Establishment of tumor-specific copy number alterations from plasma DNA of patients with cancer

TY - JOUR

T1 - Establishment of tumor-specific copy number alterations from plasma DNA of patients with cancer

AU - Heitzer, Ellen

AU - Auer, Martina

AU - Hoffmann, Eva Maria

AU - Pichler, Martin

AU - Gasch, Christin

AU - Ulz, Peter

AU - Lax, Sigurd

AU - Waldispuehl-Geigl, Julie

AU - Mauermann, Oliver

AU - Mohan, Sumitra

AU - Pristauz, Gunda

AU - Lackner, Carolin

AU - Höfler, Gerald

AU - Eisner, Florian

AU - Petru, Edgar

AU - Sill, Heinz

AU - Samonigg, Hellmut

AU - Pantel, Klaus

AU - Riethdorf, Sabine

AU - Bauernhofer, Thomas

AU - Geigl, Jochen B

AU - Speicher, Michael R

N1 - Copyright © 2013 UICC.

PY - 2013/7/15

Y1 - 2013/7/15

N2 - With the increasing number of available predictive biomarkers, clinical management of cancer is becoming increasingly reliant on the accurate serial monitoring of tumor genotypes. We tested whether tumor-specific copy number changes can be inferred from the peripheral blood of patients with cancer. To this end, we determined the plasma DNA size distribution and the fraction of mutated plasma DNA fragments with deep sequencing and an ultrasensitive mutation-detection method, i.e., the Beads, Emulsion, Amplification, and Magnetics (BEAMing) assay. When analyzing the plasma DNA of 32 patients with Stage IV colorectal carcinoma, we found that a subset of the patients (34.4%) had a biphasic size distribution of plasma DNA fragments that was associated with increased circulating tumor cell numbers and elevated concentration of mutated plasma DNA fragments. In these cases, we were able to establish genome-wide tumor-specific copy number alterations directly from plasma DNA. Thus, we could analyze the current copy number status of the tumor genome, which was in some cases many years after diagnosis of the primary tumor. An unexpected finding was that not all patients with progressive metastatic disease appear to release tumor DNA into the circulation in measurable quantities. When we analyzed plasma DNA from 35 patients with metastatic breast cancer, we made similar observations suggesting that our approach may be applicable to a variety of tumor entities. This is the first description of such a biphasic distribution in a surprisingly high proportion of cancer patients which may have important implications for tumor diagnosis and monitoring.

AB - With the increasing number of available predictive biomarkers, clinical management of cancer is becoming increasingly reliant on the accurate serial monitoring of tumor genotypes. We tested whether tumor-specific copy number changes can be inferred from the peripheral blood of patients with cancer. To this end, we determined the plasma DNA size distribution and the fraction of mutated plasma DNA fragments with deep sequencing and an ultrasensitive mutation-detection method, i.e., the Beads, Emulsion, Amplification, and Magnetics (BEAMing) assay. When analyzing the plasma DNA of 32 patients with Stage IV colorectal carcinoma, we found that a subset of the patients (34.4%) had a biphasic size distribution of plasma DNA fragments that was associated with increased circulating tumor cell numbers and elevated concentration of mutated plasma DNA fragments. In these cases, we were able to establish genome-wide tumor-specific copy number alterations directly from plasma DNA. Thus, we could analyze the current copy number status of the tumor genome, which was in some cases many years after diagnosis of the primary tumor. An unexpected finding was that not all patients with progressive metastatic disease appear to release tumor DNA into the circulation in measurable quantities. When we analyzed plasma DNA from 35 patients with metastatic breast cancer, we made similar observations suggesting that our approach may be applicable to a variety of tumor entities. This is the first description of such a biphasic distribution in a surprisingly high proportion of cancer patients which may have important implications for tumor diagnosis and monitoring.

KW - Aged

KW - Aged, 80 and over

KW - Biological Markers

KW - Breast Neoplasms

KW - Case-Control Studies

KW - Colorectal Neoplasms

KW - DNA, Neoplasm

KW - Female

KW - Gene Dosage

KW - Genes, ras

KW - High-Throughput Nucleotide Sequencing

KW - Humans

KW - Male

KW - Middle Aged

KW - Mutation

KW - Neoplasm Metastasis

KW - Neoplastic Cells, Circulating

KW - Sequence Analysis, DNA

U2 - 10.1002/ijc.28030

DO - 10.1002/ijc.28030

M3 - SCORING: Journal article

C2 - 23319339

VL - 133

SP - 346

EP - 356

JO - INT J CANCER

JF - INT J CANCER

SN - 0020-7136

IS - 2

ER -