MYC DNA Methylation in Prostate Tumor Tissue is Associated with Gleason Score
Abstract
:1. Introduction
2. Materials and Methods
2.1. Study Samples
2.2. Nucleic Acid Extraction/Preparation and RNA Quality Assessment
2.3. MYC DNA Methylation Assays
2.4. RNA Expression Data
2.5. The Cancer Genome Atlas (TCGA) DNA Methylation Data
2.6. Statistical Analysis
3. Results
3.1. Study Population Characteristics
3.2. MYC DNA Methylation CpG-CpG Correlations and Prostate Tumor–Normal Differences
3.3. MYC DNA Methylation Differences by GS in Prostate Tumor Tissue
3.4. RNA Expression Tumor-Normal Differences and Differences by GS in Prostate Tumor Tissue
3.5. Prostate tumor MYC DNA methylation and RNA expression in prostate tumor tissue
4. Discussion
Author Contributions
Funding
Acknowledgments
Conflicts of Interest
Appendix A
Assay ID | Genomic Target Sequence | Bisulfite Converted Target Sequence | Pyrosequencing Dispensation Order |
---|---|---|---|
ADS3573-FS | ACTTGTTGCGGAAACGACGAGAACAG TTGAAACACAAACTTGAACAGCTACGG AACTCTTGTGCGTAAGGAAAAGTAAGG AAAACGATTCCTTCTAACAGAAATG | ATTTGTTGYGGAAAYGAYGAGAATA GTTGAAATATAAATTTGAATAGTTA YGGAATTTTTGTGYGTAAGGAAAAG TAAGGAAAAYGATTTTTTTTAATAG AAATG | ACTGTAGTCGATCGATCGAGATCAGTGA TCATCACTGATCAGCTGATCGACTCTGT GTCGTCAGAAGTCAGATCGA |
ADS3573-FS2 | AACTTGAACAGCTACGGAACTCTTGTG CGTAAGGAAAAGTAAGGAAAACGATT CCTTCTAACAGAAATGTCCTGA | AATTTGAATAGTTAYGGAATTTTTGT GYGTAAGGAAAAGTAAGGAAAAYG ATTTTTTTTAATAGAAATGTTTTGA | ACTGACTAGCTGATCGATCTGTAGTCGT AGAAGTAGAATCGA |
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Characteristic | Overall (n = 89) | GS 6 (n = 40) | GS 7 (n = 49) |
---|---|---|---|
Age at surgery, median (range) | 58 (42, 75) | 56.5 (42, 72) | 58 (47, 75) |
Age at diagnosis, median (range) | 57 (42, 75) | 56 (42, 72) | 57.5 (47, 75) |
Surgery year, n (col %) | |||
2001–2009 | 18 (20.2) | 18 (45.0) | 0 (0.0) |
2010–2017 | 71 (79.8) | 22 (55.0) | 49 (100.0) |
Race, n (col %) | |||
Caucasian | 46 (51.7) | 21 (52.5) | 25 (51.0) |
African American | 43 (48.3) | 19 (47.5) | 24 (49.0) |
Gleason pattern, n (col %) | |||
3 + 3 | 40 (44.9) | 40 (100.0) | 0 (0.0) |
3 + 4 | 35 (39.3) | 0 (0) | 35 (71.4) |
4 + 3 | 14 (15.7) | 0 (0) | 14 (28.6) |
pT stage, n (col %) | |||
2 | 60 (67.4) | 29 (72.5) | 31 (63.3) |
3a | 11 (12.4) | 2 (5.0) | 9 (18.4) |
3b | 7 (7.9) | 1 (2.5) | 6 (12.2) |
3—not specified | 4 (4.5) | 1 (2.5) | 3 (6.1) |
Unknown | 7 (7.9) | 7 (17.5) | 0 (0.0) |
pN status, n (col %) | |||
N0 | 55 (61.8) | 15 (37.5) | 40 (81.6) |
N1 | 3 (3.4) | 0 (0.0) | 3 (6.1) |
Unknown | 31 (34.8) | 25 (62.5) | 6 (12.2) |
PSA (ng/mL), median (IQR) | 6.2 (4.8, 8.0) | 6.2 (4.7, 7.2) | 6.6 (5.0, 9.0) |
CpG Site (GRCH37/hg19 Coordinate) | Median % DNA methylation (IQR) for Normal Prostate Tissue Samples | Median % DNA methylation (IQR) for Prostate Tumor Tissue Samples | Median Tumor-Normal Difference in % DNA Methylation (IQR) | Wilcoxon Signed-Rank p-Value a |
---|---|---|---|---|
University of Maryland samples (n = 89 pairs) | ||||
CpG 212 (Chr8:128753145) | 88.27 (85.32, 91.48) | 88.29 (82.35, 91.07) | −0.20 (−7.58, 2.91) | 0.06 |
CpG 213 (Chr8:128753151) | 85.65 (82.00, 88.48) | 78.72 (72.39, 84.20) | −7.36 (−18.40, 0.43) | 1.8 × 10−8 |
CpG 214 (Chr8:128753154) | 89.72 (87.03, 93.23) | 86.09 (78.82, 90.38) | −2.98 (−11.38, 2.04) | 4.9 × 10−5 |
CpG 215 (Chr8:128753187) | 86.65 (83.90, 89.65) | 82.68 (79.23, 87.12) | −2.84 (−9.79, 0.67) | 1.7 × 10−6 |
CpG 216 (Chr8:128753200) | 83.39 (80.67, 86.29) | 81.41 (77.56, 85.22) | −1.88 (−5.70, 2.00) | 3.9 × 10−3 |
CpG 217 (Chr8:128753221) | 66.66 (60.81, 71.15) | 49.09 (41.30, 58.63) | −14.74 (−25.53, −6.86) | 9.1 × 10−19 |
Across all 6 CpG sites | 83.23 (81.77, 84.82) | 77.40 (73.43, 81.46) | −4.01 (−12.12, 1.32) | 5.9 × 10−14 |
TCGA samples (n = 50 pairs) | ||||
cg00163372 (Chr8:128752987) | 94.52 (91.57, 95.50) | 84.62 (78.10, 92.01) | −6.89 (−16.92, −2.47) | 9.4 × 10−7 |
cg08526705 (Chr8:128753028) | 93.01 (91.03, 94.42) | 87.30 (80.87, 91.82) | −5.46 (−13.41, −0.32) | 1.3 × 10−5 |
Decreasing DNA Methylation (GRCH37/hg19 Coordinate) | Overall, n = 89 OR (95% CI) | African American, n = 43 OR (95% CI) | Caucasian, n = 46 OR (95% CI) | p-int b |
---|---|---|---|---|
CpG 212 (Chr8:128753145) | 1.10 (1.03–1.18) | 1.23 (1.04–1.45) | 1.07 (1.00–1.15) | 0.15 |
CpG 213 (Chr8:128753151) | 1.02 (0.99–1.06) | 1.06 (0.99–1.14) | 1.01 (0.97–1.05) | 0.20 |
CpG 214 (Chr8:128753154) | 1.07 (1.02–1.13) | 1.08 (0.99–1.17) | 1.07 (1.00–1.14) | 0.87 |
CpG 215 (Chr8:128753187) | 1.03 (0.97–1.09) | 1.09 (0.98–1.20) | 1.00 (0.94–1.07) | 0.19 |
CpG 216 (Chr8:128753200) | 1.08 (1.01–1.16) | 1.15 (0.99–1.32) | 1.06 (0.98–1.15) | 0.36 |
CpG 217 (Chr8:128753221) | 1.01 (0.98–1.04) | 1.01 (0.96–1.06) | 1.01 (0.97–1.06) | 0.99 |
Across all 6 sites | 1.01 (1.00–1.02) | 1.01 (1.00–1.02) | 1.01 (0.99–1.03) | 0.89 |
Tumor-Normal Difference (n = 100 Pairs a) | Differences by GS (n = 100 Tumor Tissue Samples a) | ||||||
---|---|---|---|---|---|---|---|
Gene/ncRNA | GRCH37/hg19 Coordinate from UCSC Genome Browser | Human Clariom D TC | Median Difference in log2 Expression (IQR) | Wilcoxon Signed-Rank p | GS 6, Median log2 Expression (IQR) | GS 7, Median log2 Expression (IQR) | Wilcoxon Rank Sum p |
MYC | chr8:128748315–128753680 | TC0800008845.hg.1 | 0.2 (−0.2, 0.5) | 0.01 | 5.9 (5.6, 6.2) | 5.9 (5.7, 6.4) | 0.21 |
UPSTREAM of MYC | |||||||
PCAT1 | chr8:128025399–128033259 | TC0800008832.hg.1 | 0.1 (−0.2, 0.4) | 0.06 | 4.2 (4.0, 4.4) | 4.1 (3.9, 4.3) | 0.18 |
PCAT2 | chr8:128084939–128094466 | TC0800012460.hg.1 | 0.1 (−0.5, 0.7) | 0.39 | 4.0 (3.6, 4.3) | 3.9 (3.5, 4.3) | 0.69 |
PRNCR1 | chr8:128092119–128104840 | TC0800008833.hg.1 | 0.2 (−0.2, 0.7) | 1.6 × 10−4 | 4.3 (4.1, 4.6) | 4.4 (4.1, 4.7) | 0.64 |
RP11-255B23.1 | chr8:128098508–128099755 | TC0800012461.hg.1 | −0.7 (−0.3, 0.2) | 0.04 | 4.3 (4.1, 4.6) | 4.4 (4.2, 4.8) | 0.08 |
CASC19 | chr8:128200030–128209872 | TC0800012462.hg.1 | 0.0 (−0.2, 0.3) | 0.52 | 3.4 (3.3, 3.7) | 3.4 (3.2, 3.7) | 0.22 |
CCAT1 | chr8:128219627–128231513 | TC0800012463.hg.1 | 0.1 (−0.3, 0.5) | 0.10 | 3.5 (3.3, 3.9) | 3.2 (3.0, 3.6) | 1.5 × 10−3 |
CASC21 | chr8:128256882–128404876 | TC0800008836.hg.1 | 0.0 (−0.2, 0.4) | 0.17 | 3.7 (3.5, 4.1) | 3.7 (3.3, 3.9) | 0.35 |
RP11-382A18.3 | chr8:128304478–128304685 | TC0800008837.hg.1 | 0.2 (−0.2, 0.8) | 6.8 × 10−4 | 5.5 (5.3, 5.8) | 5.6 (5.1, 6.1) | 0.81 |
CCAT2 | chr8:128412644–128414395 | TC0800008838.hg.1 | 0.1 (−0.3, 0.3) | 0.53 | 3.4 (3.2, 3.5) | 3.3 (3.2, 3.6) | 0.83 |
POU5F1B | chr8:128428070–128429455 | TC0800008839.hg.1 | 0.1 (−0.2, 0.5) | 0.02 | 5.1 (4.8, 5.4) | 5.0 (4.8, 5.2) | 0.13 |
CASC8 | chr8:128455595–128494384 | TC0800012464.hg.1 | 0.0 (−0.3, 0.5) | 0.34 | 3.2 (3.0, 3.5) | 3.3 (3.1, 3.5) | 0.70 |
LOC727677 | chr8:128455595–128494384 | (same as above) | |||||
CASC11 | chr8:128712853–128746213 | TC0800011782.hg.1 | 0.0 (−0.3, 0.4) | 0.40 | 3.8 (3.4, 4.1) | 3.7 (3.4, 3.9) | 0.56 |
DOWNSTREAM OF MYC | |||||||
PVT1 | chr8:128806779–129113499 | TC0800008848.hg.1 | 0.0 (−0.5, 0.5) | 0.75 | 4.6 (4.2, 4.9) | 4.4 (4.0, 5.0) | 0.72 |
miR-1204 | chr8:128808208–128808274 | (same as above) | |||||
TMEM75 | chr8:128958805–128960969 | TC0800011789.hg.1 | 0.0 (−0.3, 0.4) | 0.49 | 3.9 (3.7, 4.1) | 3.8 (3.6, 4.1) | 0.33 |
miR-1205 | chr8:128972879–128972941 | TC0800008855.hg.1 | 0.0 (−0.7, 0.8) | 0.92 | 4.8 (4.2, 5.4) | 4.8 (4.5, 5.6) | 0.34 |
RNU1-106P | chr8:129011377–129011540 | TC0800008856.hg.1 | 0.0 (−0.4, 0.5) | 0.96 | 13.9 (13.3, 14.5) | 14.2 (13.6, 14.9) | 0.09 |
RNU4-25P | chr8:129022628–129022857 | TC0800011790.hg.1 | 0.2 (−0.2, 0.5) | 0.02 | 5.8 (5.5, 6.2) | 5.3 (4.9, 5.6) | 3.6 × 10−5 |
RN7SKP226 | chr8:129232750–129232998 | TC0800008864.hg.1 | −0.1 (−0.7, 0.3) | 0.12 | 5.2 (4.7, 5.7) | 5.4 (4.9, 5.9) | 0.31 |
miR-1206 | chr8:129021144–129021202 | TC0800008857.hg.1 | 0.4 (−0.9, 1.6) | 0.07 | 5.9 (4.1, 7.8) | 6.5 (4.9, 8.0) | 0.38 |
miR-1207 | chr8:129061398–129061484 | TC0800008858.hg.1 | 0.1 (−0.1, 0.3) | 0.05 | 4.2 (4.1, 4.4) | 4.2 (4.1, 4.5) | 0.86 |
miR-1208 | chr8:129162362–129162434 | TC0800008862.hg.1 | 0.0 (−0.2, 0.3) | 0.44 | 4.6 (4.5, 4.9) | 4.6 (4.4, 4.8) | 0.06 |
Non-coding RNA | Description | Coordinates (GRCh37/hg19) | MYC CpG Site and Position (hg19) | Linear regression β (s.e.); p-Value (q-Value) a |
---|---|---|---|---|
PRNCR1 | prostate cancer associated non-coding RNA 1 | chr8:128092119–128104840 | CpG 216 (chr8:128753200) CpG 217 (chr8:128753221) | β = −0.022 (0.007); p = 2.0 × 10−3 (q = 0.04) β = −0.0094 (0.0039); p = 0.02 (q = 0.20) |
CASC11 | cancer susceptibility candidate 11 (non-protein coding), transcript variant 2 | chr8:128712853–128746213 | CpG 212 (chr8:128753145) CpG 217 (chr8:128753221) | β = −0.011 (0.005); p = 0.05 (q = 0.59) β = −0.010 (0.003); p = 4.1 × 10−3 (q = 0.09) |
miR-1206 | microRNA 1206 | chr8:129021144–129021202 | CpG 212 (chr8:128753145) | β = 0.053 (0.025); p = 0.03 (q = 0.59) |
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Barry, K.H.; Mohanty, K.; Erickson, P.A.; Wang, D.; Shi, J.; Rose, G.; Cellini, A.; Clark, K.; Ambulos, N., Jr.; Yin, J.; et al. MYC DNA Methylation in Prostate Tumor Tissue is Associated with Gleason Score. Genes 2021, 12, 12. https://0-doi-org.brum.beds.ac.uk/10.3390/genes12010012
Barry KH, Mohanty K, Erickson PA, Wang D, Shi J, Rose G, Cellini A, Clark K, Ambulos N Jr., Yin J, et al. MYC DNA Methylation in Prostate Tumor Tissue is Associated with Gleason Score. Genes. 2021; 12(1):12. https://0-doi-org.brum.beds.ac.uk/10.3390/genes12010012
Chicago/Turabian StyleBarry, Kathryn Hughes, Kareshma Mohanty, Patricia A. Erickson, Difei Wang, Jianxin Shi, Gary Rose, Ashley Cellini, Kimberly Clark, Nicholas Ambulos, Jr., Jing Yin, and et al. 2021. "MYC DNA Methylation in Prostate Tumor Tissue is Associated with Gleason Score" Genes 12, no. 1: 12. https://0-doi-org.brum.beds.ac.uk/10.3390/genes12010012