As mentioned in the note added in proof, a recent paper by Engreitz et al. [1] argues that three-dimensional genome architecture influences partner selection for chromosomal translocations. However, our results in this paper [2] suggest that, at least for ‘driver’ mutations, this effect is negligible considering the strength of oncogenic selection and expansion of the clone with a genetic lesion.

The fact that spatial proximity influences the frequencies of chromosomal rearrangement events was shown recently for a model B-cell system without positive selection [3, 4]. Notably, it was shown that proximity effects were very small compared to the effects induced by spikes of chromosomal breakage in genomic regions related to immunoglobulin gene rearrangement [3]. Only by saturating DSB frequency using ionizing radiation did the pattern of chromosomal translocations start to resemble the pattern of chromosomal contacts [4]. Characteristic chromosomal rearrangements are also originated by induced spatial proximity in prostate cancer [5].

However, in these cases fusion genes are also under the influence of oncogenic selection. Fusions with immunoglobulin genes increase transcription of the fusion gene [6] due to the action of an immunoglobulin enhancer. In case of prostate cancer, TMPRSS2-ERG fusion includes an androgen-responsive gene (TMPRSS2) which is highly expressed in prostate and thus leads to overexpression of ERG [7]. These examples emphasize that mutations resulting in cancer generally happen in rare cells and must be able to drive the process of transformation by evading multiple tumor-suppressor mechanisms [8]. This raises the question of whether the recurrent detection of tumorigenic rearrangements reflects their exceptional capacity to confer growth advantage, while the physical process of translocation formation plays little role in modulating recurrence [9].

In order to explore the discrepancy between our findings and the results of Engreitz et al. we have performed some additional analyses (available as a pdf file at www.unav.es/genetica/hall...) replicating their data. We show that using chromosomal bands (instead of the actual gene pairs at 1-Mb resolution afforded by HiC, as we have done in our paper) and using all translocations reported in Mitelman database (instead of only those for which both partner genes have been identified) might explain our different conclusions regarding genome organization and partner selection in chromosomal translocations.

CITATIONS
1. Engreitz JM, Agarwala V, Mirny LA. Three-dimensional genome architecture influences partner selection for chromosomal translocations in human disease. PLoS One. 2012;7(9):e44196. doi: 10.1371/journal.pone.0044196. Epub 2012 Sep 28. PMID: 22341456
2. Shugay M, Ortiz de Mendíbil I, Vizmanos JL, Francisco J. Novo FJ. Genomic Hallmarks of Genes Involved in Chromosomal Translocations in Hematological Cancer. PLoS Comput Biol. 2012 Dec;8(12): e1002797. doi:10.1371/journal.pcbi.1002797.
3. Klein IA, Resch W, Jankovic M, Oliveira T, Yamane A, Nakahashi H, Di Virgilio M, Bothmer A, Nussenzweig A, Robbiani DF, Casellas R, Nussenzweig MC. Translocation-capture sequencing reveals the extent and nature of chromosomal rearrangements in B lymphocytes. Cell. 2011 Sep 30;147(1):95-106. PMID: 19962179
4. Zhang Y, McCord RP, Ho YJ, Lajoie BR, Hildebrand DG, Simon AC, Becker MS, Alt FW, Dekker J. Spatial organization of the mouse genome and its role in recurrent chromosomal translocations. Cell. 2012 Mar 2;148(5):908-21. doi: 10.1016/j.cell.2012.02.002. Epub 2012 Feb 16. PMID: 22341456
5. Mani RS, Tomlins SA, Callahan K, Ghosh A, Nyati MK, Varambally S, Palanisamy N, Chinnaiyan AM. Induced chromosomal proximity and gene fusions in prostate cancer. Science. 2009 Nov 27;326(5957):1230. Epub 2009 Oct 29. PMID: 19933109
6. Xiang H, Noonan EJ, Wang J, Duan H, Ma L, Michie S, Boxer LM. The immunoglobulin heavy chain gene 3' enhancers induce Bcl2 deregulation and lymphomagenesis in murine B cells. Leukemia. 2011 Sep;25(9):1484-93. doi: 10.1038/leu.2011.115. Epub 2011 May 24. PMID: 21606958
7. Casey OM, Fang L, Hynes PG, Abou-Kheir WG, Martin PL, Tillman HS, Petrovics G, Awwad HO, Ward Y, Lake R, Zhang L, Kelly K. TMPRSS2-driven ERG expression in vivo increases self-renewal and maintains expression in a castration resistant subpopulation. PLoS One. 2012;7(7):e41668. Epub 2012 Jul 30. PMID: 22860005
8. Hanahan D, Weinberg RA. Hallmarks of cancer: the next generation. Cell. 2011 Mar 4;144(5):646-74. PMID: 21376230
9. Wijchers PJ, de Laat W. Genome organization influences partner selection for chromosomal rearrangements. Trends Genet. 2011 Feb;27(2):63-71. Epub 2010 Dec 7. PMID: 21144612