Table 1.
Clinical studies associating genetic variation, epigenetic variation, gene expression, and protein expression with adverse normal-tissue reaction to radiotherapy (RT).
| Candidate gene SNP studies | |||||
|---|---|---|---|---|---|
| Gene | RT site | N.T. effect | # pat. | signif. | Reference |
| HSPB1 | lung | esophagitis | n=120+181 | * | [83] Lopez-Guerra et al. 2011 |
| TGFB1 | lung | esophagitis | n=97+101 | * | [82] Guerra et al., 2012 |
| APEX | mastect. | fibrosis | n=41 | n.s. | [62] Andreassen et al., 2003 |
| APEX | mastect. | fibrosis | n=120 | n.s. | [68] Andreassen et al., 2006b |
| ATM | mastect. | fibrosis | n=41 | * | [63] Andreassen et al., 2006a |
| ATM | mastect. | fibrosis | n=120 | n.s. | [68] Andreassen et al., 2006b |
| GSTA1 | breast | fibrosis | n=257 | * | [67] Terrazino et al., 2012 |
| GSTP1 | breast | fibrosis | n=257 | * | [67] Terrazino et al., 2012 |
| NOS3 | breast | fibrosis | n=257 | n.s. | [67] Terrazino et al., 2012 |
| SOD2 | mastect. | fibrosis | n=41 | * | [62] Andreassen et al., 2003 |
| SOD2 | mastect. | fibrosis | n=120 | n.s. | [68] Andreassen et al., 2006b |
| TGFB1 | breast | fibrosis | n=103 | * | [66] Quarmby et al., 2003 |
| TGFB1 | breast | fibrosis | n=257 | * | [67] Terrazino et al., 2012 |
| TGFB1 | breast | fibrosis | n=778 | n.s. | [36] Barnett et al., 2010 |
| TGFB1 | mastect. | fibrosis | n=41 | * | [62] Andreassen et al., 2003 |
| TGFB1 | mastect. | fibrosis | n=120 | n.s. | [68] Andreassen et al., 2006b |
| TP53 | breast | fibrosis | n=257 | n.s. | [67] Terrazino et al., 2012 |
| XRCC1 | breast | fibrosis | n=257 | n.s. | [67] Terrazino et al., 2012 |
| XRCC1 | mastect. | fibrosis | n=41 | * | [62] Andreassen et al., 2003 |
| XRCC1 | mastect. | fibrosis | n=120 | n.s. | [68] Andreassen et al., 2006b |
| XRCC3 | mastect. | fibrosis | n=41 | * | [62] Andreassen et al., 2003 |
| XRCC3 | mastect. | fibrosis | n=120 | n.s. | [68] Andreassen et al., 2006b |
| XRCC3 | breast | fibrosis | n=257 | n.s. | [67] Terrazino et al., 2012 |
| ATM | various | late | n=34 | n.s. | [64] Azria et al., 2008 |
| RAD21 | various | late | n=34 | n.s. | [64] Azria et al., 2008 |
| SOD2 | various | late | n=34 | n.s. | [64] Azria et al., 2008 |
| TGFB1 | gynaecol | late | n=78 | * | [69] De Ruyck et al., 2006 |
| TGFB1 | various | late | n=34 | n.s. | [64] Azria et al., 2008 |
| XCRR1 | various | late | n=34 | n.s. | [64] Azria et al., 2008 |
| XRCC3 | various | late | n=34 | n.s. | [64] Azria et al., 2008 |
| HSPB1 | lung | pneumonitis | n=146+125 | * | [84] Pang et al., 2013 |
| TGFB1 | lung | pneumonitis | n=164 | * | [77] Yuan et al., 2009 |
| TGFB11 | lung | pneumonitis | n=209 | n.s. | [76] Wang et al., 2010 |
| TGFB1 | lung | pneumonitis | n=178 | n.s. | [75] Voets et al., 2012 |
| APEX | mastect. | telangiectasia | n=41 | n.s. | [62] Andreassen et al., 2003 |
| APEX1 | breast | telangiectasia | n=409 | n.s. | [70] Chang-Claude et al., 2009 |
| CDKN1A | breast | telangiectasia | n=409 | n.s. | [70] Chang-Claude et al., 2009 |
| SOD2 | mastect. | telangiectasia | n=41 | n.s. | [62] Andreassen et al., 2003 |
| TGFB1 | mastect. | telangiectasia | n=41 | n.s. | [62] Andreassen et al., 2003 |
| TP53 | breast | telangiectasia | n=409 | * | [70] Chang-Claude et al., 2009 |
| XRCC1 | mastect. | telangiectasia | n=41 | n.s. | [62] Andreassen et al., 2003 |
| XRCC1 | breast | telangiectasia | n=409 | n.s. | [70] Chang-Claude et al., 2009 |
| XRCC2 | breast | telangiectasia | n=409 | n.s. | [70] Chang-Claude et al., 2009 |
| XRCC3 | mastect. | telangiectasia | n=41 | n.s. | [62] Andreassen et al., 2003 |
| XRCC3 | breast | telangiectasia | n=409 | n.s. | [70] Chang-Claude et al., 2009 |
| Test/discovery-and-validation gene SNP studies | |||||
|---|---|---|---|---|---|
| Gene(#SNPs) | RT site | N.T. effect | # pat. | signif. | Reference |
| CYP2C8(528) | breast | fibrosis | n=92 | *d.s. | [80] Edvardsen et al., 2013 |
| IL8(528) | breast | fibrosis | n=92 | *d.s. | [80] Edvardsen et al., 2013 |
| MGMT(528) | breast | fibrosis | n=92 | *d.s. | [80] Edvardsen et al., 2013 |
| TDG(305) | breast | fibrosis | n=753 | (*)d.s. | [81] Seibold et al., 2015 |
| TGFB1 | various | fibrosis | n=2782 | n.s. | [73] Barnett et al., 2012 |
| TGFB1 | various | fibrosis | n=2783 | n.s. | [74] Zhu et al., 2013 |
| TGFBR2(528) | breast | fibrosis | n=92 | *d.s. | [80] Edvardsen et al., 2013 |
| TNF(305) | breast | fibrosis | n=753 | (*)d.s. | [81] Seibold et al., 2015 |
| TXN(305) | breast | fibrosis | n=753 | (*)d.s. | [81] Seibold et al., 2015 |
| TXNRD2(528) | breast | fibrosis | n=92 | *d.s. | [80] Edvardsen et al., 2013 |
| TXNRD2(7) | breast | fibrosis | n=433 | *v.s. | [80] Edvardsen et al., 2013 |
| XRCC1(305) | breast | fibrosis | n=753 | *d.s. | [81] Seibold et al., 2015 |
| XRCC1(10) | breast | fibrosis | n=2036 | *v.s. | [81] Seibold et al., 2015 |
| TNF(43) | breast | late(STAT) | n=633 | *d.s. | [79] Talbot et al., 2012 |
| TNF(1) | breast | late(STAT) | n=2036 | *v.s. | [79] Talbot et al., 2012 |
| GWAS | |||||
|---|---|---|---|---|---|
| Gene #SNPs | RT site | N.T. effect | # pat. | signif. | Reference |
| FSHR | prostate | erect. dysfct. | n=79 | * | [93] Kerns et al., 2010 |
| 4 | prostate | erect. dysfct. | n=79 | (*) | [93] Kerns et al., 2010 |
| 12 | prostate | erect. dysfct. | n=235+230 | (*) | [94] Kerns et al., 2013 |
| block of 8 | prostate | urinary | n=346+377 | * | [96] Kerns et al., 2013 |
| 2 | prostate | rectal bleed. | n=368+781 | * | [95] Kerns et al., 2013 |
| TANC1 | prostate | late(STAT) | n=741 | *d.s. | [97] Fachal et al., 2014 |
| TANC1 | prostate | late(STAT) | n=1742 | * | [97] Fachal et al., 2014 |
| 29 | breast | late(STAT) | n=1217 | *d.s. | [98] Barnett et al., 2014 |
| 164 | prostate | late(STAT) | n=633 | *d.s. | [98] Barnett et al., 2014 |
| 11 | br.+prost. | late(STAT) | n=1850+1733 | (*) | [98] Barnett et al., 2014 |
| Epigenetics studies | |||||
|---|---|---|---|---|---|
| Gene | RT site | N.T. effect | # pat. | signif. | Reference |
| XRCC2 | cervix | late | n=54 | * | [129] Paulikova et al. 2013 |
| DGKA | breast | fibrosis | n=24+75 | * | [130] Weigel et al., 2016 |
| miR-99a | prostate | rectal bleed. | n=8+97 | * | [144] Someya et al., 2015 |
| Ku80 mRNA | prostate | rectal bleed. | n=8+97 | * | [144] Someya et al., 2015 |
| Gene expression signatures, fibroblasts | |||||
|---|---|---|---|---|---|
| Gene #genes | RT site | N.T. effect | # pat. | signif. | Reference |
| 18 | mastect. | fibrosis | n=31 | * | [155] Rödningen et al., 2005 |
| [153] Alsner et al., 2007 | |||||
| [154] Rödningen et al., 2008 | |||||
| 9 | H&N | fibrosis | n=160 | * | [156] Andreassen et al., 2013 |
| Gene expression signatures, lymphocytes/blood cells | |||||
|---|---|---|---|---|---|
| Gene #genes | RT site | N.T. effect | # pat. | signif. | Reference |
| 24 | various | early | n=57 | * | [146] Rieger et al., 2004 |
| 19 | prostate | early | n=58 | (*) | [147] Hümmerich et al., 2006 |
| 67 | H&N+Br. | early | n=24 | - | [150] Mayer et al., 2011 |
| 67 | H&N | early | n=24 | - | [149] Greve et al., 2012 |
| 50 | breast | br. appear. | n=59 | * | [151] Finnon et al., 2012 |
| 87 | breast | fibrosis | n=254 | (*) | [157] Landmark-Hoyvik et al., 2011 |
| 72 | prostate | late | n=50 | * | [148] Svensson et al., 2006 |
| RAD51 | prostate | late | n=61 | * | [152] van Oorschot et al., 2014 |
| Cytokines, plasma | |||||
|---|---|---|---|---|---|
| Protein | RT site | N.T. effect | # pat. | signif. | Reference |
| IL-6 | lung | pneumonitis | n=52 | n.s. | [163] Rübe et al., 2009 |
| IL-8 | lung | late | n=55 | * | [166] Hart et al., 2005 |
| IL-8 | lung | late | n=58 | * | [161] Stenmark et al., 2012 |
| TGF-β1 | cervix | late | n=79 | n.s. | [165] Dickson et al., 2000 |
| TGF-β1 | lung | late | n=26 | n.s. | [164] Zhao et al., 2008 |
| TGF-β1 | lung | late | n=58 | (*) | [161] Stenmark et al., 2012 |
| TGF-β1 | lung | pneumonitis | n=73 | (*). | [159] Anscher et al., 1998 |
| TGF-β1 | lung | pneumonitis | n=68 | n.s. | [162] De Jaeger et al., 2004 |
| TGF-β1 | lung | pneumonitis | n=46 | (*) | [160] Novakova-Jiresova et al., 2004 |
| TGF-β1 | lung | pneumonitis | n=52 | n.s. | [163] Rübe et al., 2009 |
| Proteomics, cells | |||||
|---|---|---|---|---|---|
| Protein | RT site | N.T. effect | # pat. | signif. | Reference |
| A2M | lung | late | n=6+20 | * | [168] Oh et al., 2011 |
| C4BPA | lung | late | n=57 | * | [169] Cai et al., 2011 |
| VTN | lung | late | n=57 | * | [169] Cai et al., 2011 |
N.T. (normal tissue); br. (breast); gynaecol. (gynaecological cancer); H&N (head-and-neck); mastect. (post-mastectomy RT); fibr. (fibrosis); br.appear. (breast appearance); # pat. (number of RT patients); signif. (statistical significance); SNP (single-nucleotide polymorphism); GWAS (genome-wide association studies). For candidate SNP studies incorporating a validation cohort, the number of patients in each cohort is given, separated by a ‘+’ sign. For studies using a test/discovery plus validation design, the significant gene is shown with the number of candidate SNPs in the discovery set given in brackets; for validation sets, the number of genes tested is shown. The significance is indicated for the discovery and validation data sets: d.s. (discovery set); v.s. (validation set). For GWAS, a single gene or the number of significant genes identified is given. * (significant); n.s. (not significant). Brackets (*) signify borderline significance or limited inference.