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Are There Any Critiques of This Paper?
Overall Garraway et al. did a good job of synthesizing a huge amount of data into a short Nature paper. The paper really sets out to be the first, and really to open a new line of research, which I think it accomplishes. It is clear that Garraway et al. intend this paper to illustrate the potential for genome sequencing of prostate tumors, rather than to actually draw too many conclusions from the sequencing they performed. The language they use (“suggest a link” and “may reflect”) is a direct result of this goal, which is not to determine THE genomic cause of prostate cancer. The most glaring problem with this paper is a result of their exceptionally large set of data. Figures 1 and especially 2 (of the paper) are difficult to read because there is so much information, but the diagrams are so small. Even enlarged on my computer, I am still not sure I am seeing all of Figure 2b (of the paper).
What Can We Do With This Information?
The high number of gene fusions observed in the seven prostate tumors sequenced brings the role of chromosomal rearrangement in cancer development to the forefront. Obviously the ultimate goal of whole genome sequencing is the potential for specialized treatments. The focus of this paper was primarily to pave the way for future research. The Prostate Cancer Foundation described the publication as a “Lewis and Clark moment” because “a great journey begins with a small step.” In the future, as more prostate cancer genomes are sequenced, different rearrangements may become more meaningful. The Circos plot of patient PR-0508 may look similar to that of a new prostate cancer patient, thus treatments that worked for PR-0508 might be the first, and most effective, choice for this new patient. Typically the sooner effective treatment begins, the better, therefore anything that helps indicate what the most effective treatment would be is a great advancement.
Further research is needed to fully utilize whole genome sequencing. A sample of just seven patients is not a large enough sample size for meaningful correlations between genomic rearrangements and treatment. Another problem is that Garraway et al. specifically chose patients with aggressive stage T2c tumors, with a Gleason grade of 7 or higher. Choosing patients with advanced tumors was a wise decision, because it is likely that their genomes contain more deviation from the standard, which results in more data. However less aggressive forms of prostate cancer exist, and sequencing the genomes of those tumors is just as important. By looking at differences between the two we can determine not only what may be the root of prostate cancer in general, but what causes some forms to be so deadly, while others remain quiet for years.
References
Lin,C.et al.Nuclear receptor-induced chromosomal proximity and DNA breaks underlie specific translocations in cancer.Cell139, 1069–1083 (2009).
Garraway, Levi A, et al. The genomic complexity of primary human prostate cancer. Nature 470 (2011): 214-220.