Asynchronous Growth of Prostate Cancer Is Reflected by Circulating Tumor Cells Delivered from Distinct, Even Small Foci, Harboring Loss of Heterozygosity of the PTEN Gene

Abstract

The clinical value of prostate-specific antigen (PSA)-positive circulating tumor cells (CTCs) is still a matter of debate and it is also still unclear if these CTCs actually represent the primary tumor. Therefore, we isolated PSA-positive CTCs from the peripheral blood of patients suffering from multifocal cancers and did genetic profiling of each cancer focus by a multiplex PCR-based microsatellite analysis (D7S522, D8S522, NEFL, D10S541, D13S153, D16S400, D16S402, D16S422, and D17S855). In 17 of 20 prostate cancer cases, the loss of heterozygosity (LOH) pattern of the CTCs was identical with only one focus of the primary tumor. Moreover, in six cases, the LOH pattern suggested that smaller foci, down to 0.2 cm 3 , might deliver CTCs. Interestingly, the highest number of LOHs was observed at the marker D10S541 (85%), the PTEN gene, which was observed much less frequently in unifocal prostate cancer (48%). Furthermore, the infrequently occurring LOH in the BRCA1 gene (38%) was found in four of the five cases where a biochemical recurrence was seen within 3 years after prostatectomy. Therefore, the data might support the assumption that CTCs in prostate cancer are derived from distinct foci of a primary tumor. The size of the tumor focus is not related to the delivery of cells. Although the number of cases that were investigated in this study was small, it might be suggested that the LOH at distinct markers such as D10S541 and D17S855 represent the genes PTEN and BRCA1, which might be associated with the occurrence of CTCs in the peripheral blood of patients as well as an early biochemical recurrence. (Cancer Res 2006; 66(18): 8959-65)

Histological characteristics of the index lesion in whole-mount radical prostatectomy specimens: implications for focal therapy

“…Thus, they hypothesized that the index tumour may not always be representative of the pathological stage. Similarly, other investigators observed that even small foci, down to 0.2 cm 3 in size, may show a significant release of tumour cells into the bloodstream 26 and can lead to lymph node metastasis. 27 As Miller and Cygan 10 pointed out, tumours need not acquire a large volume before they become locally invasive.…”

Detection of Circulating Tumor Cells in Peripheral Blood of Patients with Metastatic Breast Cancer: A Validation Study of the CellSearch System

“…2, 3). One advantage of immunocytochemical methods is the opportunity to include morphologic criteria and to further characterize individual cells by additional antibodies, fluorescence in situ hybridization technology, or molecular methods after detection (22,23).…”

Clinical Relevance of Circulating Nucleic Acids in Blood of Prostate Cancer Patients

“…Besides the concordance of tumour-related LOH on cell-free DNA in blood with LOH on DNA from matched primary tumour tissues, discrepancies have also been found (Fleischhacker & Schmidt, 2007). These contradictory LOH data derived from blood and tumour tissue and the low incidence of LOH on cell-free DNA have been explained in part by technical problems and the dilution of tumour-associated cell-free DNA in blood by DNA released from normal cells Schmidt et al, 2006). Moreover, abnormal proliferation of benign cells, due to inflammation or tissue repair processes, also leads to an increase in apoptotic cell death, the accumulation of small, fragmented DNA in blood and the masking of LOH (Schulte-Hermann et al, 1995).…”

“…Deletions in the BRCA1 gene have recently been implicated in metastatic spread and tumour progression in prostate cancer (Bednarz et al, 2010). A comparative genetic profiling of isolated PSA-positive CTCs and multifocal prostate tumour tissues was performed by Schmidt et al They showed that the detection of LOH at the BRCA1 locus in CTCs and primary tumours was associated with an early biochemical recurrence (Schmidt et al, 2006). In a recent study, Okegawa et al determined for the first time the relation between CTCs detected on the CellSearch System and circulating tumour-related methylated DNA using a sensitive SYBR green methylation-specific PCR (Okegawa et al, 2010).…”