Single-Cell NGS-Based Analysis of Copy Number Alterations Reveals New Insights in Circulating Tumor Cells Persistence in Early-Stage Breast Cancer
Abstract
:Simple Summary
Abstract
1. Introduction
2. Results
2.1. Isolation of CTCs
2.2. Single-Cell CNA Analysis of CTCs with Whole-Genome NGS
2.3. Identification of Aberrations Shared Between CTCs and Matched Tumor Tissue
2.4. Enrichment Analyses of CNA in Single CTCs
3. Discussion
4. Materials and Methods
4.1. Patients
4.2. CTC Enrichment and Isolation at The Single-Cell Level From Peripheral Whole Blood
4.3. DNA Extraction From FFPE Specimens
4.4. Library Preparation and Whole-Genome Low-Coverage Sequencing
4.5. Bioinformatic Analyses and Statistical Analyses
5. Conclusions
Supplementary Materials
Author Contributions
Funding
Acknowledgments
Conflicts of Interest
References
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Patient Code | BC Subtype | Access Time | Total | ||
---|---|---|---|---|---|
A | B | C | |||
1 | TNBC | 6 | 0 | 0 | 6 |
2 | TNBC | 1 | 2 | 1 | 4 |
3 | TNBC | 0 | 1 | 3 | 4 |
4 | TNBC | 6 | 3 | 3 | 12 |
TNBC total | 13 | 6 | 7 | 26 | |
6 | HER2+ | 1 | 1 | 1 | 3 |
7 | Luminal A | 1 | 1 | 1 | 3 |
8 | Luminal A | 2 | 3 | 0 | 5 |
9 | Luminal A | 1 | 1 | 1 | 3 |
10 | Luminal A | 1 | 0 | 2 | 3 |
11 | Luminal A | 3 | 0 | 0 | 3 |
12 | Luminal A | 2 | 1 | 0 | 3 |
Non-TNBC total | 11 | 7 | 5 | 23 | |
Total | 24 | 13 | 12 | 49 |
Chromosome:Start–End (bp) | Region/s | CTC ID Timepoint A | CTC ID Timepoint B | CTC ID Timepoint C | Reference |
---|---|---|---|---|---|
Patient P02 | |||||
16:81368788–82403137 | 16q23.3 | P02A__2 | P02B_1 | P02C_1, P02C_2 | |
21:40355250–43442658 | 21q22.2, 21q22.3 | - | P02B_1 | P02C_1 | [21] |
Patient 04 | |||||
1:33248192–58929280 | 1p35.1, 1p34.3, 1p34.2, 1p34.1, 1p33, 1p32.3, 1p32.2 | P04A_5 | - | P04C_3 | |
1:156891657–162239674 | 1q23.1, 1q23.2, 1q23.3 | P04A_2, P04A_5 | P04B_2 | P04C_1, P04C_3 | [19,22,23,24] |
1:162239674–167163992 | 1q23.3, 1q24.1 | - | P04B_1 | P04C_1 | [19,22,23,24] |
1:231729524–234612196 | 1q42.2 | - | - | P04C_1, P04C_3 | [22,23,24] |
2:36278338–54693738 | 2p22.2, 2p22.1, 2p21, 2p16.3, 2p16.2 | P04A_6 | - | P04C_1, P04C_3 | |
3:72930104–74214062 | 3p13 | - | - | P04C_1, P04C_3 | |
5:0–2025694 | 5p15.33 | P04A_7, P04A_9 | - | P04C_3 | [21,25] |
6:19336170–21177710 | 6p22.3 | - | - | P04C_1, P04C_3 | |
7:36023910–36646646 | 7p14.2 | 04C458_7 | - | P04C_3 | |
7:151606990–156715054 | 7q36.1, 7q36.2, 7q36.3 | - | P04B_2 | P04C_1 | |
8:92927068–94286848 | 8q21.2 | P04A_8 | - | P04C_1, P04C_3 | |
8:121094607–123567334 | 8q24.12, 8q24.13 | P04A_9 | - | P04C_3 | |
9:109019168–109755681 | 9q31.2 | 04A459_9 | - | P04C_1 | |
10:124680720–129276108 | 10q26.13 | P04A_6 | - | P04C_3 | |
11:17862938–20072786 | 11p15.1 | P04A_2 | - | P04C_1 | |
11:112838832–119700100 | 11q23.2, 11q23.3 | P04A_2, P04A_5 | P04C_1 | ||
13:24308328–24860790 | 13q12.12 | - | - | P04C_1, P04C_3 | |
14:75318986–75871448 | 14q24.3 | P04A_9 | - | P04C_1 | |
14:94448360–96128388 | 14q32.13 | - | P04B_2 | P04C_1, P04C_3 | |
15:80279738–85999918 | 15q25.1, 15q25.2, 15q25.3 | P04A_2, P04A_5 | - | P04C_3 | |
16:84526686–87288996 | 16q24.1 | P04A_5 | P04B_1, P04B_2, P04B_3 | P04C_1 | |
17:17494630–19520324 | 17p11.2 | - | P04B_3 | P04C_3 | |
17:70159110–70715136 | 17q24.3 | - | P04B_1 | P04C_3 | |
18:77160526–78077248 | 18q23 | - | P04B_1 | P04C_1, P04C_3 | [21] |
20:42723728–47051680 | 20q13.12, 20q13.13 | P04A_9 | P04B_3 | P04C_1 | |
22:34700614–35725876 | 22q12.3 | P04A_5, P04A_7, P04A_9 | P04B_1 | P04C_1 | |
X:13627396–13995704 | Xp22.2 | P04A_5 | - | P04C_1, P04C_3 | |
Patient 07 | |||||
22:25992468–25992468 | 22q12.1, 22q12.2, 22q12.3 | P07A__1 | P07B_3 | P07C_2 | |
Patient 09 | |||||
15:60636100–64190630 | 15q22.2 | - | P09B__1 | P09C_2 | |
Patient 10 | |||||
16:82480932–85699185 | 16q23.3, 16q24.1 | P10A_1 | P10B__1 | P10C_1 |
Enriched Terms | Term ID | CTCs | Samples | Genes |
---|---|---|---|---|
Natural killer cell activation involved in immune response | GO:0002323 | 10 | P02A__2; P03C_1; P07A__1; P09B__2; P08A__1; P09B__3; P09B__1; P10B_1; P11A_1; P12A_2 | CD244; CORO1A; IFNA1; IFNA10; IFNA14; IFNA16; IFNA17; IFNA2; IFNA21; IFNA4; IFNA5; IFNA6; IFNA7; IFNA8; IFNB1; IFNE; IFNK; IFNW1; KLRF2; VAMP7 |
Response to dsRNA | GO:0043331 | 9 | P01A_6; P02A_2; P07A_1; P08A_1; P09B_2; P09B_1; P10B_1; P11A_1; P12A_2 | IFNA1; IFNA10; IFNA14; IFNA16; IFNA17; IFNA2; IFNA21; IFNA4; IFNA5; IFNA6; IFNA7; IFNA8; IFNB1; IFNE; IFNK; IFNW1; IRAK3; PDE12; PMAIP1; RFTN1; RIOK3; SLC3A2; TICAM1; TLR3 |
Regulation of peptidyl-serine phosphorylation of STAT protein | GO:0033139 | 9 | P01A_6; P02A_2; P07A_1; P08A_1; P09B_2; P09B_1; P10B_1; P11A_1; P12A_2 | IFNA1; IFNA10; IFNA14; IFNA16; IFNA17; IFNA2; IFNA21; IFNA4; IFNA5; IFNA6; IFNA7; IFNA8; IFNB1; IFNE; IFNG; IFNK; IFNW1; LIF |
Positive regulation of peptidyl-serine phosphorylation of STAT protein | GO:0033141 | 9 | P01A_6; P02A_2; P07A_1; P08A_1; P09B_2; P09B_1; P10B_1; P11A_1; P12A_2 | IFNA1; IFNA10; IFNA14; IFNA16; IFNA17; IFNA2; IFNA21; IFNA4; IFNA5; IFNA6; IFNA7; IFNA8; IFNB1; IFNE; IFNG; IFNK; IFNW1; LIF |
Lymphocyte activation involved in immune response | GO:0002285 | 9 | P01A_6; P02A_2; P07A_1; P08A_1; P09B_2; P09B_1; P10B_1; P11A_1; P12A_2 | CD1C; CD244; EIF2AK4; F2RL1; IFNA1; IFNA10; IFNA14; IFNA16; IFNA17; IFNA2; IFNA21; IFNA4; IFNA5; IFNA6; IFNA7; IFNA8; IFNB1; IFNE; IFNK; IFNW1; LCP1 |
Natural killer cell activation | GO:0030101 | 8 | P02A_2; P07A_1; P08A_1; P09B_2; P09B_3; P09B_1; P11A_1; P12A_2 | BAG6; CASP8; CD2; CD244; ELF4; HNF1A; IFNA1; IFNA10; IFNA14; IFNA16; IFNA17; IFNA2; IFNA21; IFNA4; IFNA5; IFNA6; IFNA7; IFNA8; IFNB1; IFNE; IFNK; IFNW1; IL12B; IL2; IL21R; KLRK1; NCR1; NCR3; PRDX1; SLAMF7; SNX27; ULBP1; ULBP2; ULBP3 |
B cell proliferation | GO:0042100 | 8 | P01A_6; P02A_2; P07A_1; P08A_1; P09B_2; P09B_1; P11A_1; P12A_2 | BCL2; CD40; CD40LG; CD79A; CR2; CTPS1; GAPT; HSPD1; IFNA1; IFNA10; IFNA14; IFNA16; IFNA17; IFNA2; IFNA21; IFNA4; IFNA5; IFNA6; IFNA7; IFNA8; IFNB1; IFNE; IFNK; IFNW1; IL10; LEF1; MEF2C; MS4A1 |
Cytidine to uridine editing | GO:0016554 | 7 | P01A_5; P04A9; P07A_1; P07C2; P08A_1; P09B_3; P11A_1 | A1CF; AICDA; APOBEC1; APOBEC2; APOBEC3A; APOBEC3B; APOBEC3C; APOBEC3D; APOBEC3F; APOBEC3G; APOBEC3H |
T cell activation involved in immune response | GO:0002286 | 7 | P01A_6; P07A_1; P08A_1; P09B_2; P09B_1; P11A_1; P12A_2 | CD1C; EIF2AK4; F2RL1; FCER1G; ICAM1; IFNA1; IFNA10; IFNA14; IFNA16; IFNA17; IFNA2; IFNA21; IFNA4; IFNA5; IFNA6; IFNA7; IFNA8; IFNB1; IFNE; IFNK; IFNW1; ITGAL; LCP1; LILRB1; SLC11A1; TNFSF18 |
Lymphocyte proliferation | GO:0046651 | 7 | P02A_2; P07A_1; P08A_1; P09B_2; P09B_1; P11A_1; P12A_2 | BCL2; CD40; CD40LG; CD79A; CR2; CTPS1; ELF4; HELLS; HSPD1; IFNA1; IFNA10; IFNA14; IFNA16; IFNA17; IFNA2; IFNA21; IFNA4; IFNA5; IFNA6; IFNA7; IFNA8; IFNB1; IFNE; IFNK; IFNW1; IL10; MEF2C; MS4A1; MSN; PIK3CG; PPP3CB; TNFRSF4; TNFSF14 |
Response to exogenous dsRNA | GO:0043330 | 7 | P01A_6; P07A_1; P08A_1; P09B_2; P09B_1; P11A_1; P12A_2 | CAV1; COLEC12; DDX58; DHX9; FLOT1; IFIH1; IFIT1; IFNA1; IFNA10; IFNA14; IFNA16; IFNA17; IFNA2; IFNA21; IFNA4; IFNA5; IFNA6; IFNA7; IFNA8; IFNB1; IFNE; IFNK; IFNW1; IRAK3; MUL1; PQBP1; RALB; RFTN1; SLC3A2; TICAM1; TLR3; TMEM173 |
DNA cytosine deamination | GO:0070383 | 6 | P01A_5; P04A9; P07A_1; P07C2 P08A_1; P11A_1 | APOBEC3A; APOBEC3C; APOBEC3D; APOBEC3F; APOBEC3G; APOBEC3H |
B cell differentiation | GO:0030183 | 6 | P01A_6; P07A_1; P08A_1; P09B_1; P11A_1; P12A_2 | ADAM17; AICDA; BLNK; CD79A; CEBPG; CLCF1; DNAJB9; HDAC5; HDAC9; HHEX; IFNA1; IFNA10; IFNA14; IFNA16; IFNA17; IFNA2; IFNA21; IFNA4; IFNA5; IFNA6; IFNA7; IFNA8; IFNB1; IFNE; IFNK; IFNW1; IL11; ITGA4; JAK3; KIT; KLF6; LYL1; MSH2; NFAM1; NHEJ1; PLCG2; RAG1; RAG2; TCF3; TPD52; VCAM1 |
Regulation of type I interferon-mediated signaling pathway | GO:0060338 | 6 | P07A_1; P08A_1; P09B_2; P09B_1; P11A_1; P12A_2 | CACTIN; CDC37; FADD; HSP90AB1; IFNA1; IFNA10; IFNA14; IFNA16; IFNA17; IFNA2; IFNA21; IFNA4; IFNA5; IFNA6; IFNA7; IFNA8; IFNAR1; IFNAR2; IFNB1; JAK1; NLRC5; PTPN1; PTPN11; PTPN6; TYK2; WNT5A; ZBP1 |
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Rossi, T.; Gallerani, G.; Angeli, D.; Cocchi, C.; Bandini, E.; Fici, P.; Gaudio, M.; Martinelli, G.; Rocca, A.; Maltoni, R.; et al. Single-Cell NGS-Based Analysis of Copy Number Alterations Reveals New Insights in Circulating Tumor Cells Persistence in Early-Stage Breast Cancer. Cancers 2020, 12, 2490. https://doi.org/10.3390/cancers12092490
Rossi T, Gallerani G, Angeli D, Cocchi C, Bandini E, Fici P, Gaudio M, Martinelli G, Rocca A, Maltoni R, et al. Single-Cell NGS-Based Analysis of Copy Number Alterations Reveals New Insights in Circulating Tumor Cells Persistence in Early-Stage Breast Cancer. Cancers. 2020; 12(9):2490. https://doi.org/10.3390/cancers12092490
Chicago/Turabian StyleRossi, Tania, Giulia Gallerani, Davide Angeli, Claudia Cocchi, Erika Bandini, Pietro Fici, Michele Gaudio, Giovanni Martinelli, Andrea Rocca, Roberta Maltoni, and et al. 2020. "Single-Cell NGS-Based Analysis of Copy Number Alterations Reveals New Insights in Circulating Tumor Cells Persistence in Early-Stage Breast Cancer" Cancers 12, no. 9: 2490. https://doi.org/10.3390/cancers12092490