Introduction
Methods
Inclusion Criteria
Exclusion Criteria
Literature Search
Study Data
Evidence Quality
Meta-Analysis
Heterogeneity and Bias
Results
Literature Search
Studies Assessing Germline Markers of Susceptibility
Variants Associated with BE Susceptibility
Marker | Individual studies | Association (meta-analysis/individual study) | ||||||||||||
---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
LOE | Variant | Gene | Association | EV | LOE | Ethnicity | Methodology | |||||||
Variant | Wild-type | None | Phenotype and OR (95 % CI) |
I
2
| Chi |
p
|
n
| |||||||
III | rs9257809 | MHC region | A | C | Caucasian | Multistage GWAS Pro/retro archived | BEA 1.21 (1.13–1.28) | NA | NA | 4.09 × 10−9
| 1 | |||
rs9936833 |
FOXF1
| C | BEA 1.14 (1.10–1.19) | 2.74 × 10−10
| ||||||||||
rs3072 |
GDF7
| A | BEA 1.14 (1.09–1.18) | 1.75 × 10−11
| ||||||||||
rs2701108 |
TBX5
| A | BEA 0.90 (0.86–0.93) | 7.48 × 10−9
| ||||||||||
rs2687201 |
FOXP1
| T | BEA 1.16 (1.10–1.23) | 4.61 × 10−8
| ||||||||||
III | rs3776082 |
CDX1
| Ren et al. [43] | AA | C | Caucasian | Candidate Prospective | BE-v-RE 4.02 (1.80–9.00) | NA | NA | <0.005 | 1 | ||
III | rs2237091 |
CDX1
| Ren et al. [43] | AA | C | Caucasian | Candidate Prospective | BE-v-RE 0.28 (0.13–0.59) | NA | NA | <0.005 | 1 | ||
III | rs717746 |
CDX1
| Ren et al. [43] | GG | C | Caucasian | Candidate Prospective | BE-v-RE 3.65 (1.73–7.69 | NA | NA | <0.005 | 1 | ||
III | rs4444903 |
EGFR
| Menke et al. [20] | GG | C | Caucasian* | Candidate Retro archived | BEA 3.00 (1.50–6.20) | NA | NA | 0.002 | 1 | ||
III | rs917997 |
IL18RAP
| Babar et al. [29] | CC | C | Caucasian** | Candidate Retro archived | BEA 0.59 (0.43–0.80) | NA | NA | 6.00 × 10−4
| 1 | ||
III | rs6785049 |
PXR
| van de Winkel et al. [44] | G | C | Caucasian* | Candidate Retro archived | BE 1.36 (1.03–1.79) | NA | NA | <0.05 (NS) | 1 | ||
III | rs6214 |
IGF1
| McElholm [21] | AA | C | Caucasian** | Candidate Retro archived | BEA 0.43 (0.24–0.75) | NA | NA | 3.00 × 10−3
| 1 | ||
III | rs2229765 + BMI > 30 |
IGF1R
| MacDonald et al. [22] | A | C | Caucasian | Candidate Retro archived | BEA 3.11 (1.12–8.63) | NA | NA | <0.05 (NS) | 1 | ||
III | rs3212227 |
IL12B
| Moons et al. [26] | C | C | Caucasian* | Candidate Retro archived | BEA 1.82 (1.17–2.69) | NA | NA | 7.00 × 10−3
| 1 | ||
II | rs1695 |
GSTP
| Bull et al. [18] | G | C | Caucasian | Meta-analysis | BE 1.50 (1.16–1.95) | NA | NA | <0.01 | 4 | ||
Kala et al. [19] | G | Caucasian | Candidate (pro) | |||||||||||
Murphy et al. [45] | G | Caucasian | Candidate (retro) | |||||||||||
Casson et al. [46] | G | NP | Candidate (pro) | |||||||||||
van Lieshout et al. [47] | G | Caucasian | Candidate (pro) | |||||||||||
III | rs9344 |
CCND1
| Casson et al. [31] | AA | C | NP | Candidate (pro) | BEA 3.69 (1.46–9.29) | NA | NA | <0.05 (NS) | 1 | ||
III | rs25487 |
XRCC1
| Casson et al. [48] | Ferguson et al. [49] | AA | C | NP | Candidate (pro) | BEA 0.65 (0.25–1.68) | 71 % | 3.42 | 0.370 | 2 | |
AA | C | Caucasian | Candidate (retro) |
Marker | Individual studies | Association (meta-analysis/individual study) | |||||||||||
---|---|---|---|---|---|---|---|---|---|---|---|---|---|
LOE | Variant | Gene | Association | EV | LOE | Ethnicity | Methodology | ||||||
Variant | Wild-type | Phenotype and OR (95 % CI) |
I
2
| Chi |
p
|
n
| |||||||
III | rs3776083 |
CDX1
| Ren et al. [43] | AG | C | Caucasian | Candidate pro | BE-v-RE 1.91 (1.09–3.33) | NA | NA | 0.02 | 1 | |
III | rs4769585 |
CDX2
| Ren et al. [43] | CT | C | Caucasian | Candidate pro | BE-v-RE 2.68 (1.20–5.98) | NA | NA | 0.02 | 1 | |
III | rs3812863 |
CDX2
| Ren et al. [43] | AG | C | Caucasian | Candidate pro | BE-v-RE 2.53 (1.24–5.14) | NA | NA | 0.01 | 1 | |
III | rs1143634 |
IL1B
| Izakovicoka-Holla et al. [27] | T | Caucasian (Czeck) | Candidate pro | BE -v-RE 0.56 (0.33–0.93) | NA | NA | 0.016 | 1 | ||
III | VNTR polymorphism |
IL1RN
| Izakovicoka-Holla et al. [27] | 1/2 | Caucasian (Czeck) | Candidate pro | BE 0.62 (0.42–0.94) | NA | NA | 0.015 | 1 | ||
III | rs1800587/rs16944/ rs1143634/IL1RN |
IL1B/ILRN
| Izakovicoka-Holla et al. [27] | C/T/C/long | Caucasian (Czeck) | Candidate pro | BE 1.95 (1.09–1.30) | NA | NA | 0.03 | 1 | ||
III | rs1800587/rs16944/r s1143634/IL1RN |
IL1B/ILRN
| Izakovicoka-Holla et al. [27] | T/C/C/long | Caucasian (Czeck) | Candidate pro | BE 2.67 (1.15–6.24) | NA | NA | 0.02 | 1 | ||
III | rs909253 |
TNFB
| Menke et al. [50] | AA | C | Caucasian (Netherlands) | Candidate retro archived | BEA 1.98 (1.03–3.81) | NA | NA | 0.04 | 1 | |
III | rs2305764 |
Myo9b
| Menke et al. [51] | GG | C | Caucasian (Netherlands) | Candidate retro archived | BEA 2.96 (1.10–7.99) | NA | NA | 0.032 | 1 | |
III | rs1946518 |
IL18
| Babar et al. [29] | CC | Caucasian (Irish) | Candidate retro archived | BEA 1.45 (1.07–1.98) | NA | NA | 0.02 | 1 | ||
III | rs1799750 |
MMP1
| Bradbury et al. [52] | GG | Caucasian (USA) | Candidate retro archived | BEA 2.21 (1.08–4.53) | NA | NA | 0.03 | 1 | ||
III | rs11209026 |
IL23R
| Gaj et al. [30] | A | Caucasians (Polish) | Candidate pro | BE 3.49 (1.37–8.90) | NA | NA | 0.011 | 1 | ||
III | rs1800566 |
NQO1
| di Martino et al. [53] | T | NP (UK) | Candidate pro | BEA-v-RE 0.22 (0.07–0.76) | NA | NA | 0.016 | 1 | ||
III | B7 | HLA | Rajendra [54] | B7 | Asian (India) | Candidate pro | BEEx 21.4 (1.22–372 | NA | NA | 0.036 | 1 | ||
III | rs415958/rs16944 |
IL1RA/IL1B
| Gough et al. [28] | CC/A | NS (UK) | Candidate pro | BE-v-RE 9.5 (1.19–75.9) | NA | NA | 0.010 | 1 | ||
III | rs1800896 |
IL10
| Gough et al. [28] | CC | NS (UK) | Candidate pro | BE-v-RE 1.84 (1.04–3.28) | NA | NA | 0.035 | 1 |
Marker | Individual study | Meta-analysis | ||||||||
---|---|---|---|---|---|---|---|---|---|---|
Association | ||||||||||
Variant | Gene | EV | Variant | Wild-type | No association | OR (95 % CI) |
I
2
| Chi |
p
|
n
|
Null |
GSTM1
| Null | Null | Kadioglu et al. [55] | BE 0.83 (0.61–1.12) | 27 % | 4.12 | 0.220 | 4 | |
Kala et al. [19] | BEno IM 0.66 (0.44–0.99) | 0 % | 0.64 | 0.420 | 2 | |||||
Casson et al. [46] | BEIM 1.12 (0.70–1.80) | 0 % | 0.64 | 0.630 | 2 | |||||
van Lieshout et al. [56] | ||||||||||
rs4880 |
SOD2
| T | T | Kadioglu et al. [55], di Martino et al. [49] | BEIM 0.90 (0.65–1.24) | 0.00 | 0.07 | 0.520 | 3 | |
Murphy et al. [45] | ||||||||||
rs16944 |
IL1B
| AA | AA | Izakovicova-Holla et al. [27], Gough et al. [28] | BE 1.13 (0.63–2.03) | 0.00 | 0.00 | 0.680 | 2 | |
rs1052133 |
OGG1
| G | G | Kadioglu et al. [55], Ferguson et al. [49] | BEA IM 1.34 (0.59–3.09) | 67 % | 3.01 | 0.480 | 2 | |
rs25487 |
XRCC1
| TT | TT | Casson et al. [48] | Ferguson et al. [49] | BEA IM 0.65 (0.25–1.68) | 71 % | 3.42 | 0.370 | 2 |
rs13181 |
ERCC2
| CC | CC | Casson et al. [48], Fergusons et al. [49] | BEA IM 0.92 (0.57–1.48) | 31 % | 1.44 | 0.730 | 2 |
Studies Assessing Germline Variants Associated with Progression
Studies Assessing Somatic Variants Associated with Progression
Variants Associated with Progression
Marker | Individual study | Association (meta-analysis/individual study) | ||||||||||||
---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
LOE | Variant | Gene | Association | EV | LOE | Ethnicity | Phenotype | Adjusted for confounders? | ||||||
Variant | None | Phenotype and OR/HR (95 % CI) |
I
2
| Chi |
p
|
n
| ||||||||
II | CIN | NA | Bird-Lieberman et al. [36] | CIN | C | NP | HGD/EAC | Yes (plus length, dysplasia) | HGD/EAC OR(A) IM PB 5.98 (2.10–17.1) | 57 % | 16.2 | 8.00 × 10−4
| 5 | |
Sikkema et al. [37] | CIN | C | Cauc | HGD/EAC | Yes (plus dysplasia) | HGD/EAC HR(A) IM 1.36 (1.26–1.47) | 0 % | 0.98 | <1.00 × 10−5
| 2 | ||||
Chao et al. [57]* | CIN | C | NP | EAC | No | |||||||||
Galipeau et al. [38]* | CIN | C | NP | EAC | Yes (length, not dysplasia) | PB-adjusted for publication bias Fang 2004, Rabinovitch 2001, | ||||||||
Fang et al. [58] | CIN | C | NP | EAC | No | |||||||||
Maley et al. [39]* | CIN | C | NP | EAC | Yes (length, not dysplasia) | Teodori 1999 | ||||||||
Rabinovitch et al. [59]* | CIN | C | NP | EAC | Yes (length, not dysplasia) | |||||||||
Reid et al. [9]** | CIN | D | NP | EAC | No | Overlapping populations*** | ||||||||
Teodori et al. [60] | CIN | C | NP | HGD/EAC | No | |||||||||
Reid et al. [8]** | CIN | C | NP | EAC | No | |||||||||
James et al. [61] | CIN | D | NP | EAC | No | |||||||||
III | CNV | NA | Paulson et al. [62] | >70 Mbp | C | NP | EAC/CIN | No | EAC/CIN HR 4.90 (1.60–14.8) | NA | NA | 4.70 × 10−3 (NS) | 1 | |
III | LOH |
TP53
| Galipeau et al. [38]* | LOH | C | NP | EAC | Yes (length, not dysplasia) | EAC HRA 5.4 (2.5–12.0) | NA | NA | <1 × 10−3
| 1 | |
Maley et al. [39]* | LOH | C | ||||||||||||
Reid et al. [63]* | LOH | C | ||||||||||||
III | LOH |
P16
| Galipeau et al. [38]* | Maley et al. [39]* | LOH | C | NP | EAC | Yes (length, not dysplasia) | EACA HR 2.4 (1.0–5.5) | NA | NA | 0.045 | 1 |
LOH | C | NP | EAC | Yes (length, not dysplasia) | ||||||||||
III | Mutant |
TP53
| Galipeau et al. [38]* | Mutant | C | NP | EAC | No | EAC HRA 1.27 (1.07–1.50) | NA | NA | <0.01 (NS) | 1 | |
Maley et al. [39]* | Mutant | C | NP | EAC | Yes (length, not dysplasia) | |||||||||
Dolan et al. [64] | Mutant | C | NP | EAC | No | No meta possible as study population overlap and differing effect measures |
Variants Associated with Risk of Progression Following Photodynamic Therapy
Marker | Individual study | Association (meta-analysis/individual study) | ||||||||||||
---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
LOE | Variant | Gene | Association | EV | LOE | Ethnicity | Phenotype | Adjusted for confounders? | ||||||
Variant | None | Phenotype HR (95 % CI) |
I
2
| Chi |
p
|
n
| ||||||||
IV | CIN | NA | Dunn et al. [65] | CIN 4 m post-PDT | D | NS | HGD | Yes | EAC/HGD HRA 4.10 (1.30–13.0) | NA | NA | 9.00 × 10−3
| 1 | |
CIN 12 m post-PDT | EAC/HGD HRA 3.60 (1.05–12.3) | 2.90 × 10−3
|