| Autor: |
Kaur P; Department of Surgery, Keck School of Medicine, University of Southern California, Los Angeles, CA 90033, USA.; University of Southern California Norris Comprehensive Cancer Center, Los Angeles, CA 90033, USA., Campo D; Department of Biological Sciences, University of Southern California, Los Angeles, CA 90089, USA., Porras TB; Cancer and Blood Disease Institute, Children Hospital Los Angeles, University of Southern California, Los Angeles, CA 90027, USA., Ring A; Department of Oncology and Hematology, UniversitätsSpital Zürich, Rämistrasse 100, 8091 Zürich, Switzerland., Lu J; University of Southern California Norris Comprehensive Cancer Center, Los Angeles, CA 90033, USA.; Division of Medical Oncology, Department of Medicine and University of Southern California Norris Cancer Center, University of Southern California, Los Angeles, CA 90033, USA., Chairez Y; Department of Stem Cell Biology and Regenerative Medicine, Keck School of Medicine, University of Southern California, Los Angeles, CA 90033, USA., Su Y; Department of Surgery, Keck School of Medicine, University of Southern California, Los Angeles, CA 90033, USA.; University of Southern California Norris Comprehensive Cancer Center, Los Angeles, CA 90033, USA., Kang I; University of Southern California Norris Comprehensive Cancer Center, Los Angeles, CA 90033, USA.; Division of Medical Oncology, Department of Medicine and University of Southern California Norris Cancer Center, University of Southern California, Los Angeles, CA 90033, USA., Lang JE; Department of Surgery, Keck School of Medicine, University of Southern California, Los Angeles, CA 90033, USA.; University of Southern California Norris Comprehensive Cancer Center, Los Angeles, CA 90033, USA. |
| Abstrakt: |
The comparison of the landscape of somatic alterations in circulating tumor cells (CTCs) versus metastases is challenging. Here, we comprehensively characterized the somatic landscape in bulk (amplified and non-amplified), spike-in breast cancer cells, CTCs, and metastases from breast cancer patients using whole-exome sequencing (WES). We determined the level of genomic concordance for somatic nucleotide variants (SNVs), copy number alterations (CNAs), and structural variants (SVs). The variant allele fractions (VAFs) of somatic variants were remarkably similar between amplified and non-amplified cell line samples as technical replicates. In clinical samples, a significant fraction of somatic variants had low VAFs in CTCs compared to metastases. The most frequently recurrent gene mutations in clinical samples were associated with an elevated C > T mutational signature. We found complex rearrangement patterns including intra- and inter-chromosomal rearrangements, singleton, and recurrent gene fusions, and tandem duplications. We observed high molecular discordance for somatic alterations between paired samples consistent with marked heterogeneity of the somatic landscape. The most prevalent copy number calls were focal deletion events in CTCs and metastases. Our results demonstrate the feasibility of an integrated workflow for the identification of a complete repertoire of somatic alterations and highlight the intrapatient genomic differences that occur between CTCs and metastases. |
