title: Establishment of tumor-specific copy number alterations from plasma DNA of patients with cancer.
abstract: 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.
authors: Institute of Human Genetics, Medical University of Graz, Harrachgasse 21/8, A-8010 Graz, Austria.
authors: Ellen
authors: E
authors: Heitzer
authors: Martina
authors: M
authors: Auer
authors: Eva Maria
authors: EM
authors: Hoffmann
authors: Martin
authors: M
authors: Pichler
authors: Christin
authors: C
authors: Gasch
authors: Peter
authors: P
authors: Ulz
authors: Sigurd
authors: S
authors: Lax
authors: Julie
authors: J
authors: Waldispuehl-Geigl
authors: Oliver
authors: O
authors: Mauermann
authors: Sumitra
authors: S
authors: Mohan
authors: Gunda
authors: G
authors: Pristauz
authors: Carolin
authors: C
authors: Lackner
authors: Gerald
authors: G
authors: Höfler
authors: Florian
authors: F
authors: Eisner
authors: Edgar
authors: E
authors: Petru
authors: Heinz
authors: H
authors: Sill
authors: Hellmut
authors: H
authors: Samonigg
authors: Klaus
authors: K
authors: Pantel
authors: Sabine
authors: S
authors: Riethdorf
authors: Thomas
authors: T
authors: Bauernhofer
authors: Jochen B
authors: JB
authors: Geigl
authors: Michael R
authors: MR
authors: Speicher
mesh_terms: D000368:Aged; D000369:Aged, 80 and over; D015415:Biomarkers / Q000097:blood; D001943:Breast Neoplasms / Q000097:blood / Q000235:genetics*; D016022:Case-Control Studies; D015179:Colorectal Neoplasms / Q000097:blood / Q000235:genetics*; D004273:DNA, Neoplasm / Q000097:blood / Q000235:genetics*; D005260:Female; D018628:Gene Dosage; D011905:Genes, ras / Q000235:genetics; D059014:High-Throughput Nucleotide Sequencing / Q000379:methods; D006801:Humans; D008297:Male; D008875:Middle Aged; D009154:Mutation; D009362:Neoplasm Metastasis; D009360:Neoplastic Cells, Circulating / Q000378:metabolism*; D017422:Sequence Analysis, DNA
chemical_list: D015415:Biomarkers; D004273:DNA, Neoplasm