Genome organization in proximity to the BAP1 locus appears to play a pivotal role in a variety of cancers.

ABSTRACT

Cancer studies primarily focus on the characterization of the key driver genes and the underlying pathways. However, the contribution of other cancer-associated genes located in the genomic neighborhood of the driver genes could help to understand further aspects of cancer progression. Given the frequent involvement of chromosome 3 in multiple human cancers, in particular in the form of the prognostically highly relevant monosomy 3 in uveal melanoma (UM), we investigated the cumulative impact of cancer-associated genes on chromosome 3. Our analysis showed that these genes are enriched with repetitive elements with genes surrounded by distinctive repeats (MIR, hAT-Charlie, ERVL-MaLR, LINE-2, and simple/low complexity) in the promoter being more precisely associated with cancer-related pathways than the ones with major transposable elements (SINE/Alu and LINE-1). Additionally, these genes showed strong intrachromosomal chromatin interactions in 3D nuclear organization. Further investigations revealed a genomic hotspot in the vicinity of BAP1 locus, which is affected in 27 types of different cancers and contains abundant noncoding RNAs that are often expressed in a tissue-specific manner. The cross-species comparison of these cancer-associated genes revealed mostly a shared synteny in closer primates. However, near to the BAP1 locus signs of chromosomal inversions were observed during the course of evolution. To our knowledge, this is the first study to characterize the entire genomic neighborhood of cancer-associated genes located on any single chromosome. Based on our results, we hypothesize that monosomy of chromosome 3 will have important clinical and molecular consequences in the respective diseases and in particular in UM.