Background
Methods
Patient cohorts
IORS LABC cohort
Erasmus breast cancer cohort
RNA extraction from FFPE tissue
Microarray hybridization and data analysis
Quantitative RT-PCR and statistical analysis
Erasmus dataset processing and statistical analysis
Results
Molecular signature of radiosensitivity in LABC tumour samples
# | Gene Symbol | Gene Name | FDR-adjusted q-value | Fold Change | Super-Pathways |
---|---|---|---|---|---|
1 | ST3GAL4 | ST3 beta-galactoside alpha-2,3-sialyltransferase 4 |
0.03715
##
|
0.10
|
protein glycosylation
|
2 | C6orf105 (ADTRP) | chromosome 6 open reading frame 105 (Androgen-Dependent TFPI-Regulating Protein) |
0.03715
##
|
0.17
| No Data Available |
3 | RAP1GAP2 | RAP1 GTPase activating protein 2 |
0.03781
##
|
0.18
|
Immune System
|
4 | A1CF | APOBEC1 complementation factor |
0.03874
##
|
0.17
| mRNA Editing and Processing of Capped Intron-Containing Pre-mRNA |
5 | MAP3K4 | mitogen-activated protein kinase kinase kinase 4 |
0.03874
##
|
0.25
|
MAPK signaling pathway
|
6 | CHD5 | chromodomain helicase DNA binding protein 5 |
0.05133
#
|
0.15
|
ATP-dependent helicase activity
|
7 | LAS1L | LAS1-like (S. cerevisiae) |
0.05209
#
|
0.19
|
biogenesis of the 60S ribosomal subunit.
|
8 | DEFB128 | defensin, beta 128 |
0.05781
#
|
0.29
|
Immune System
|
9 | ENHO | energy homeostasis associated |
0.05781
#
|
0.23
|
metabolism
|
10 | CECR9 | cat eye syndrome chromosome region, candidate 9 (non-protein coding) |
0.05781
#
|
0.20
|
unknown
|
11 | IDO1 | indoleamine 2,3-dioxygenase 1 |
0.05781
#
|
0.20
|
Tryptophan metabolism
|
12 | LRRC55 | leucine rich repeat containing 55 |
0.05788
#
|
0.14
|
ion channel
|
13 | ROGDI | rogdi homolog (Drosophila) |
0.05788
#
|
0.26
|
unknown
|
14 | KRT25 | keratin 25 |
0.05796
#
|
0.22
|
cytoskeleton
|
15 | LAMA4 | laminin, alpha 4 |
0.05798
#
|
0.25
|
Focal Adhesion, ECM-receptor interaction
|
16 | PLA2G2C | phospholipase A2, group IIC |
0.05798
#
|
0.15
|
alpha-Linolenic acid metabolism and Glycerophospholipid biosynthesis
|
17 | CCDC114 | coiled-coil domain containing 114 |
0.05798
#
|
0.25
|
cell motility
|
18 | CNGB1 | cyclic nucleotide gated channel beta 1 |
0.05798
#
|
0.27
|
cAMP binding and intracellular cAMP activated cation channel activity
|
19 | PRSS53 | protease, serine, 53 |
0.05798
#
|
0.30
|
serine-type endopeptidase activity
|
20 | GSG1 | germ cell associated 1 |
0.05798
#
|
0.22
|
RNA polymerase binding
|
Candidate gene validation by qRT PCR
# | Gene Symbol | Amplicon Length | Responders (R)(n = 30) | Non-responders (NR)(n = 12) | p-value | Fold change | ||
---|---|---|---|---|---|---|---|---|
mean | sd | mean | sd | |||||
1 | APOA1 |
63
| 5.99 | 1.96 | 7.55 | 1.37 |
0.0161**
| 0.34 |
2 | CHEK2 | 109 | −4.63 | 1.69 | −4.18 | 1.06 | 0.390 | 0.73 |
3 | IDO1 |
106
| 1.06 | 2.87 | 0.63 | 2.82 | 0.662 | 1.35 |
4 | MAP3K4 | 89 | −3.00 | 1.99 | −1.78 | 1.28 | 0.0582* | 0.43 |
5 | MCM6 |
109
| −5.12 | 1.98 | −4.88 | 2.34 | 0.741 | 0.85 |
6 | MMP14 | 92 | 7.85 | 2.85 | 9.61 | 2.03 |
0.0596*
| 0.30 |
7 | ST3GAL4 |
60
| −3.95 | 2.68 | −3.38 | 3.32 | 0.566 | 0.67 |
8 | WHSC1L1 |
67
| −0.98 | 3.90 | −1.16 | 4.61 | 0.979 | 1.13 |
9 | XRCC2 |
66
| −4.68 | 2.08 | −4.04 | 2.13 | 0.455 | 0.64 |
External validation of candidate gene predictive value for radiotherapy response
Variable | Reference vs. level | Hazard Ratio | (95% CI) | p-value |
---|---|---|---|---|
MAP3K4 level
| (low vs. high) | 2.54 | (1.42, 4.55) | 0.002* |
ER/PR status
| (ER+/PR+ vs. ER-/PR+ or ER+/PR-, ER-/PR-) | 1.20 | (0.94, 1.52) | 0.146 |
Age
| (under 40 vs. 40–55, 56–70, over 70) | 0.81 | (0.53, 1.24) | 0.332 |
Menopause
| (pre-menopausal vs. postmenopausal) | 1.19 | (0.58, 2.42) | 0.639 |
T-stage
| (T1 vs. T2, T3, T4) | 1.08 | (0.75, 1.55) | 0.697 |
MAP3K4 level | Radiotherapy | Hazard Ratio | (95% CI) | p-value |
---|---|---|---|---|
low | no | Reference = 1 | ||
low | yes | 1.33 | (0.38, 4.63) | 0.652 |
high | no | 1.97 | (0.56, 6.97) | 0.294 |
high | yes | 3.21 | (1.02, 10.15) | 0.047* |