Cellular and genetic diversity in the progression of in situ human breast carcinomas to an invasive phenotype.
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.
Park
So Yeon
SY
Department of Medical Oncology, Dana-Farber Cancer Institute, Department of Medicine, Brigham and Women's Hospital, and Department of Medicine, Harvard Medical School, Boston, Massachusetts, USA.
Gönen
Mithat
M
Kim
Hee Jung
HJ
Michor
Franziska
F
Polyak
Kornelia
K
D015703:Antigens, CD / Q000032:analysis; D001943:Breast Neoplasms / Q000235:genetics* / Q000473:pathology; D002454:Cell Differentiation; D002898:Chromosomes, Human, Pair 8; D018450:Disease Progression; D005260:Female; D018734:Genes, erbB-2; D014644:Genetic Variation; D006801:Humans; D018960:Hyaluronan Receptors / Q000032:analysis; D017404:In Situ Hybridization, Fluorescence; D009361:Neoplasm Invasiveness; D017455:Receptors, IgE / Q000032:analysis
D015703:Antigens, CD; D018960:Hyaluronan Receptors; D017455:Receptors, IgE