Differentially expressed genes between primary cancer and paired lymph node metastases predict clinical outcome of node-positive breast cancer patients

Abstract

The axillary lymph node status remains the most valuable prognostic factor for breast cancer patients. However, approximately 20-30% of node-positive patients remain free of distant metastases within 15-30 years. It is important to develop molecular markers that are able to predict for the risk of distant metastasis and to develop patient-tailored therapy strategies. We hypothesize that the lymph node metastases may represent the most metastatic fraction of the primary cancers. Therefore, we sought to identify the differentially expressed genes by microarray between the primary tumors and their paired lymph node metastases samples collected from 26 patients. A set of 79 differentially expressed genes between primary cancers and metastasis samples was identified to correctly separate most of primary cancers from lymph node metastases. And decreased expression of matrix metalloproteinase 2, fibronectin, osteoblast specific factor 2, collagen type XI alpha 1 in lymph node metastases were further confirmed by real-time RT-PCR performed on 30 specimen pairs. This set of genes also classified 35 primary cancers into two groups with different prognosis: "high risk group" and "low risk group." Patients in "high risk group" had a 4.65-fold hazard ratio (95% CI 1.02-21.13, P = 0.047) to develop a distant metastasis within 43 months comparing with the "low risk group." This suggested that the gene signature consisting of 79 differentially expressed genes between primary cancers and lymph node metastases could also predict clinical outcome of node-positive patients, and that the molecular classification based on the gene signature could guide patient-tailored therapy.

Elucidation of a Conserved Proteomic Pattern of Breast Cancer Tissue and Metastatic Axillary Lymph Node

“…Those studies mainly demonstrated the similarities between the tumor tissues and the ALNs using histopathological examinations. The phenotypic similarities revealed in these studies were also confirmed in transcriptomic studies (15,(19)(20)(21). On the other hand, studies focused on chromosomal abnormalities among the primary breast tumor tissues and their respective ALNs showed some ALN (B) tissue samples.…”

“…In a study using microarray technology, researchers demonstrated that gene expression profiles of cells from primary cancer tissues and ALNs share high similarities (13). However, other studies demonstrated otherwise claiming that metastasized cells in the ALNs display major differences than their primary look-alikes at the molecular level (15)(16)(17)(18). There are studies investigated breast tumor tissues and their ALNs to which tumor was metastasized.…”

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

“…[23][24][25][26]33,34 Many factors can be responsible for this incongruence: both related to the still poorly understood biology and a well-recognized heterogeneity of the disease, low numbers of studied patients as well as factors related to the differences in the methodology. Our results from the analysis of DNA copy number actually support both conclusions.…”

“…In particular, a few of these located at chromosomes 1, 4, 8 and 11 and represented as gains or amplifications were shared by up to four patients, and were characterized by a high level of difference between metastasis and primary tumor. The majority of these regions encompassed genes for which DNA amplification is strongly correlated with overexpression, and genes that have been previously shown as differentially expressed in metastasis relative to primary tumor [20][21][22][23][24][25][26] (Table 3; Supplementary Table 2). For example, an aberrant region unique to class II at 6q15-6q16 (87.55-97.56 Mb) and exclusively deleted in metastasis of breast cancer contains candidate tumor suppressor genes described earlier for prostate cancer: PNRC1 and CASP8AP2.…”

Breast cancer metastases are molecularly distinct from their primary tumors

“…To date, there is no clear evidence in this direction, and data in favor of, or against, the molecular diversity of breast primary tumors and their metastases have been reported (Weigelt et al, 2003(Weigelt et al, , 2005Hao et al, 2004;Feng et al, 2007;Suzuki and Tarin, 2007). Again, this is not surprising given the paramount impact of individual genetic noise in this type of analysis, the limited number of samples analysed (and, sometimes, their heterogeneity), and the difficulty of determining the impact of noncancerous or non-metastatic tissue contamination from the host organs.…”