Genomic analysis of single cytokeratin-positive cells from bone marrow reveals early mutational events in breast cancer

Abstract

Chromosomal instability in human breast cancer is known to take place before mammary neoplasias display morphological signs of invasion. We describe here the unexpected finding of a tumor cell population with normal karyotypes isolated from bone marrow of breast cancer patients. By analyzing the same single cells for chromosomal aberrations, subchromosomal allelic losses, and gene amplifications, we confirmed their malignant origin and delineated the sequence of genomic events during breast cancer progression. On this trajectory of genomic progression, we identified a subpopulation of patients with very early HER2 amplification. Because early changes have the highest probability of being shared by genetically unstable tumor cells, the genetic characterization of disseminated tumor cells provides a novel rationale for selecting patients for targeted therapies.

Frequent genetic differences between matched primary and metastatic breast cancer provide an approach to identification of biomarkers for disease progression

“…It has been shown that the early disseminated tumor cells, the potential metastatic progenitors, are genetically significantly less aberrant than the matched primary tumors. 39,40 The above issue requires further analysis in a considerably larger cohort of patients.…”

A concept for the standardized detection of disseminated tumor cells in bone marrow from patients with primary breast cancer and its clinical implementation

“…However, molecular analysis has provided enough evidence to assume that cytokeratin-positive DTCs are malignant cells. [38][39][40][41][42] Nevertheless, several investigators use >2 categories to describe immunostained cells, including apoptotic cells, probable hematopoietic cells, or probable tumor cells. 24,25,37 The clinical significance of such multiple categories is under investigation.…”

Expulser les cellules suspectes

“…En cas d'extrusion, une migration métastatique très précoce de cellules tumorales est possible. Or on sait que des cellules métastatiques ayant les caractéris-tiques génomiques de cellules tumorales « préinvasives» ont été détectées dans la moelle osseuse de patientes atteintes de cancer du sein [8].…”