Table 2.
Two Stage Candidate Pathway Analysis of Angiogenesis and Inflammation Variants and Breast Cancer Survival
| Disease Free Survival (DFS) | Overall Survival (OS) | ||||||||||||
|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
| Gene, SNP, and Information |
Genotyping Method** |
HR (95% CI)*** | P values**** | HR (95% CI)*** | P values**** | ||||||||
| Cases / Events | Heterozygotes | Homozygotes | Allelic | Dominant | Recessive | Cases / Events | Heterozygotes | Homozygotes | Allelic | Dominant | Recessive | ||
| CCL2 rs41416652 (T/C, 44.1) | |||||||||||||
| Study Stage 1 | Affy 6.0 | 2,000 / 497 | 0.98 (0.80–1.20) | 0.86 (0.66–1.11) | 0.272 | 0.541 | 0.217 | 2,448 / 394 | 1.02 (0.82–1.27) | 0.71 (0.52–0.97) | 0.060 | 0.483 | 0.012 |
| Study Stage 2 | iSelect | 1,292 / 225 | 0.91 (0.68–1.22) | 0.78 (0.53–1.14) | 0.202 | 0.324 | 0.260 | 1,324 / 197 | 1.08 (0.79–1.48) | 0.98 (0.65–1.47) | 0.989 | 0.748 | 0.718 |
| Combined | NA | 3,292 / 722 | 0.96 (0.82–1.13) | 0.83 (0.67–1.03) | 0.106 | 0.308 | 0.092 | 3,772 / 591 | 1.05 (0.87–1.25) | 0.79 (0.62–1.01) | 0.130 | 0.736 | 0.022 |
| COL18A1 rs6518240 (A/G, 8.7) | |||||||||||||
| Study Stage 1 | Affy 6.0 | 1,999 / 496 | 0.99 (0.78–1.27) | 1.82 (0.75–4.39) | 0.667 | 0.858 | 0.183 | 2,448 / 393 | 1.04 (0.79–1.36) | 2.97 (1.32–6.66) | 0.225 | 0.464 | 0.009 |
| Study Stage 2 | iSelect | 1,301 / 226 | 1.04 (0.74–1.47) | 2.11 (0.52–8.47) | 0.587 | 0.701 | 0.299 | 1,333 / 198 | 0.95 (0.65–1.39) | 0.00 (no events) | 0.606 | 0.707 | 0.969 |
| Combined | NA | 3,300 / 722 | 1.01 (0.83–1.24) | 1.94 (0.92–4.09) | 0.472 | 0.679 | 0.081 | 3,781 / 591 | 1.02 (0.82–1.27) | 2.17 (0.97–4.85) | 0.442 | 0.655 | 0.060 |
| COL18A1 rs8126650 (G/T, 26.0) | |||||||||||||
| Study Stage 1 | Affy 6.0 | 1,895 / 453 | 0.84 (0.69–1.03) | 0.63 (0.41–0.97) | 0.013 | 0.029 | 0.072 | 2,326 / 364 | 0.80 (0.64–1.00) | 0.60 (0.37–0.99) | 0.008 | 0.015 | 0.091 |
| Study Stage 2 | Sequenom | 2,152 / 265 | 0.86 (0.67–1.11) | 0.90 (0.54–1.51) | 0.319 | 0.251 | 0.868 | 2,344 / 207 | 0.85 (0.64–1.14) | 1.19 (0.70–2.04) | 0.779 | 0.448 | 0.376 |
| Combined | NA | 4,047 / 718 | 0.85 (0.73–0.99) | 0.72 (0.52–1.00) | 0.009 | 0.013 | 0.110 | 4,670 / 571 | 0.81 (0.68–0.97) | 0.77 (0.54–1.11) | 0.015 | 0.011 | 0.325 |
| FLT1 rs3794396 (G/C, 6.1) | |||||||||||||
| Study Stage 1 | Affy 6.0 | 1,993 / 492 | 1.26 (0.97–1.63) | 3.58 (1.34–9.58) | 0.016 | 0.038 | 0.013 | 2,440 / 391 | 1.30 (0.98–1.73) | 4.04 (1.51–10.83) | 0.010 | 0.028 | 0.007 |
| Study Stage 2 | iSelect | 1,292 / 225 | 1.02 (0.69–1.52) | 0.86 (0.12–6.11) | 0.961 | 0.931 | 0.874 | 1,324 / 197 | 1.00 (0.65–1.54) | 0.00 (no events) | 0.688 | 0.844 | 0.976 |
| Combined | NA | 3,285 / 717 | 1.19 (0.96–1.48) | 2.22 (0.92–5.36) | 0.037 | 0.062 | 0.083 | 3,764 / 588 | 1.21 (0.95–1.53) | 2.03 (0.76–5.44) | 0.052 | 0.076 | 0.172 |
| FLT1 rs7326277 (T/C, 31.3) | |||||||||||||
| Study Stage 1 | Targeted | 733 / 282 | 1.12 (0.88–1.44) | 0.69 (0.45–1.08) | 0.429 | 0.883 | 0.057 | 821 / 223 | 1.12 (0.86–1.48) | 0.52 (0.30–0.90) | 0.166 | 0.834 | 0.010 |
| Study Stage 2 | iSelect | 1,298 / 225 | 0.94 (0.71–1.25) | 1.06 (0.69–1.64) | 0.998 | 0.797 | 0.676 | 1,330 / 197 | 0.94 (0.70–1.27) | 1.10 (0.70–1.74) | 0.906 | 0.854 | 0.579 |
| Combined | NA | 2,031 / 507 | 1.03 (0.86–1.24) | 0.85 (0.62–1.15) | 0.537 | 0.937 | 0.230 | 2,151 / 420 | 1.04 (0.85–1.27) | 0.77 (0.54–1.09) | 0.351 | 0.805 | 0.108 |
| FLT1 rs9551471 (A/G, 20.9) | |||||||||||||
| Study Stage 1 | Affy 6.0 | 1,991 / 497 | 0.86 (0.71–1.04) | 0.69 (0.42–1.14) | 0.045 | 0.065 | 0.204 | 2,440 / 394 | 1.00 (0.81–1.23) | 0.92 (0.56–1.53) | 0.829 | 0.902 | 0.752 |
| Study Stage 2 | Sequenom | 3,355 / 472 | 0.86 (0.71–1.05) | 0.87 (0.54–1.39) | 0.152 | 0.126 | 0.695 | 3,448 / 383 | 0.95 (0.76–1.18) | 1.02 (0.62–1.70) | 0.758 | 0.669 | 0.871 |
| Combined | NA | 5,346 / 969 | 0.86 (0.75–0.99) | 0.77 (0.55–1.09) | 0.016 | 0.019 | 0.227 | 5,888 / 777 | 0.98 (0.84–1.14) | 0.96 (0.67–1.37) | 0.728 | 0.736 | 0.858 |
| FLT1 rs9319425 (T/C, 49.8) | |||||||||||||
| Study Stage 1 | Targeted | 733 / 282 | 1.07 (0.81–1.41) | 0.89 (0.64–1.24) | 0.527 | 0.961 | 0.265 | 821 / 223 | 1.02 (0.75–1.38) | 0.66 (0.45–0.97) | 0.047 | 0.435 | 0.012 |
| Study Stage 2 | iSelect | 1,304 / 226 | 1.07 (0.78–1.48) | 1.04 (0.71–1.53) | 0.834 | 0.695 | 0.953 | 1,336 / 198 | 1.06 (0.75–1.50) | 1.01 (0.67–1.52) | 0.951 | 0.789 | 0.861 |
| Combined | NA | 2,037 / 508 | 1.07 (0.86–1.31) | 0.94 (0.73–1.21) | 0.660 | 0.814 | 0.331 | 2,157 / 421 | 1.03 (0.82–1.29) | 0.79 (0.60–1.05) | 0.116 | 0.637 | 0.035 |
| FLT1 rs9513116 (G/A, 37.4) | |||||||||||||
| Study Stage 1 | Targeted | 734 / 283 | 0.86 (0.67–1.11) | 1.00 (0.71–1.43) | 0.690 | 0.350 | 0.606 | 821 / 225 | 0.72 (0.54–0.95) | 0.81 (0.54–1.21) | 0.088 | 0.025 | 0.830 |
| Study Stage 2 | iSelect | 1,280 / 222 | 0.91 (0.68–1.21) | 1.10 (0.75–1.63) | 0.875 | 0.722 | 0.415 | 1,313 / 193 | 1.01 (0.74–1.37) | 1.15 (0.75–1.75) | 0.604 | 0.798 | 0.506 |
| Combined | NA | 2,014 / 505 | 0.89 (0.74–1.08) | 1.07 (0.82–1.38) | 0.956 | 0.424 | 0.309 | 2,134 / 418 | 0.85 (0.69–1.04) | 0.96 (0.72–1.29) | 0.436 | 0.177 | 0.717 |
| MMP1 rs1939008 (A/G, 43.3) | |||||||||||||
| Study Stage 1 | Affy 6.0 | 1,992 / 493 | 0.94 (0.77–1.15) | 1.20 (0.94–1.52) | 0.230 | 0.895 | 0.045 | 2,436 / 392 | 1.02 (0.81–1.28) | 1.16 (0.88–1.53) | 0.324 | 0.591 | 0.257 |
| Study Stage 2 | iSelect | 1,300 / 226 | 1.10 (0.83–1.47) | 0.77 (0.51–1.16) | 0.369 | 0.949 | 0.092 | 1,332 / 198 | 1.06 (0.77–1.44) | 0.77 (0.50–1.19) | 0.349 | 0.858 | 0.142 |
| Combined | NA | 3,292 / 719 | 0.99 (0.84–1.17) | 1.05 (0.86–1.30) | 0.678 | 0.932 | 0.521 | 3,768 / 590 | 1.03 (0.85–1.23) | 1.02 (0.81–1.29) | 0.843 | 0.782 | 0.978 |
| MMP1 rs470215 (A/G, 8.1) | |||||||||||||
| Study Stage 1 | Affy 6.0 | 1,996 / 497 | 1.17 (0.93–1.49) | 2.14 (1.01–4.52) | 0.046 | 0.093 | 0.053 | 2,442 / 394 | 1.14 (0.88–1.49) | 1.94 (0.80–4.69) | 0.142 | 0.215 | 0.154 |
| Study Stage 2 | iSelect | 1,291 / 225 | 1.17 (0.83–1.65) | 0.57 (0.08–4.10) | 0.556 | 0.439 | 0.562 | 1,323 / 197 | 1.18 (0.82–1.70) | 0.68 (0.10–4.89) | 0.512 | 0.424 | 0.683 |
| Combined | NA | 3,287 / 722 | 1.16 (0.96–1.42) | 1.55 (0.77–3.11) | 0.062 | 0.084 | 0.245 | 3,765 / 591 | 1.15 (0.93–1.43) | 1.43 (0.64–3.20) | 0.137 | 0.161 | 0.413 |
| MMP7 rs11568818 (T/C, 8.9) | |||||||||||||
| Study Stage 1 | Targeted | 739 / 284 | 1.02 (0.75–1.40) | 4.31 (1.37–13.55) | 0.437 | 0.666 | 0.013 | 827 / 225 | 1.04 (0.73–1.47) | 6.04 (1.92–19.05) | 0.320 | 0.567 | 0.002 |
| Study Stage 2 | iSelect | 1,289 / 223 | 0.96 (0.67–1.39) | 0.60 (0.08–4.28) | 0.699 | 0.768 | 0.614 | 1,321 / 195 | 0.91 (0.61–1.36) | 0.75 (0.11–5.39) | 0.590 | 0.607 | 0.791 |
| Combined | NA | 2,028 / 507 | 0.99 (0.78–1.26) | 1.69 (0.63–4.52) | 0.774 | 0.915 | 0.298 | 2,148 / 420 | 0.97 (0.75–1.27) | 2.25 (0.84–6.04) | 0.744 | 0.960 | 0.106 |
| MMP7 rs643281 (G/A, 9.9) | |||||||||||||
| Study Stage 1 | Affy 6.0 | 2,002 / 496 | 1.09 (0.87–1.37) | 2.35 (1.17–4.74) | 0.109 | 0.240 | 0.019 | 2,450 / 394 | 1.08 (0.84–1.38) | 1.97 (0.88–4.42) | 0.249 | 0.392 | 0.107 |
| Study Stage 2 | iSelect | 1,300 / 226 | 1.33 (0.97–1.83) | 0.92 (0.23–3.70) | 0.132 | 0.092 | 0.840 | 1,332 / 198 | 1.09 (0.77–1.57) | 1.11 (0.28–4.49) | 0.616 | 0.610 | 0.900 |
| Combined | NA | 3,302 / 722 | 1.16 (0.97–1.40) | 1.74 (0.93–3.25) | 0.032 | 0.057 | 0.101 | 3,782 / 592 | 1.08 (0.88–1.32) | 1.56 (0.78–3.15) | 0.260 | 0.360 | 0.223 |
| PTGES rs10448290 (C/T, 20.7) | |||||||||||||
| Study Stage 1 | Affy 6.0 | 1,958 / 487 | 0.93 (0.77–1.13) | 0.62 (0.37–1.02) | 0.094 | 0.224 | 0.071 | 2,406 / 385 | 0.92 (0.74–1.14) | 0.51 (0.27–0.97) | 0.065 | 0.183 | 0.047 |
| Study Stage 2 | iSelect | 1,299 / 225 | 0.99 (0.75–1.31) | 0.81 (0.38–1.73) | 0.704 | 0.819 | 0.589 | 1,331 / 197 | 1.14 (0.85–1.53) | 0.96 (0.45–2.05) | 0.557 | 0.434 | 0.813 |
| Combined | NA | 3,257 / 712 | 0.95 (0.81–1.11) | 0.67 (0.44–1.01) | 0.099 | 0.239 | 0.066 | 3,737 / 582 | 0.99 (0.83–1.17) | 0.63 (0.39–1.03) | 0.215 | 0.492 | 0.066 |
| PTGIS rs522962 (T/C, 27.4) | |||||||||||||
| Study Stage 1 | Affy 6.0 | 1,903 / 455 | 0.81 (0.67–0.99) | 0.81 (0.56–1.18) | 0.042 | 0.027 | 0.520 | 2,335 / 365 | 0.83 (0.67–1.04) | 0.87 (0.57–1.32) | 0.146 | 0.096 | 0.760 |
| Study Stage 2 | iSelect | 1,298 / 225 | 0.82 (0.62–1.09) | 1.15 (0.72–1.82) | 0.683 | 0.305 | 0.339 | 1,330 / 197 | 0.95 (0.70–1.28) | 1.32 (0.82–2.13) | 0.557 | 0.950 | 0.204 |
| Combined | NA | 3,201 / 680 | 0.82 (0.69–0.96) | 0.92 (0.69–1.24) | 0.062 | 0.018 | 0.964 | 3,665 / 562 | 0.88 (0.74–1.05) | 1.03 (0.75–1.41) | 0.455 | 0.224 | 0.599 |
| SERPINE1 rs2227672 (G/T, 8.9) | |||||||||||||
| Study Stage 1 | Targeted | 738 / 284 | 0.92 (0.67–1.25) | 3.27 (1.04–10.26) | 0.967 | 0.785 | 0.040 | 826 / 225 | 1.01 (0.72–1.42) | 4.75 (1.51–14.95) | 0.444 | 0.704 | 0.008 |
| Study Stage 2 | iSelect | 1,304 / 226 | 1.20 (0.86–1.67) | 0.66 (0.09–4.72) | 0.417 | 0.336 | 0.656 | 1,336 / 198 | 1.24 (0.87–1.77) | 1.47 (0.36–5.95) | 0.200 | 0.210 | 0.625 |
| Combined | NA | 2,042 / 510 | 1.03 (0.82–1.29) | 1.62 (0.61–4.35) | 0.601 | 0.710 | 0.339 | 2,162 / 423 | 1.10 (0.86–1.40) | 2.53 (1.05–6.14) | 0.168 | 0.289 | 0.043 |
| THBS1 rs2292305 (A/G, 32.1) | |||||||||||||
| Study Stage 1 | Targeted | 734 / 281 | 0.95 (0.75–1.21) | 0.58 (0.35–0.95) | 0.071 | 0.284 | 0.033 | 821 / 223 | 0.93 (0.71–1.21) | 0.32 (0.16–0.67) | 0.009 | 0.130 | 0.003 |
| Study Stage 2 | iSelect | 1,297 / 224 | 0.97 (0.74–1.29) | 0.97 (0.62–1.50) | 0.838 | 0.834 | 0.917 | 1,328 / 197 | 0.99 (0.73–1.33) | 1.05 (0.66–1.65) | 0.917 | 0.998 | 0.820 |
| Combined | NA | 2,031 / 505 | 0.97 (0.81–1.16) | 0.75 (0.54–1.05) | 0.159 | 0.397 | 0.096 | 2,149 / 420 | 0.96 (0.79–1.17) | 0.66 (0.45–0.96) | 0.075 | 0.292 | 0.034 |
| VEGFA rs3024994 (C/T, 5.4) | |||||||||||||
| Study Stage 1 | Affy 6.0 | 1,994 / 496 | 1.31 (1.02–1.69) | 0.67 (0.09–4.76) | 0.066 | 0.046 | 0.665 | 2,443 / 393 | 1.14 (0.84–1.54) | 0.79 (0.11–5.60) | 0.493 | 0.446 | 0.799 |
| Study Stage 2 | iSelect | 1,300 / 225 | 1.00 (0.65–1.56) | 0.00 (no events) | 0.822 | 0.920 | 0.973 | 1,331 / 198 | 0.81 (0.49–1.35) | 0.00 (no events) | 0.338 | 0.375 | 0.976 |
| Combined | NA | 3,294 / 721 | 1.23 (0.98–1.53) | 0.49 (0.07–3.48) | 0.138 | 0.094 | 0.460 | 3,774 / 591 | 1.04 (0.80–1.35) | 0.59 (0.08–4.21) | 0.901 | 0.824 | 0.597 |
| VEGFA rs3025035 (C/T, 14.6) | |||||||||||||
| Study Stage 1 | Targeted | 728 / 278 | 1.17 (0.90–1.53) | 1.12 (0.53–2.39) | 0.263 | 0.227 | 0.855 | 816 / 219 | 1.36 (1.02–1.81) | 1.64 (0.81–3.35) | 0.019 | 0.023 | 0.258 |
| Study Stage 2 | iSelect | 1,305 / 225 | 0.78(0.56–1.07) | 1.34 (0.60–3.04) | 0.358 | 0.199 | 0.391 | 1,337 / 197 | 0.81 (0.58–1.14) | 0.95 (0.35–2.58) | 0.302 | 0.249 | 0.997 |
| Combined | NA | 2,033 / 503 | 0.98 (0.80–1.20) | 1.19 (0.68–2.07) | 0.877 | 0.973 | 0.525 | 2,153 / 416 | 1.07 (0.86–1.34) | 1.29 (0.72–2.30) | 0.336 | 0.412 | 0.423 |
| VEGFA rs6905288 (A/G, 26.7) | |||||||||||||
| Study Stage 1 | Affy 6.0 | 2,000 / 497 | 0.95 (0.79–1.14) | 0.74 (0.50–1.10) | 0.183 | 0.348 | 0.158 | 2,449 / 394 | 0.92 (0.75–1.13) | 0.57 (0.35–0.94) | 0.048 | 0.168 | 0.034 |
| Study Stage 2 | iSelect | 1,300 / 226 | 0.89 (0.67–1.18) | 1.24 (0.80–1.94) | 0.842 | 0.692 | 0.232 | 1,332 / 198 | 0.93 (0.69–1.25) | 1.25 (0.78–2.02) | 0.705 | 0.915 | 0.276 |
| Combined | NA | 3,300 / 723 | 0.93 (0.80–1.09) | 0.92 (0.68–1.23) | 0.344 | 0.328 | 0.682 | 3,781 / 592 | 0.92 (0.78–1.09) | 0.81 (0.58–1.14) | 0.163 | 0.222 | 0.304 |
*
SNP information includes (Major / Minor allele, and minor allele frequecy) as determined by all available genotyped breast cancer cases
**
Genotyping Methods: Stage 1 genotyping by Affymetrix Targeted genotyping among 1,062 cases from the SBCS (Targeted) or the Affymetrix Genome Wide Array 6.0 among 2,918 cases from the SBCS (Affy 6.0); Stage 2 genotyping by Illumina iSelect Beadchip among 1,613 cases from the SBCS and SBCSS (iSelect) or by a Sequenom iPLEX platform among 2,601 cases from the SBCSS and SWHS (Sequenom)
***
Hazard Ratios (HR) and 95% Confidence Intervals (CI) from Cox Proportional Hazards Regression, including adjustment for age at diagnosis, and study stage when appropriate; Major allele homozygotes are referent, estimates are for heterozygotes and minor allele homozygotes
****
P values from tests for allelic associations (trend), dominant associations, and recessive associations (bold values denote significance at ≤ 0.05)