Intratumor genetic heterogeneity is a key mechanism underlying tumor progression and therapeutic resistance. The prevailing model for explaining intratumor diversity, the clonal evolution model, has recently been challenged by proponents of the cancer stem cell hypothesis. To investigate this issue, we performed combined analyses of markers associated with cellular differentiation states and genotypic alterations in human breast carcinomas and evaluated diversity with ecological and evolutionary methods. Our analyses showed a high degree of genetic heterogeneity both within and between distinct tumor cell populations that were defined based on markers of cellular phenotypes including stem cell–like characteristics. In several tumors, stem cell–like and more-differentiated cancer cell populations were genetically distinct, leading us to question the validity of a simple differentiation hierarchy–based cancer stem cell model. The degree of diversity correlated with clinically relevant breast tumor subtypes and in some tumors was markedly different between the in situ and invasive cell populations. We also found that diversity measures were associated with clinical variables. Our findings highlight the importance of genetic diversity in intratumor heterogeneity and the value of analyzing tumors as distinct populations of cancer cells to more effectively plan treatments.
So Yeon Park, Mithat Gönen, Hee Jung Kim, Franziska Michor, Kornelia Polyak
This file is in Adobe Acrobat (PDF) format. If you have not installed and configured the Adobe Acrobat Reader on your system.
PDFs are designed to be printed out and read, but if you prefer to read them online, you may find it easier if you increase the view size to 125%.
Many versions of the free Acrobat Reader do not allow Save. You must instead save the PDF from the JCI Online page you downloaded it from. PC users: Right-click on the Download link and choose the option that says something like "Save Link As...". Mac users should hold the mouse button down on the link to get these same options.