How normal is normal? Surprising mutations in normal-looking prostate tissue

Series on Tumor Evolution

“Analysis of the genetic phylogeny of multifocal prostate cancer identifies multiple independent clonal expansions in neoplastic and morphologically normal prostate tissue,” is the title of another recent paper that caught my attention.

I like long titles, because they often already contain the full story without the bothersome detail of the rest of the paper. Let’s look at the pieces of this one; two things stand out:

First of all, prostate cancer is generally multifocal, which means that cancer develops in different regions of the prostate, and the authors have found independent clonal expansions for these different foci. So it is not that the cancer started in one spot and then spread, these different tumors in the prostate developed independently from each other.

Morphologically normal is not always genetically normal

Second, and that is for me the highlight of the paper, the authors found a surprising number of mutations in tissue that didn’t look like cancer tissue but exactly like normal tissue – they call it morphologically normal. And this not-so-normal tissue could even be distant from the cancer:

Somatic mutations, not present in cancer and blood samples, were observed at notable levels in morphologically normal prostate tissue distant from cancer (…)

So we are dealing here with three ‘compartments’ in the prostate:

Mutations in morphologically normal tissue

Looks like normal tissue and shows only germline variation. Looks like normal tissue but has somatic mutations. Looks like cancer and -as expected- has lots of somatic mutations.

I will call the morphologically normal tissue `Normal*‘ from now on. If all the mutations in Normal* were also found in the cancer tissue and if Normal* and cancer had been close to each other, we might have inferred that Normal* was a percursor of cancer or an early step in cancer development. But in the phylogenetic trees Normal* branches off very early on and goes down its individual path.

If Normal* is not leading to cancer, then maybe the cancer cells interact with Normal* to increase its mutation rate? No one knows.

Whether the clones of cells observed in morphologically normal prostate are generated by a pathological process or are the product of somatic mosaicism involving unexpectedly high mutation rates, the resulting clonal fields of cells may influence cancer development and/or contribute to multifocality and the presence of multiple cancer lineages in a single cancer mass.

I think the paper presents a very interesting observation. I would be really interested to see a mechanism or any kind of explanation for it.



Cooper CS, Eeles R, Wedge DC, Van Loo P, Gundem G, Alexandrov LB, Kremeyer B, Butler A, Lynch AG, Camacho N, Massie CE, Kay J, Luxton HJ, Edwards S, Kote-Jarai Z, Dennis N, Merson S, Leongamornlert D, Zamora J, Corbishley C, Thomas S, Nik-Zainal S, O’Meara S, Matthews L, Clark J, Hurst R, Mithen R, Bristow RG, Boutros PC, Fraser M, Cooke S, Raine K, Jones D, Menzies A, Stebbings L, Hinton J, Teague J, McLaren S, Mudie L, Hardy C, Anderson E, Joseph O, Goody V, Robinson B, Maddison M, Gamble S, Greenman C, Berney D, Hazell S, Livni N, the ICGC Prostate Group, Fisher C, Ogden C, Kumar P, Thompson A, Woodhouse C, Nicol D, Mayer E, Dudderidge T, Shah NC, Gnanapragasam V, Voet T, Campbell P, Futreal A, Easton D, Warren AY, Foster CS, Stratton MR, Whitaker HC, McDermott U, Brewer DS, & Neal DE (2015). Analysis of the genetic phylogeny of multifocal prostate cancer identifies multiple independent clonal expansions in neoplastic and morphologically normal prostate tissue. Nature genetics PMID: 25730763

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