loci at chromosome 8q24 is consistent with enhancer activity. (Top) The 800-kb region of 8q24 containing prostate, breast, and colon cancer risk loci and the MYC proto-oncogene. (Middle) Approximately 6-kb segments within the risk loci, which bear the epigenetic marks of histone acetylation (8). The red bars represent the restriction fragments analyzed by 3C for their interactions with MYC. The purple bars encompass the segment interrogated with tiled primers for ChIP-qPCR. (Bottom) Fold enrichment by ChIP-qPCR for histone 3 lysine 4 dimethylation (H3K4me2) and for p300, ±1 SD.

Fig. 2.

8q24 region and 3C interaction frequency of risk loci with MYC: x axis: genomic position (not drawn to scale); y axis: 3C interaction frequency ±1 SEM of the constant fragment with each of the target fragments including MYC, normalized to a 3C interaction within a housekeeping gene, FAM32A. (A) Schematic depicting the 8q24 risk loci in relation to the closest genes, as well as the locations of the constant fragments (red ticks) and target fragments (black ticks) interrogated; (B) normalized 3C interaction frequency of colon cancer risk locus (red line plot) and prostate cancer region 2 (blue line plot) in a colon cancer cell line—LS174T; (C) normalized 3C interaction frequency of breast cancer risk locus (yellow line plot) and prostate cancer region 2 (blue line plot) in a breast cancer cell line—MCF-7; (D) normalized 3C interaction frequency of prostate cancer region 2 (blue line plot) and breast cancer risk region (yellow line plot) in a prostate cancer cell line—LNCaP. Vertical hatched lines denote genomic positions of respective constant fragments (color-coded).