Intratumor genomic heterogeneity in breast cancer with clonal divergence between primary carcinomas and lymph node metastases

Abstract

Conflicting theories of epithelial carcinogenesis disagree on the clonal composition of primary tumors and on the time at which metastases occur. In order to study the spatial distribution of disparate clonal populations within breast carcinomas and the extent of the genetic relationship between primary tumors and regional metastases, we have analyzed by comparative genomic hybridization 122 tissue samples from altogether 60 breast cancer patients, including 34 tumor samples obtained from different quadrants of 9 breast carcinomas, as well as paired primary-metastatic samples from 12 patients. The median intratumor genetic heterogeneity score (HS) was 17.4% and unsupervised hierarchical clustering analysis comparing the genetic features to those of an independent series of 41 breast carcinomas confirmed intratumor clonal divergence in a high proportion of cases. The median HS between paired primary breast tumors and lymph node metastases was 33.3%, but the number of genomic imbalances did not differ significantly. Clustering analysis confirmed extensive clonal divergence between primary carcinomas and lymph node metastases in several cases. In the independent series of 41 breast carcinomas, the number of genomic imbalances in primary tumors was significantly higher in patients presenting lymph node metastases (median = 15.5) than in the group with no evidence of disease spreading at diagnosis (median = 5.0). We conclude that primary breast carcinomas may be composed of several genetically heterogeneous and spatially separated cell populations and that paired primary breast tumors and lymph node metastases often present divergent clonal evolution, indicating that metastases may occur relatively early during breast carcinogenesis.

Molecular analysis reveals a genetic basis for the phenotypic diversity of metaplastic breast carcinomas

“…In agreement with our results, previous studies using conventional comparative genomic hybridization or loss-of-heterozygosity techniques have described the existence of intra-tumour heterogeneity in a significant proportion of breast cancers [47][48][49], and the analyses of matched ductal carcinoma in situ and invasive carcinoma [49,50] or matched invasive . Unsupervised hierarchical cluster analysis.…”

“…In fact, some studies have suggested that metastases may occur early during carcinogenesis and follow a distinct clonal progression [46,47]. This is unlikely, however, as the breakpoints of 17q12 amplification in the primary tumour components and metastatic deposit were identical.…”

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

“…However, this finding likely reflects the heterogeneity of different clones of cells having different genetic profiles that are present within a primary tumor, which is related to the multistage process of cancer development. Our results and others from primary breast tumors suggest frequent intratumoral heterogeneity of genetic aberrations 12,15,[35][36][37][38] implying a coexistence, within the same mass of primary tumor, of different cell subpopulations with different genetic profiles. Metastasis is likely established by a minority of cells from the primary tumor, which migrate to a single distant site.…”

“…[7][8][9][10] Primary tumors and matched ALN metastases from breast cancer patients have been studied by low-resolution genomic approaches for assessment of copy number changes, such as metaphase CGH, allelic imbalance and low-resolution array-CGH. [11][12][13][14] In one report using metaphase CGH, 12 divergence between the primary tumors and ALN metastases was noted in several cases. In another recent report, genome-wide array-CGH with average resolution of 1 Mb per data point was used in the analysis of ALN metastases and primary tumors from 29 patients.…”

Breast Tumor Heterogeneity: Cancer Stem Cells or Clonal Evolution?

“…65 Also, multiple research groups have shown that individual breast tumors contain significant mutational heterogeneity. 66 For example, using FISH, Aubele and colleagues 67 found that different cells from the same invasive breast tumor had different chromosomal gains and losses. Likewise, Torres and others 66 showed that primary breast carcinomas are composed of several genetically heterogeneous and spatially separated cell populations using CGH, and Fujii and coworkers 64 identified distinct allelic losses in different cells from the same in situ breast cancer.…”