Epigenetic Scanning of KEAP1 CpG Sites Uncovers New Molecular-Driven Patterns in Lung Adeno and Squamous Cell Carcinomas
Abstract
:1. Introduction
2. Materials and Methods
2.1. KEAP1 Promoter and Intragenic CpGs
2.2. TCGA Data Analysis
2.3. Statistical Analysis
3. Results
3.1. KEAP1 Is Hypermethylated in Tumor Compared to Non-Neoplastic Tissues
3.2. KEAP1 CpGs Methylation Inversely Correlates with mRNA Expression of KEAP1
3.3. Identification of Gene Expression Signature Associated with KEAP1 Methylation in NSCLC
4. Discussion
5. Conclusions
Supplementary Materials
Author Contributions
Funding
Conflicts of Interest
References
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Gene Symbol | CpG | Chromosome | Exonic/Intronic Location | Strand | Start | End |
---|---|---|---|---|---|---|
KEAP1 | cg25801292 | chr19 | Exon 1 | + | 10614272 | 10614273 |
KEAP1 | cg02428100 | chr19 | Exon 1 | − | 10614022 | 10614023 |
KEAP1 | cg26500801 | chr19 | Intron 1 | − | 10613855 | 10613856 |
KEAP1 | cg03890664 | chr19 | Intron 1 | + | 10613492 | 10613493 |
KEAP1 | cg15676203 | chr19 | Intron 1 | + | 10613488 | 10613489 |
KEAP1 | cg06911149 | chr19 | Intron 1 | + | 10613456 | 10613457 |
KEAP1 | cg15204119 | chr19 | Intron 1 | + | 10613180 | 10613181 |
KEAP1 | cg26988016 | chr19 | Intron 1 | + | 10612802 | 10612803 |
KEAP1 | cg20226327 | chr19 | Intron 2 | − | 10602960 | 10602961 |
KEAP1 | cg10505024 | chr19 | Exon 3 | + | 10602877 | 10602878 |
KEAP1 | cg07695362 | chr19 | Exon 3 | − | 10602691 | 10602692 |
KEAP1 | cg00522555 | chr19 | Exon 3 | - | 10602587 | 10602588 |
KEAP1 | cg01018726 | chr19 | Exon 3 | − | 10602314 | 10602315 |
KEAP1 | cg22779878 | chr19 | Exon 4 | + | 10600446 | 10600447 |
KEAP1 | cg02337283 | chr19 | Exon 5 | + | 10599976 | 10599977 |
KEAP1 | cg01586432 | chr19 | Exon 6 | − | 10597016 | 10597017 |
Characteristics | Total | Characteristics | Total |
---|---|---|---|
All Stages | Non-Metastatic Disease | ||
Cohort size (n) | 617 | 128 | |
Age at diagnosis Mean ± devst | 65.94 ± 9.88 | Age at diagnosis Mean ± devst | 64.55 ± 9.82 |
Sex | Sex | ||
Male | 284 (46%) | Male | 60 (46.9%) |
Female | 333 (54%) | Female | 68 (53.1%) |
Race | Race | ||
White | 465 (75.4%) | White | 101 (78.9%) |
Black or African American | 59 (9.6%) | Black or African American | 19 (14.8%) |
Asian | 10 (1.6%) | Asian | 2 (1.6%) |
NA | 83 (13.5%) | NA | 6 (4.7%) |
Number of packs/year Mean ± SD | 41.63 ± 27.22 | Number of packs/year Mean ± SD | 41.62 ± 24.71 |
Stage of disease | Stage of disease | ||
Stage I | 5 (0.8%) | Stage I | 1 (0.8%) |
Stage IA | 164 (26.6%) | Stage IA | 47 (36.7%) |
Stage IB | 163 (26.4%) | Stage IB | 30 (23.4%) |
Stage II | 1 (0.2%) | Stage II | 1 (0.8%) |
Stage IIA | 63 (10.2%) | Stage IIA | 22 (17.2%) |
Stage IIB | 87 (14.1%) | Stage IIB | 14 (10.9%) |
Stage IIIA | 98 (15.9%) | Stage IIIA | 13 (10.2%) |
Stage IV | 28 (4.5%) | ||
NA | 8 (1.3%) |
Characteristics | Total | Characteristics | Total |
---|---|---|---|
All Stages | Non-Metastatic Disease | ||
Cohort size (n) | 571 | 141 | |
Age at diagnosis Mean ± SD | 67.65 ± 8.58 | Age at diagnosis Mean ± SD | 65.91 ± 8.66 |
Sex | Sex | ||
Male | 424 (74.3%) | Male | 112 (79.4%) |
Female | 147 (25.7%) | Female | 29 (20.6%) |
Race | Race | ||
White | 402 (70.4%) | White | 124 (87.9%) |
Black or African American | 40 (7%) | Black or African American | 4 (2.8%) |
Asian | 10 (1.8%) | Asian | 4 (2.8%) |
NA | 119 (20.8%) | NA | 9 (6.4%) |
Number of packs/year Mean ± SD | 53.62 ± 32.12 | Number of packs/year Mean ± SD | 49.29 ± 25.24 |
Stage of disease | Stage of disease | ||
Stage I | 5 (0.9%) | Stage IA | 29 (20.6%) |
Stage IA | 107 (18.7%) | Stage IB | 40 (28.4%) |
Stage IB | 172 (30.1%) | Stage IIA | 30 (21.3%) |
Stage II | 3 (0.5%) | Stage IIB | 24 (17%) |
Stage IIA | 75 (13.1%) | Stage IIIA | 18 (12.8%) |
Stage IIB | 108 (18.9%) | ||
Stage III | 3 (0.5%) | ||
Stage IIIA | 66 (11.6%) | ||
Stage IIIB | 21 (3.7%) | ||
Stage IV | 7 (1.2%) | ||
NA | 4 (0.7%) |
CpG | Regulatory Feature | ||||||||
---|---|---|---|---|---|---|---|---|---|
Exonic/Intronic Location | Strand | Start | End | CpG | Feat Start | Feat End | Name | Score | UCSC Track |
Exon 1 | + | 10614272 | 10614273 | cg25801292 | 10613910 | 10614318 | E2F6 | 1000 | A |
Exon 1 | + | 10614272 | 10614273 | cg25801292 | 10613919 | 10614347 | E2F6_(H-50) | 1000 | A |
Exon 1 | − | 10614022 | 10614023 | cg02428100 | 10613910 | 10614318 | E2F6 | 1000 | A |
Exon 1 | − | 10614022 | 10614023 | cg02428100 | 10613919 | 10614347 | E2F6_(H-50) | 1000 | A |
Intron 2 | − | 10602960 | 10602961 | cg20226327 | 10602751 | 10603103 | CTCF | 1000 | A |
Exon 3 | + | 10602877 | 10602878 | cg10505024 | 10602751 | 10603103 | CTCF | 1000 | A |
Exon 1 | + | 10614272 | 10614273 | cg25801292 | 10612580 | 10614352 | POLR2A | 1000 | B |
Exon 1 | + | 10614272 | 10614273 | cg25801292 | 10612955 | 10614326 | PHF8 | 1000 | B |
Exon 1 | + | 10614272 | 10614273 | cg25801292 | 10613272 | 10614430 | MAX | 1000 | B |
Exon 1 | + | 10614272 | 10614273 | cg25801292 | 10613814 | 10614366 | E2F6 | 1000 | B |
Exon 1 | - | 10614022 | 10614023 | cg02428100 | 10612580 | 10614352 | POLR2A | 1000 | B |
Exon 1 | − | 10614022 | 10614023 | cg02428100 | 10612955 | 10614326 | PHF8 | 1000 | B |
Exon 1 | − | 10614022 | 10614023 | cg02428100 | 10613272 | 10614430 | MAX | 1000 | B |
Exon 1 | − | 10614022 | 10614023 | cg02428100 | 10613814 | 10614366 | E2F6 | 1000 | B |
Intron 2 | − | 10602960 | 10602961 | cg20226327 | 10602731 | 10603130 | CTCF | 1000 | B |
Exon 3 | + | 10602877 | 10602878 | cg10505024 | 10602731 | 10603130 | CTCF | 1000 | B |
Exon 3 | − | 10602691 | 10602692 | cg07695362 | 10602731 | 10603130 | CTCF | 1000 | B |
Exon 5 | + | 10599976 | 10599977 | cg02337283 | 10599967 | 10599986 | V$GR_Q6 | 850 | C |
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Fabrizio, F.P.; Mazza, T.; Castellana, S.; Sparaneo, A.; Muscarella, L.A. Epigenetic Scanning of KEAP1 CpG Sites Uncovers New Molecular-Driven Patterns in Lung Adeno and Squamous Cell Carcinomas. Antioxidants 2020, 9, 904. https://doi.org/10.3390/antiox9090904
Fabrizio FP, Mazza T, Castellana S, Sparaneo A, Muscarella LA. Epigenetic Scanning of KEAP1 CpG Sites Uncovers New Molecular-Driven Patterns in Lung Adeno and Squamous Cell Carcinomas. Antioxidants. 2020; 9(9):904. https://doi.org/10.3390/antiox9090904
Chicago/Turabian StyleFabrizio, Federico Pio, Tommaso Mazza, Stefano Castellana, Angelo Sparaneo, and Lucia Anna Muscarella. 2020. "Epigenetic Scanning of KEAP1 CpG Sites Uncovers New Molecular-Driven Patterns in Lung Adeno and Squamous Cell Carcinomas" Antioxidants 9, no. 9: 904. https://doi.org/10.3390/antiox9090904