Unmasking Intra-Tumoral Heterogeneity and Clonal Evolution in NF1-MPNST
Abstract
:1. Introduction
2. Materials and Methods
2.1. Study Approvals
2.2. Sample Collection
2.3. Histology
2.4. Sequencing and Bioinformatics Analysis
2.4.1. Library Construction and Sequencing
2.4.2. IDT Exome Sequencing Variant Detection
2.4.3. Copy Number Analysis
2.4.4. Inference of Clonal Phylogeny
2.4.5. RNA Sequence Preprocessing
2.4.6. Gene Differential Expression Analysis
2.4.7. Pathway Analysis
3. Results
3.1. Patient Information
3.2. Histology of Biopsy Sites
3.3. Whole Exome Sequencing (WES), RNA Sequencing (RNA-Seq), and Copy Number Analysis
4. Discussion
5. Conclusions
Supplementary Materials
Author Contributions
Funding
Conflicts of Interest
References
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Age at Diagnosis, Years | Sex | Tumor Location | Tumor Size/Grade | Surgical Margin Status | Disease Status | Metastasis | Adjuvant Treatment | OS *, Months |
---|---|---|---|---|---|---|---|---|
40 | Male | Left neck | 10.2 cm, Grade 3 1 | Negative | Recurred | Lung | None | 33 |
Gene Symbol | p-Value (1 vs. 2) | Fold Change (1 vs. 2) | p-Value (1 vs. 3) | Fold Change (1 vs. 3) | p-Value (2 vs. 3) | Fold Change (2 vs. 3) |
---|---|---|---|---|---|---|
EEF1A1 | 2.04 × 10−84 | −3.32 | 3.33 × 10−16 | 2.20 | 1.35 × 10−119 | 7.31 |
RPS27 | 4.32 × 10−24 | −2.51 | 7.64 × 10−13 | 3.01 | 4.27 × 10−46 | 7.55 |
RPS27A | 1.69 × 10−12 | −2.62 | 9.42 × 10−05 | 2.27 | 4.16 × 10−21 | 5.95 |
H3C3 | 7.46 × 10−12 | −4.51 | 5.05 × 10−04 | 11.2 | 5.54 × 10−09 | 50.6 |
RPLP1 | 2.36 × 10−10 | −2.57 | 7.25 × 10−04 | 2.13 | 2.43 × 10−17 | 5.48 |
SNORD13 | 3.24 × 10−10 | 3.00 | 8.25 × 10−62 | −4.91 | 3.52 × 10−66 | −14.8 |
RPLP0 | 1.05 × 10−09 | −2.26 | 1.60 × 10−04 | 2.09 | 1.73 × 10−18 | 4.72 |
TPI1 | 1.65 × 10−08 | −2.27 | 5.61 × 10−04 | 2.08 | 6.52 × 10−16 | 4.72 |
RPL23AP42 | 3.77 × 10−07 | −2.21 | 8.40 × 10−04 | 2.16 | 8.65 × 10−14 | 4.78 |
RPS23 | 5.34 × 10−06 | −2.46 | 1.17 × 10−03 | 2.92 | 9.16 × 10−11 | 7.19 |
MT-TI | 4.64 × 10−05 | 3.44 | 1.19 × 10−15 | −3.67 | 6.36 × 10−20 | −12.6 |
SNORA81 | 2.28 × 10−04 | 33.3 | 4.00 × 10−11 | −3.39 | 5.12 × 10−07 | −11.3 |
RNY1 | 2.45 × 10−04 | 2.65 | 4.67 × 10−24 | −4.71 | 8.10 × 10−27 | −12.5 |
RNVU1-31 | 5.00 × 10−04 | −4.18 | 3.83 × 10−14 | −17.7 | 7.07 × 10−13 | −4.23 |
MT-TM | 6.37 × 10−04 | 3.70 | 2.29 × 10−07 | −2.89 | 2.69 × 10−11 | −10.7 |
TMSB4XP6 | 1.16 × 10−03 | 3.19 | 2.89 × 10−04 | −2.15 | 7.91 × 10−09 | −6.87 |
(a) | |||||||
---|---|---|---|---|---|---|---|
Gene | Area | Genomic Location | Variant | Amino Acid Change | Functional Domain Affected | Gene Expression Altered | Pathogenicity Prediction |
C2orf91 | 1 | Chr2:41953024 | missense | p.(Arg91Ile) | N | NA | Possibly damaging |
CCL16 | 1 | Chr17:35978161 | missense | p.(Cys60Ser) | Y | NA | Probably damaging |
PAG1 | 1 | Chr8:80984896 | synonymous | p.(Pro252=) | Y | NA | Unknown |
VPS13D | 1 | Chr1:12283596 | missense | p.(Phe1832Val) | N | - | Probably damaging |
VPS4B | 1 | Chr18:63400074 | missense | p.(Lys255Thr) | Y | NA | Probably damaging |
ZNF750 | 1 | Chr17:82830337 | synonymous | p.(Pro659=) | N | NA | Unknown |
RIMBP3C | 2 | Chr22:21546513 | missense | p.(Arg1488Ser) | N | NA | Possibly Damaging |
SPATA31A5 | 2 | Chr9:60919364 | missense | p.(Leu970Phe) | N | - | Possibly Damaging |
CCDC27 | 3 | Chr1:3752496 | synonymous | p.(Ile5=) | N | + | Unknown |
LETM2 | 3 | Chr8:38400906 | synonymous | p.(Leu279=) | Y | + | Unknown |
NTRK2 | 3 | Chr9:84670796 | missense | p.(Trp16Cys) | N | NA | Possibly Damaging |
(b) | |||||
---|---|---|---|---|---|
Gene | Area | Genomic Location | Variant | Amino Acid Change | Functional Domain Affected |
CSK | 2 | Chr15:74798671 | frameshift | p.(Glu25fs) | Y |
TSPAN9 | 2 | Chr12:3283047 | frameshift | p.(Leu218fs) | Y |
(c) | |||||
---|---|---|---|---|---|
Gene | Area | Genomic Location | Variant | Gene Expression Altered | IMPACT |
MAP3K2 | 1 | Chr2:127387525 | intron | - | Modifier |
RIPK3 | 1 | Chr14:24332669 or Chr14:24332869 | downstream gene | + | Modifier |
RNPS1 | 1 | Chr16:2266329 | intron | - | Modifier |
SNX32 | 1 | Chr11:65832561 | upstream gene | - | Modifier |
AC138649.1 | 2 | Chr15:22768761 | intron | NA | Modifier |
FAM157B | 2 | Chr9:138231054 | non-coding transcript exon | + | Modifier |
FANCD2P2 | 2 | Chr3:11871392 | non-coding transcript exon | + | Modifier |
LAIR1 | 2 | Chr19:54358582 | intron | NA | Modifier |
NFAM1 | 2 | Chr22:42432412 | upstream gene | + | Modifier |
TET2 | 2 | Chr4:105241954 | intron | NA | Modifier |
TMEM114 | 2 | Chr16:8569715 | 3 prime UTR | NA | Modifier |
MOCS2 | 3 | Chr5:53109455 | 5 prime UTR | - | Unknown |
PSMB2 | 3 | Chr1:35641574 | 5 prime UTR | NA | Modifier |
RUFY1 | 3 | Chr5:179608552 | intron | - | Modifier |
WDR6 | 3 | Chr3:49005134 | upstream gene | NA | Modifier |
Z82190.2 | 3 | Chr22:31821630 | intron | NA | Modifier |
Location | Chromosome | Start Position | End Position | Raw Copy Number | Genes | Role in Tumorigenesis |
---|---|---|---|---|---|---|
Area1 | chr17 | 81509970 | 81523847 | 3.151914 | ACTG1 | Anti-apoptosis, motility [64,65] |
Area1 | chr17 | 81887843 | 81891586 | 3.151914 | ALYREF | Genomic stability [66] |
Area1 | chr14 | 20455190 | 20457772 | 4.883921 | APEX1 | Base-excision repair [49] |
Area1 | chr17 | 81867720 | 81871406 | 3.151914 | ARHGDIA | Invasiveness, metastasis [67] |
Area1 | chr12 | 7080208 | 7092607 | 5.842557 | C1R | Inflammation [68] |
Area1 | chr17 | 79778131 | 79787983 | 3.109085 | CBX2 | Transcription [69] |
Area1 | chr17 | 50183288 | 50201632 | 3.060268 | COL1A1 | Metastasis [70] |
Area1 | chr17 | 82078332 | 82098332 | 3.562293 | FASN | Metabolism [71] |
Area1 | chr7 | 128830376 | 128859274 | 3.66148 | FLNC | Invasiveness [72] |
Area1 | chr17 | 82050690 | 82057470 | 3.562293 | GPS1 | COP9 signalosome subunit/ubiquitin-proteasome pathway |
Area1 | chr19 | 11164266 | 11197791 | 7.563794 | KANK2 | Cytoskeleton formation [73] |
Area1 | chrX | 54807598 | 54816012 | 3.320925 | MAGED2 | Cell-cycle regulator [74] |
Area1 | chrX | 55452104 | 55453566 | 3.320925 | MAGEH1 | Proliferation [75] |
Area1 | chr7 | 100092727 | 100101940 | 4.16605 | MCM7 | Proliferation [76] |
Area1 | chr14 | 22836556 | 22849027 | 4.136412 | MMP14 | Invasiveness, metastasis [77] |
Area1 | chr14 | 39175182 | 39183218 | 3.038443 | PNN | Splicing [51] |
Area1 | chr9 | 107283136 | 107332194 | 14.61502 | RAD23B | Nucleotide-excision repair [53] |
Area1 | chr18 | 49488452 | 49492523 | 3.095593 | RPL17 | Ribosome biogenesis, protein translation [61] |
Area1 | chrX | 54814369 | 54814497 | 3.320925 | SNORA11 | Maturation of ribosomal RNA [62] |
Area1 | chr7 | 102194075 | 102194164 | 4.159154 | SNORA48 | Maturation of ribosomal RNA |
Area1 | chr2 | 5692666 | 5701385 | 3.929294 | SOX11 | Transcription |
Area1 | chr17 | 76734114 | 76737374 | 3.109085 | SRSF2 | Splicing [54] |
Area1 | chr9 | 35099775 | 35103195 | 3.374564 | STOML2 | Anti-apoptosis [78] |
Area1 | chr17 | 61399895 | 61409466 | 3.52571 | TBX2 | Transcription [79] |
Area1 | chr19 | 58544090 | 58550722 | 3.012426 | TRIM28 | Proliferation [80] |
Area1 | chr9 | 35056063 | 35073249 | 3.374564 | VCP | Protein degradation [81] |
Area1 | chr7 | 101162508 | 101165593 | 4.159154 | VGF | Transcription [82] |
Area2 | chr2 | 47335314 | 47335514 | 4.114423 | BCYRN1 | Transcription [56] |
Area2 | chr6 | 73515749 | 73523797 | 3.582945 | EEF1A1 | Translation [57] |
Area2 | chr19 | 3976055 | 3985469 | 3.359182 | EEF2 | Translation [58] |
Area2 | chr1 | 150574550 | 150579738 | 4.140715 | MCL1 | Anti-apoptosis [83] |
Area2 | chr1 | 151399533 | 151401944 | 4.140715 | PSMB4 | Proteasomal function [59] |
Area2 | chr11 | 67583594 | 67586660 | 3.211531 | GSTP1 | Metabolism [84] |
Area2 | chr15 | 65296050 | 65296166 | 3.976034 | RNU5A-1 | RNA processing |
Area2 | chr15 | 65304676 | 65304792 | 3.976034 | RNU5B-1 | RNA processing |
Area2 | chr7 | 148983754 | 148983856 | 3.383375 | RNY3 | RNA processing |
Area2 | chr13 | 27251308 | 27256691 | 6.141368 | RPL21 | Ribosome biogenesis, protein translation |
Area2 | chr9 | 19375714 | 19380254 | 3.739665 | RPS6 | Ribosome biogenesis, protein translation |
Area2 | chr2 | 24273613 | 24273741 | 4.326829 | SCARNA21 | RNA processing |
Area2 | chr15 | 78091171 | 78091297 | 3.898802 | SNORA63 | Maturation of ribosomal RNA |
Area2 | chr1 | 12221147 | 12221271 | 3.552826 | SNORA70 | Maturation of ribosomal RNA |
Area2 | chr2 | 10446713 | 10446849 | 4.496897 | SNORA80B | Maturation of ribosomal RNA |
Area2 | chr12 | 124911603 | 124917368 | 3.034233 | UBC | Ubiquitin homeostasis [85] |
Area3 | chr16 | 28823034 | 28837237 | 5.159031 | ATXN2L | Stress granule regulator [86] |
Area3 | chr9 | 136862118 | 136866286 | 3.830137 | EDF1 | Transcription |
Area3 | chr11 | 2129111 | 2141238 | 7.774932 | IGF2 | Proliferation [87] |
Area3 | chr11 | 2608327 | 2699994 | 7.774932 | KCNQ1OT1 | Transcription [88] |
Area3 | chr11 | 2134133 | 2134209 | 7.774932 | MIR483 | Transcription [89] |
Area3 | chr9 | 127447673 | 127451405 | 3.212283 | RPL12 | Ribosome biogenesis, protein translation |
Area3 | chr19 | 49487553 | 49492308 | 3.051258 | RPL13A | Ribosome biogenesis, protein translation |
Area3 | chr19 | 48615327 | 48619536 | 3.174325 | RPL18 | Ribosome biogenesis, protein translation |
Area3 | chr1 | 6181268 | 6209389 | 3.792397 | RPL22 | Ribosome biogenesis, protein translation |
Area3 | chr17 | 74203581 | 74210655 | 3.363835 | RPL38 | Ribosome biogenesis, protein translation |
Area3 | chr11 | 809646 | 812880 | 3.117378 | RPLP2 | Ribosome biogenesis, protein translation |
Area3 | chr19 | 49496364 | 49499689 | 3.051258 | RPS11 | Ribosome biogenesis, protein translation |
Area3 | chr19 | 39433206 | 39435948 | 3.408557 | RPS16 | Ribosome biogenesis, protein translation |
Area3 | chr16 | 1962051 | 1964860 | 3.301972 | RPS2 | Ribosome biogenesis, protein translation |
Area3 | chr19 | 8321157 | 8323340 | 3.044231 | RPS28 | Ribosome biogenesis, protein translation |
Area3 | chr17 | 76557765 | 76565348 | 3.374444 | SNHG16 | Transcription [90] |
Area3 | chr16 | 1962333 | 1962466 | 3.301972 | SNORA10 | Maturation of ribosomal RNA |
Area3 | chr2 | 30187433 | 30187566 | 3.83836 | SNORA10B | Maturation of ribosomal RNA |
Area3 | chr9 | 136726104 | 136726234 | 3.830137 | SNORA17B | Maturation of ribosomal RNA |
Area3 | chrY | 16138247 | 16138379 | 3.968437 | SNORA20 | Maturation of ribosomal RNA |
Area3 | chr16 | 1965183 | 1965310 | 3.301972 | SNORA78 | Maturation of ribosomal RNA |
Area3 | chr19 | 10109756 | 10109835 | 5.45924 | SNORD105B | Ribosomal RNA modification [63] |
Area3 | chr19 | 49490614 | 49490699 | 3.051258 | SNORD33 | Ribosomal RNA modification |
Area3 | chr14 | 21397291 | 21397401 | 3.835309 | SNORD8 | Ribosomal RNA modification |
Area3 | chr14 | 21392149 | 21392253 | 3.835309 | SNORD9 | Ribosomal RNA modification |
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Moon, C.-I.; Tompkins, W.; Wang, Y.; Godec, A.; Zhang, X.; Pipkorn, P.; Miller, C.A.; Dehner, C.; Dahiya, S.; Hirbe, A.C. Unmasking Intra-Tumoral Heterogeneity and Clonal Evolution in NF1-MPNST. Genes 2020, 11, 499. https://doi.org/10.3390/genes11050499
Moon C-I, Tompkins W, Wang Y, Godec A, Zhang X, Pipkorn P, Miller CA, Dehner C, Dahiya S, Hirbe AC. Unmasking Intra-Tumoral Heterogeneity and Clonal Evolution in NF1-MPNST. Genes. 2020; 11(5):499. https://doi.org/10.3390/genes11050499
Chicago/Turabian StyleMoon, Chang-In, William Tompkins, Yuxi Wang, Abigail Godec, Xiaochun Zhang, Patrik Pipkorn, Christopher A. Miller, Carina Dehner, Sonika Dahiya, and Angela C. Hirbe. 2020. "Unmasking Intra-Tumoral Heterogeneity and Clonal Evolution in NF1-MPNST" Genes 11, no. 5: 499. https://doi.org/10.3390/genes11050499
APA StyleMoon, C.-I., Tompkins, W., Wang, Y., Godec, A., Zhang, X., Pipkorn, P., Miller, C. A., Dehner, C., Dahiya, S., & Hirbe, A. C. (2020). Unmasking Intra-Tumoral Heterogeneity and Clonal Evolution in NF1-MPNST. Genes, 11(5), 499. https://doi.org/10.3390/genes11050499