Deconvolution of the Genomic and Epigenomic Interaction Landscape of Triple-Negative Breast Cancer
Abstract
:1. Introduction
2. Materials and Methods
2.1. Germline Mutations and Associated Genes
2.2. Gene Expression and DNA Methylation Data and Somatic Mutation Information
2.3. Bioinformatics Analysis of Gene Expression and DNA Methylation Data
2.4. Network and Pathway Analysis
3. Results
3.1. Discovery of a Signature of Aberrantly Methylated Genes Associated with TNBC
3.2. Discovery of a Signature of Differentially Expressed Genes Associated with TNBC
3.3. Discovery of a Signature of Aberrantly Methylated Genes Transcriptionally Associated with TNBC
3.4. Discovery of a Signature of Genes Containing Both Somatic and Epigenetic Variation
3.5. Discovery of a Signature of Genes Containing Germline, Somatic and Epigenomic Variation
3.6. Molecular Networks and Signaling Pathways Enriched for Germline, Somatic and Epigenomic Variation
4. Discussion
4.1. Integrating Transcription with DNA Methylation Profiling
4.2. Integrating Somatic Variation with Epigenomic Variation
4.3. Oncogenic Interactions between Genes Containing Germline and Epigenetic Variation
4.4. Disease Networks and Pathways as Potential Therapeutic Targets
4.5. Limitations and Future Research Directions
5. Conclusions
Supplementary Materials
Author Contributions
Funding
Acknowledgments
Conflicts of Interest
References
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Data Type | TNBC | ||
---|---|---|---|
Genes or Probes | Tumor Samples | Control Samples | |
Gene expression | 60,484 Probes | 110 | 113 |
Methylation | 485,578 probes | 83 | 83 |
Somatic | 7659 genes | 110 | 113 |
GWAS * | 825 genes | >300,000 | >300,000 |
Gene_Symbol | Chromosome | Methylation | RNAseq | |
---|---|---|---|---|
Event | Adjust p-Value | Adjust p-Value | ||
RP1 | 8q11.23 | 992 | 3.96 × 10−24 | 8.94 × 10−5 |
PTPRN2 | 7q36.3 | 917 | 7.85 × 10−24 | 4.24 × 10−16 |
PRDM16 | 1p36.32 | 434 | 1.78 × 10−22 | 3.42 × 10−17 |
TNXB | 6p21.33 | 364 | 3.11 × 10−22 | 1.29 × 10−24 |
MAD1L1 | 7p22.3 | 317 | 3.89 × 10−23 | 2.29 × 10−7 |
DIP2C | 10p15.3 | 298 | 4.71 × 10−23 | 1.24 × 10−9 |
PCDHGA2 | 5q31.3 | 291 | 3.57 × 10−24 | 1.30 × 10−19 |
SNHG14 | 15q11.2 | 283 | 1.56 × 10−20 | 2.15 × 10−13 |
PCDHGA3 | 5q31.3 | 277 | 3.57 × 10−24 | 2.05 × 10−21 |
ERICH1 | 8p23.3 | 270 | 3.25 × 10−23 | 1.47 × 10−2 |
ADARB2 | 10p15.3 | 257 | 5.96 × 10−24 | 6.18 × 10−10 |
PCDHGA4 | 5q31 | 253 | 3.57 × 10−24 | 3.25 × 10−15 |
PCDHGB2 | 5q31 | 239 | 3.57 × 10−24 | 4.51 × 10−8 |
PCDHGA5 | 5q31 | 229 | 3.57 × 10−24 | 6.38 × 10−15 |
EIF2B5 | 3q27.1 | 217 | 2.57 × 10−23 | 2.26 × 10−4 |
PCDHGB3 | 5q31 | 213 | 3.57 × 10−24 | 2.64 × 10−8 |
TBCD | 17q25.3 | 204 | 1.30 × 10−23 | 8.35 × 10−7 |
HDAC4 | 2q37.3 | 202 | 6.13 × 10−24 | 3.71 × 10−8 |
MCF2L | 13q34 | 202 | 6.15 × 10−24 | 9.10 × 10−5 |
PCDHGA6 | 5q31 | 202 | 3.57 × 10−24 | 3.20 × 10−14 |
SDK1 | 7p22.2 | 202 | 4.35 × 10−22 | 1.13 × 10−8 |
INPP5A | 10q26.3 | 190 | 3.55 × 10−22 | 4.39 × 10−13 |
PCDHGA7 | 5q31 | 188 | 3.57 × 10−24 | 1.69 × 10−13 |
ATP11A | 13q34 | 177 | 6.26 × 10−23 | 2.83 × 10−2 |
PCDHGB4 | 5q31 | 175 | 3.57 × 10−24 | 6.45 × 10−10 |
KCNQ1 | 11p15.5 | 174 | 2.29 × 10−22 | 2.51 × 10−3 |
HOXA3 | 7p15.2 | 168 | 1.26 × 10−23 | 3.43 × 10−11 |
PCDHGA8 | 5q31.3 | 166 | 3.57 × 10−24 | 3.74 × 10−3 |
C7orf50 | 7p22.3 | 163 | 4.59 × 10−23 | 1.54 × 10−7 |
AGAP1 | 2q37.2 | 160 | 5.28 × 10−21 | 2.25 × 10−3 |
Gene | Chromosome | Methylation | RNAseq | Somatic Events | |
---|---|---|---|---|---|
DM_Sites | Adjust p-Value | Adjust p-Value | |||
TTN * | 2q31.2 | 20 | 1.53 × 10−13 | 8.34 × 10−10 | 27 |
MUC4 * | 3q29 | 28 | 3.91 × 10−19 | 7.60 × 10−4 | 13 |
FAT3 | 11q14.3 | 23 | 9.50 × 10−15 | 1.67 × 10−9 | 12 |
USH2A | 1q41 | 12 | 1.53 × 10−11 | 1.73 × 10−6 | 12 |
SYNE1 * | 6q25.2 | 29 | 1.04 × 10−18 | 1.66 × 10−20 | 9 |
FCGBP | 19q13.2 | 14 | 1.60 × 10−17 | 3.48 × 10−2 | 9 |
SPTA1 | 1q23.1 | 3 | 2.00 × 10−14 | 8.63 × 10−5 | 9 |
DNAH17 | 17q25.3 | 76 | 3.52 × 10−21 | 3.74 × 10−4 | 8 |
DST | 6p12.1 | 41 | 1.76 × 10−18 | 1.14 × 10−21 | 8 |
MUC5B | 11p15.5 | 40 | 9.44 × 10−16 | 1.71 × 10−8 | 8 |
PIK3CA * | 3q26.32 | 7 | 1.11 × 10−16 | 3.26 × 10−6 | 8 |
PLEC | 8q24.3 | 103 | 1.36 × 10−21 | 1.28 × 10−4 | 7 |
CSMD2 | 1p35.1 | 47 | 1.81 × 10−19 | 8.84 × 10−12 | 7 |
CREBBP | 16p13.3 | 38 | 1.40 × 10−21 | 1.85 × 10−3 | 7 |
FLG | 1q21.3 | 33 | 3.22 × 10−17 | 4.48 × 10−9 | 7 |
KMT2D | 12q13.12 | 17 | 3.06 × 10−17 | 6.93 × 10−4 | 7 |
AHCTF1 | 1q44 | 10 | 1.20 × 10−7 | 3.48 × 10−4 | 7 |
ASPM * | 1q31.3 | 10 | 1.17 × 10−12 | 5.39 × 10−24 | 7 |
MYO18B | 22q12.1 | 4 | 4.93 × 10−16 | 3.73 × 10−6 | 7 |
USP34 | 2p15 | 4 | 2.38 × 10−3 | 1.36 × 10−2 | 7 |
KIF26B | 1q44 | 79 | 8.82 × 10−15 | 7.07 × 10−16 | 6 |
SPTBN1 | 2p16.2 | 54 | 4.56 × 10−24 | 8.06 × 10−21 | 6 |
LRP1 | 12q13.3 | 52 | 5.94 × 10−23 | 1.08 × 10−17 | 6 |
COL18A1 | 21q22.3 | 47 | 1.17 × 10−21 | 1.41 × 10−3 | 6 |
ARID1B * | 6q25.3 | 43 | 1.71 × 10−16 | 5.95 × 10−3 | 6 |
ZNF512B | 20q13.33 | 42 | 3.57 × 10−24 | 4.92 × 10−5 | 6 |
AHNAK * | 11q12.3 | 30 | 8.81 × 10−23 | 1.94 × 10−24 | 6 |
CACNA1B | 9q34.3 | 24 | 6.13 × 10−15 | 1.31 × 10−7 | 6 |
STAB1 | 3p21.1 | 19 | 1.17 × 10−17 | 2.65 × 10−4 | 6 |
LAMA3 | 18q11.2 | 18 | 1.13 × 10−22 | 7.72 × 10−19 | 6 |
Gene Symbol | Chromosome | Methylation | RNAseq | Somatic Events | GWAS | |||
---|---|---|---|---|---|---|---|---|
DM Sites | Adjust p-Value | Adjust p-Value | SNP | p-Value | Event | |||
BRCA1 | 17q21.31 | 12 | 2.01 × 10−5 | 2.78 × 10−3 | 5 | rs1799950 | 2.00 × 10−4 | 2 |
FHOD3 | 18q12.2 | 11 | 8.83 × 10−14 | 9.05 × 10−11 | 5 | rs9956546 | 2.90 × 10−6 | 2 |
MYO10 | 5p15.1 | 45 | 1.86 × 10−19 | 2.29 × 10−11 | 4 | rs2562343 | 9.20 × 10−3 | 2 |
CNTNAP2 | 7q35 | 30 | 8.36 × 10−17 | 1.83 × 10−3 | 4 | rs10487920 | 3.90 × 10−4 | 2 |
RELN | 7q22.1 | 12 | 1.92 × 10−13 | 2.94 × 10−18 | 4 | rs17157903 | 1.00 × 10−2 | 2 |
MSH3 | 5q14.1 | 10 | 2.46 × 10−10 | 7.38 × 10−15 | 4 | rs6151904 | 1.24 × 10−2 | 2 |
ATM | 11q22.3 | 20 | 9.88 × 10−7 | 1.47 × 10−5 | 3 | rs1801516 | 2.00 × 10−4 | 2 |
MTHFR | 1p36.22 | 9 | 7.33 × 10−12 | 1.33 × 10−6 | 3 | rs180113 | 4.10 × 10−2 | 2 |
PALB2 | 16p12.2 | 3 | 1.54 × 10−2 | 1.87 × 10−3 | 3 | deletion | 4.00 × 10−4 | 2 |
FBXL7 | 5p15.1 | 35 | 2.85 × 10−19 | 9.65 × 10−12 | 2 | rs12652447 | 5.60 × 10−4 | 2 |
NUMA1 | 11q13.4 | 28 | 7.97 × 10−20 | 1.17 × 10−7 | 2 | rs3750913 | 1.00 × 10−2 | 2 |
RB1 | 13q14.2 | 24 | 2.24 × 10−21 | 9.05 × 10−11 | 2 | rs2854344 | 7.00 × 10−3 | 2 |
AACS | 12q24.31 | 19 | 1.04 × 10−15 | 1.12 × 10−3 | 2 | rs7307700 | 2.00 × 10−2 | 2 |
WRN | 8p12 | 15 | 3.30 × 10−16 | 3.19 × 10−4 | 2 | rs1346044 | 2.00 × 10−2 | 2 |
GRIN3A | 9q31.1 | 12 | 7.03 × 10−11 | 8.98 × 10−5 | 2 | rs10512287 | 2.30 × 10−4 | 2 |
BID | 22q11.21 | 11 | 3.11 × 10−22 | 3.39 × 10−10 | 2 | rs8190315 | 1.00 × 10−2 | 2 |
DMBT1 | 10q26.13 | 11 | 3.79 × 10−18 | 1.85 × 10−7 | 2 | rs11523871 | 2.00 × 10−3 | 2 |
FOXM1 | 12p13.33 | 8 | 1.67 × 10−6 | 2.57 × 10−24 | 2 | rs2074985 | 3.40 × 10−2 | 2 |
MSH6 | 2p16.3 | 8 | 1.11 × 10−11 | 5.51 × 10−10 | 2 | rs3136337 | 3.39 × 10−2 | 2 |
MTR | 1q43 | 4 | 7.78 × 10−10 | 7.42 × 10−3 | 2 | rs1805087 | 2.00 × 10−2 | 2 |
DSEL | 18q22.1 | 2 | 2.37 × 10−14 | 4.19 × 10−19 | 2 | rs17827708 | 9.00 × 10−3 | 2 |
FANCG | 9p13.3 | 2 | 1.85 × 10−16 | 8.14 × 10−14 | 2 | rs4986940 | 2.79 × 10−2 | 2 |
EHMT2 | 6p21.33 | 99 | 6.80 × 10−20 | 4.19 × 10−12 | 1 | rs535586 | 1.00 × 10−2 | 2 |
MCC | 5q22.2 | 45 | 3.79 × 10−18 | 1.41 × 10−17 | 1 | rs6890833 | 3.40 × 10−2 | 2 |
PRDM2 | 1p36.21 | 31 | 4.55 × 10−18 | 1.41 × 10−8 | 1 | rs2235515 | 2.00 × 10−2 | 2 |
POR | 7q11.23 | 20 | 5.42 × 10−21 | 2.25 × 10−13 | 1 | rs10262966 | 3.00 × 10−2 | 2 |
KCNJ6 | 21q22.13 | 17 | 8.09 × 10−18 | 8.25 × 10−15 | 1 | rs4817896 | 2.40 × 10−2 | 2 |
SORBS1 | 10q24.1 | 17 | 8.00 × 10−9 | 5.09 × 10−23 | 1 | rs10450393 | 1.00 × 10−2 | 2 |
SHBG | 17p13.1 | 14 | 3.97 × 10−12 | 5.12 × 10−5 | 1 | rs858524 | 3.00 × 10−2 | 2 |
VDR | 12q13.11 | 14 | 1.39 × 10−18 | 6.75 × 10−3 | 1 | rs731236 | 3.00 × 10−2 | 2 |
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Wu, J.; Mamidi, T.K.K.; Zhang, L.; Hicks, C. Deconvolution of the Genomic and Epigenomic Interaction Landscape of Triple-Negative Breast Cancer. Cancers 2019, 11, 1692. https://doi.org/10.3390/cancers11111692
Wu J, Mamidi TKK, Zhang L, Hicks C. Deconvolution of the Genomic and Epigenomic Interaction Landscape of Triple-Negative Breast Cancer. Cancers. 2019; 11(11):1692. https://doi.org/10.3390/cancers11111692
Chicago/Turabian StyleWu, Jiande, Tarun Karthik Kumar Mamidi, Lu Zhang, and Chindo Hicks. 2019. "Deconvolution of the Genomic and Epigenomic Interaction Landscape of Triple-Negative Breast Cancer" Cancers 11, no. 11: 1692. https://doi.org/10.3390/cancers11111692