TY - JOUR

T1 - Detection of copy number alterations in cell-free tumor DNA from plasma

AU - Østrup, Olga

AU - Ahlborn, Lise Barlebo

AU - Lassen, Ulrik

AU - Mau-Sørensen, Morten

AU - Nielsen, Finn Cilius

PY - 2017/6

Y1 - 2017/6

N2 - Background Somatic copy number alterations (SCNAs) occurring in tumors can provide information about tumor classification, patient's outcome or treatment targets. Liquid biopsies, incl. plasma samples containing circulating cell-free tumor DNA (ccfDNA) can be used to assess SCNAs for clinical purposes, however specify and reliability of methods have to be tested. Methods SNP microarrays (Affymetrix) were used to generate whole-genome copy number profiles from plasma ccfDNA (OncoScan) and paired tumor biopsies (CytoScan) from ten patients with metastatic cancers. Numerical, segmental and focal SCNAs were assessed using ASCAT/TuScan and SNP-FASST2. Results Aberrations in ccfDNA in 4 patients resembled numerical (76%) and segmental (80%) aberrations in tDNA. Three patients represented low correlation due to postponed sampling time, ccfDNA quality and possible treatment interference. Breakpoints of high-amplitude amplification were assessed with high accuracy and relative breakpoints difference of only 7% (0.02–37%). Similarly, biallelic losses were reliably detected. Array was 100% successful in detection of SCNAs on clinically relevant genes compared to SCNAs in tumor biopsies. Tracking of SCNAs changes during the treatment course of one patient also indicated that apoptosis/necrosis of non-cancerous cells presumably induced by treatment can influence ccfDNA composition and introduce false-negative findings into the analysis of liquid biopsies. Conclusions Genomic alterations detected in ccfDNA from liquid biopsies by comprehensive SNP array are reliable source for information for stratification of patients for targeted treatment. General significance Clinically relevant SCNAs can be detected in ccfDNA with high resolution and can therefore serve as an alternative to tumor biopsy in defining treatment targets.

AB - Background Somatic copy number alterations (SCNAs) occurring in tumors can provide information about tumor classification, patient's outcome or treatment targets. Liquid biopsies, incl. plasma samples containing circulating cell-free tumor DNA (ccfDNA) can be used to assess SCNAs for clinical purposes, however specify and reliability of methods have to be tested. Methods SNP microarrays (Affymetrix) were used to generate whole-genome copy number profiles from plasma ccfDNA (OncoScan) and paired tumor biopsies (CytoScan) from ten patients with metastatic cancers. Numerical, segmental and focal SCNAs were assessed using ASCAT/TuScan and SNP-FASST2. Results Aberrations in ccfDNA in 4 patients resembled numerical (76%) and segmental (80%) aberrations in tDNA. Three patients represented low correlation due to postponed sampling time, ccfDNA quality and possible treatment interference. Breakpoints of high-amplitude amplification were assessed with high accuracy and relative breakpoints difference of only 7% (0.02–37%). Similarly, biallelic losses were reliably detected. Array was 100% successful in detection of SCNAs on clinically relevant genes compared to SCNAs in tumor biopsies. Tracking of SCNAs changes during the treatment course of one patient also indicated that apoptosis/necrosis of non-cancerous cells presumably induced by treatment can influence ccfDNA composition and introduce false-negative findings into the analysis of liquid biopsies. Conclusions Genomic alterations detected in ccfDNA from liquid biopsies by comprehensive SNP array are reliable source for information for stratification of patients for targeted treatment. General significance Clinically relevant SCNAs can be detected in ccfDNA with high resolution and can therefore serve as an alternative to tumor biopsy in defining treatment targets.

KW - Array profiling

KW - Circulating cell-free tumor DNA

KW - Copy number alterations

KW - Diagnostics

U2 - 10.1016/j.bbacli.2017.03.006

DO - 10.1016/j.bbacli.2017.03.006

M3 - Journal article

C2 - 28417079

AN - SCOPUS:85017290791

VL - 7

SP - 120

EP - 126

JO - BBA Clinical

JF - BBA Clinical

SN - 2214-6474

ER -