Association of Genetic Variants in ANGPT/TEK and VEGF/VEGFR with Progression and Survival in Head and Neck Squamous Cell Carcinoma Treated with Radiotherapy or Radiochemotherapy
Abstract
:1. Introduction
2. Results
2.1. Clinical Features and Survival
2.2. SNPs and Patient Characteristics
2.3. Association of Individual SNPs with Treatment Outcome
2.4. Independent Risk Factors in the Whole Group and in Treatment Subgroups
2.5. Cumulative Effect of SNP Combinations Overall and According to Treatment
3. Discussion
4. Materials and Methods
4.1. Study Population
4.2. Treatment
4.3. SNP Selection and Genotyping
4.4. Statistical Analysis
5. Conclusions
Supplementary Materials
Author Contributions
Funding
Acknowledgments
Conflicts of Interest
References
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Clinical and Demographic Features | All Patients | RT + CHT | RT Alone | pa |
---|---|---|---|---|
n (%) | n (%) | n (%) | ||
Total | 422 (100) | 203 (100) | 219 (100) | |
Age at diagnosis | ||||
Mean ± SD, years | 59.6 ± 8.4 | 57.0 ± 7.8 | 62.0 ± 8.3 | |
<59 years | 196 (46.4) | 120 (59.1) | 76 (34.7) | |
≥59 years | 226 (53.6) | 83 (40.9) | 143 (65.3) | <1 × 10−5 |
Gender | ||||
Male | 339 (80.3) | 164 (80.8) | 175 (80.0) | |
Female | 83 (19.7) | 39 (19.2) | 44 (20.0) | 0.82 |
Tumor site | ||||
Oropharynx | 163 (38.6) | 106 (52.2) | 57 (26.0) | |
Hypopharynx | 53 (12.6) | 38 (18.7) | 15 (6.9) | |
Larynx | 206 (48.8) | 59 (29.1) | 147 (67.1) | <1 × 10−5 |
Clinical stage | ||||
I | 45 (10.7) | 2 (1.0) | 43 (19.6) | |
II | 87 (20.6) | 5 (2.5) | 82 (37.5) | |
III | 74 (17.5) | 38 (18.7) | 36 (16.4) | |
IVA/B | 216 (51.2) | 158 (77.8) | 58 (26.5) | <1 × 10−5 |
T stage | ||||
1–2 | 214 (50.7) | 59 (29.1) | 155 (70.8) | |
3–4 | 208 (49.3) | 144 (70.9) | 64 (29.2) | <1 × 10−5 |
N stage | ||||
0 | 187 (44.3) | 33 (16.3) | 154 (70.3) | |
1–3 | 235 (55.7) | 170 (83.7) | 65 (29.7) | <1 × 10−5 |
Smoking status | ||||
Never | 85 (20.1) | 46 (22.7) | 39 (17.8) | |
Ever | 337 (79.9) | 157 (77.3) | 180 (82.2) | 0.214 |
Alcohol consumption b | ||||
Never | 97 (23.0) | 47 (23.1) | 50 (22.8) | |
Ever | 322 (76.3) | 154 (75.9) | 168 (76.7) | 0.914 |
Treatment modality | ||||
RT alone | 219 (51.9) | 219 (100) | ||
Concurrent CHRT | 131 (31.0) | 131 (64.5) | ||
iCHT/RT | 32 (7.6) | 32 (15.8) | ||
iCHT/concurrent CHRT | 40 (9.5) | 40 (19.7) |
Endpoint | Gene | SNP | Genotype | Event/n | pLog-rank | uHR (95% CI) | p | mHR (95% CI) | p |
---|---|---|---|---|---|---|---|---|---|
OS | ANGPT2 | rs3739391 | GG | 141/312 | 1 | 1 | |||
GA/AA | 55/105 | 0.096 | 1.31 (0.96–1.80) | 0.087 | 1.39 (1.01–1.92) | 0.046 | |||
ANGPT2 | rs3020221 | CT/TT | 107/240 | 1 | 1 | ||||
CC | 91/182 | 0.325 | 1.15 (0.87–1.52) | 0.325 | 1.44 (1.08–1.93) | 0.013 | |||
TEK | rs639225 | GG | 46/105 | 1 | 1 | ||||
GA/AA | 152/316 | 0.517 | 1.11 (0.80–1.55) | 0.519 | 1.34 (0.96–1.88) | 0.087 | |||
VEGF | rs2010963 | CG/GG | 172/382 | 1 | 1 | ||||
CC | 26/40 | 0.013 | 1.75 (1.16–2.64) | 0.008 | 1.63 (1.06–2.49) | 0.025 | |||
LRRFS | VEGF | rs699947 | AC/CC | 88/321 | 1 | 1 | |||
AA | 34/93 | 0.095 | 1.38 (0.93–2.05) | 0.113 | 1.49 (1.00–2.23) | 0.053 | |||
VEGFR2 | rs2071559 | CT/TT | 87/322 | 1 | 1 | ||||
CC | 38/100 | 0.050 | 1.43 (0.98–2.10) | 0.063 | 1.41 (0.95–2.08) | 0.088 | |||
VEGFR2 | rs1870377 | TA/AA | 51/194 | 1 | 1 | ||||
TT | 72/223 | 0.181 | 1.26 (0.88–1.80) | 0.207 | 1.37 (0.94–1.98) | 0.099 | |||
LRFS | VEGF | rs699947 | AC/CC | 68/321 | 1 | 1 | |||
AA | 28/93 | 0.085 | 1.45 (0.94–2.26) | 0.096 | 1.61 (1.03–2.52) | 0.037 | |||
VEGFR2 | rs2071559 | TT | 17/107 | 1 | 1 | ||||
TC/CC | 82/315 | 0.047 | 1.65 (0.98–2.69) | 0.059 | 1.70 (1.00–2.89) | 0.051 | |||
VEGFR2 | rs1870377 | TA/AA | 37/194 | 1 | 1 | ||||
TT | 60/223 | 0.070 | 1.44 (0.95–2.17) | 0.082 | 1.65 (1.08–2.52) | 0.021 | |||
NRFS | VEGFR2 | rs2071559 | CT/TT | 38/322 | 1 | 1 | |||
CC | 21/100 | 0.025 | 1.79 (1.05–3.04) | 0.033 | 1.67 (0.97–2.89) | 0.066 | |||
MFS | ANGPT2 | rs3739391 | GG | 33/312 | 1 | 1 | |||
GA/AA | 15/105 | 0.162 | 1.57 (0.85–2.90) | 0.149 | 1.73 (0.92–3.25) | 0.087 | |||
VEGF | rs2010963 | CG/GG | 40/382 | 1 | 1 | ||||
CC | 8/40 | 0.032 | 2.43 (1.14–5.21) | 0.022 | 2.43 (1.09–5.38) | 0.029 |
RT + CHT Subgroup | |||||||||
---|---|---|---|---|---|---|---|---|---|
Endpoint | Gene | SNP | Genotype | Event/n | pLog-rank | uHR (95% CI) | p | mHR (95% CI) | p |
OS | ANGPT2 | rs3739391 | GG | 63/146 | 1 | 1 | |||
GA/AA | 34/55 | 0.011 | 1.76 (1.15–2.68) | 0.008 | 1.78 (1.14–2.78) | 0.012 | |||
ANGPT2 | rs3020221 | CT/TT | 53/116 | 1 | 1 | ||||
CC | 46/87 | 0.335 | 1.22 (0.82–1.81) | 0.334 | 1.52 (1.01–2.30) | 0.046 | |||
TEK | rs639225 | GG | 21/52 | 1 | 1 | ||||
GA/AA | 78/151 | 0.140 | 1.42 (0.88–2.30) | 0.153 | 1.71 (1.04–2.82) | 0.036 | |||
VEGF | rs2010963 | CG/GG | 83/180 | 1 | 1 | ||||
CC | 16/23 | 0.044 | 1.79 (1.05–3.05) | 0.034 | 2.09 (1.19–3.67) | 0.010 | |||
LRRFS | VEGF | rs699947 | AC/CC | 41/153 | 1 | 1 | |||
AA | 21/47 | 0.022 | 1.77 (1.04–2.99) | 0.034 | 2.08 (1.21–3.58) | 0.008 | |||
VEGFR1 | rs9582036 | AC/CC | 23/90 | 1 | 1 | ||||
AA | 40/110 | 0.08 | 1.52 (0.91–2.55) | 0.109 | 1.67 (0.97–2.86) | 0.062 | |||
LRFS | VEGF | rs699947 | AC/CC | 29/153 | 1 | 1 | |||
AA | 15/47 | 0.071 | 1.72 (0.92–3.21) | 0.087 | 2.20 (1.14–4.22) | 0.018 | |||
VEGFR1 | rs9582036 | AC/CC | 15/90 | 1 | 1 | ||||
AA | 30/110 | 0.076 | 1.69 (0.91–3.15) | 0.096 | 1.75 (0.91–3.36) | 0.091 | |||
NRFS | VEGF | rs699947 | CC | 5/61 | 1 | 1 | |||
CA/AA | 34/139 | 0.008 | 3.07 (1.20–7.85) | 0.019 | 3.05 (1.18–7.90) | 0.021 | |||
VEGFR2 | rs2071559 | CT/TT | 23/153 | 1 | 1 | ||||
CC | 16/50 | 0.014 | 2.08 (1.10–3.94) | 0.025 | 1.99 (1.02–3.87) | 0.043 | |||
MFS | ANGPT2 | rs3739391 | GG | 18/146 | 1 | 1 | |||
GA/AA | 10/55 | 0.123 | 1.89 (0.87–4.12) | 0.107 | 2.02 (0.90–4.50) | 0.088 | |||
VEGFR2 | rs1870377 | TA/AA | 10/93 | 1 | 1 | ||||
TT | 18/109 | 0.125 | 1.85 (0.84–4.08) | 0.128 | 2.21 (0.96–5.10) | 0.063 | |||
RT Alone Subgroup | |||||||||
Endpoint | Gene | SNP | Genotype | Event/n | pLog-rank | uHR (95% CI) | p | mHR (95% CI) | p |
LRFS | VEGFR2 | rs2071559 | CT/TT | 35/169 | 1 | 1 | |||
CC | 18/50 | 0.031 | 1.84 (1.04–3.25) | 0.036 | 1.71 (0.94–3.08) | 0.076 | |||
VEGFR2 | rs1870377 | TA/AA | 19/101 | 1 | 1 | ||||
TT | 33/114 | 0.128 | 1.53 (0.87–2.69) | 0.141 | 1.79 (1.00–3.22) | 0.051 |
Endpoint | Variables | HR (95% CI) | p |
---|---|---|---|
All patients | |||
OS | VEGF rs2010963 CC | 1.61 (1.04–2.49) | 0.032 |
TEK rs639225 GA/AA | 1.44 (1.01–2.04) | 0.041 | |
Alcohol: ever | 1.49 (1.04–2.14) | 0.030 | |
Stage N1–N3 | 1.66 (1.20–2.30) | 0.002 | |
HPSCC | 1.57 (1.05–2.33) | 0.026 | |
Local recurrence: yes | 4.62 (3.35–6.38) | <1 × 10−6 | |
Regional recurrence: yes | 1.58 (1.08–2.34) | 0.020 | |
Metastasis: yes | 1.64 (1.10–2.43) | 0.015 | |
SPC: yes | 2.19 (1.47–3.27) | 1.2 × 10−4 | |
LRFS | VEGFR2 rs1870377 TT | 1.54 (1.02–2.32) | 0.040 |
Stage T3–T4 | 2.52 (1.57–4.06) | 0.0001 | |
Stage N1–N3 | 1.72 (1.05–2.81) | 0.032 | |
Chemotherapy: no | 1.66 (1.03–2.68) | 0.036 | |
Non-OPSCC | 2.84 (1.73–4.65) | 3.4 × 10−5 | |
MFS | VEGF rs2010963 CC | 2.51 (1.17–5.40) | 0.019 |
HPSCC | 2.53 (1.21–5.27) | 0.014 | |
Regional recurrence: yes | 4.53 (2.34–8.78) | 8 × 10−6 | |
RT + CHT subgroup | |||
OS | ANGPT2 rs3739391 GA/AA | 1.61 (1.04–2.51) | 0.033 |
TEK rs639225 GA/AA | 1.67 (1.01–2.76) | 0.048 | |
VEGF rs2010963 CC | 2.32 (1.31–4.11) | 0.004 | |
Alcohol: ever | 2.09 (1.16–3.77) | 0.014 | |
HPSCC | 2.33 (1.42–3.84) | 9 × 10−4 | |
Local recurrence: yes | 4.37 (2.66–7.18) | <1 × 10−6 | |
Regional recurrence: yes | 2.07 (1.23–3.48) | 0.006 | |
LRRFS | VEGF rs699947 AA | 1.77 (1.04–2.99) | 0.034 |
NRFS | VEGF rs699947 CA/AA | 2.99 (1.17–7.65) | 0.022 |
VEGFR2 rs2071559 CC | 1.98 (1.04–3.75) | 0.037 | |
RT alone subgroup | |||
LRFS | VEGFR2 rs2071559 CC | 1.89 (1.07–3.34) | 0.028 |
Stage T3–T4 | 4.32 (2.48–7.54) | <1 × 10−6 | |
Non-OPSCC | 2.58 (1.24–5.37) | 0.011 |
All Patients | |||||||
SNP Combination | OS | ||||||
Events/n | 2-Year OS | 5-Year OS | uHR (95% CI) | p | mHR (95% CI) | p | |
rs3739391/rs3020221/rs2010963 | |||||||
0 risk genotypes | 64/154 | 82% | 59% | 1 | 1 | ||
1 risk genotype | 95/204 | 76% | 58% | 1.14 (0.83–1.57) | 0.404 | 1.19 (0.86–1.64) | 0.298 |
2–3 risk genotypes | 37/59 | 72% | 36% | 1.98 (1.32–2.97) | 0.001 | 1.93 (1.27–2.93) | 0.002 |
SNP combination | LRFS | ||||||
Events/n | 1-year LRFS | 3-year LRFS | uHR (95% CI) | p | mHR (95% CI) | p | |
rs699947/rs1870377 | |||||||
0 risk genotypes | 28/150 | 88% | 83% | 1 | 1 | ||
1 risk genotype | 48/212 | 85% | 79% | 1.20 (0.75–1.91) | 0.447 | 1.46 (0.90–2.38) | 0.128 |
2 risk genotypes | 19/51 | 74% | 61% | 2.13 (1.19–3.80) | 0.011 | 2.43 (1.33–4.23) | 0.004 |
RT + CHT Subgroup | |||||||
SNP combination | OS | ||||||
Events/n | 2-year OS | 5-year OS | uHR (95% CI) | p | mHR (95% CI) | p | |
rs3739391/rs3020221/rs639225/rs2010963 | |||||||
0 risk genotypes | 5/21 | 90% | 81% | 1 | 1 | ||
1–2 risk genotypes | 72/152 | 77% | 57% | 2.37 (0.96–5.86) | 0.063 | 3.26 (1.26–8.41) | 0.015 |
3–4 risk genotypes | 20/28 | 60% | 26% | 5.33 (2.00–14.23) | 8 × 10−4 | 7.79 (2.77–21.87) | 9.8 × 10−5 |
SNP combination | NRFS | ||||||
Events/n | 1-year NRFS | 3-year NRFS | uHR (95% CI) | p | mHR (95% CI) | p | |
rs699947/rs2071559 | |||||||
0 risk genotypes | 2/47 | 96% | 96% | 1 | 1 | ||
1 risk genotype | 24/117 | 84% | 80% | 4.94 (1.67–20.89) | 0.030 | 4.69 (1.10–20.03) | 0.037 |
2 risk genotypes | 13/36 | 72% | 69% | 8.51 (1.92–37.69) | 0.005 | 8.21 (1.82–37.10) | 0.006 |
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Butkiewicz, D.; Gdowicz-Kłosok, A.; Krześniak, M.; Rutkowski, T.; Krzywon, A.; Cortez, A.J.; Domińczyk, I.; Składowski, K. Association of Genetic Variants in ANGPT/TEK and VEGF/VEGFR with Progression and Survival in Head and Neck Squamous Cell Carcinoma Treated with Radiotherapy or Radiochemotherapy. Cancers 2020, 12, 1506. https://doi.org/10.3390/cancers12061506
Butkiewicz D, Gdowicz-Kłosok A, Krześniak M, Rutkowski T, Krzywon A, Cortez AJ, Domińczyk I, Składowski K. Association of Genetic Variants in ANGPT/TEK and VEGF/VEGFR with Progression and Survival in Head and Neck Squamous Cell Carcinoma Treated with Radiotherapy or Radiochemotherapy. Cancers. 2020; 12(6):1506. https://doi.org/10.3390/cancers12061506
Chicago/Turabian StyleButkiewicz, Dorota, Agnieszka Gdowicz-Kłosok, Małgorzata Krześniak, Tomasz Rutkowski, Aleksandra Krzywon, Alexander Jorge Cortez, Iwona Domińczyk, and Krzysztof Składowski. 2020. "Association of Genetic Variants in ANGPT/TEK and VEGF/VEGFR with Progression and Survival in Head and Neck Squamous Cell Carcinoma Treated with Radiotherapy or Radiochemotherapy" Cancers 12, no. 6: 1506. https://doi.org/10.3390/cancers12061506