TERT Promoter Mutations are Associated with Visceral Spreading in Melanoma of the Trunk
Abstract
:1. Introduction
2. Results
2.1. Clinical Characteristics
2.2. Mutational Assessment
2.3. Association Between Trunk Site and TERT Mutation
2.4. Validation in the Independent Cohort of the Instituto Valenciano de Oncologia Data Set
3. Discussion
4. Material and Methods
4.1. Patients
4.2. Mutational Status and TERT Promoter Assessment
4.3. Statistical Analyses
5. Conclusions
Author Contributions
Funding
Acknowledgments
Conflicts of Interest
References
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Patients | Pattern of First Relapse | |||||
---|---|---|---|---|---|---|
Total (105) | Regional (A) (58; 55.2%) | Regional + Distant (B) (15; 14.3%) | Visceral Only (C) (32; 30.5%) | p ** | ||
Median time to relapse (years. 25th–75th) | 1.9 (0.7–3.8) | 1.8 (0.7–3.8) | 1.8 (0.5–5.7) | 2.2 (0.8–3.8) | 0.956 | |
Gender | F | 42 (40%) | 27 (70.5%) | 8 (53.3%) | 7 (21.9%) | 0.038 (C vs. A 0.06) |
M | 63 (60%) | 31 (29.5%) | 7 (46.7%) | 25 (78.1%) | ||
Age at diagnosis | Median (interval) | 70 (22–88) | 71 (28–87) | 72 (34–86) | 66 (22–88) | 0.249 |
Primary site | Head/neck a | 16 (15.2%) | 8 (13.8%) | 5 (33.3%) | 3 (9.4%) | 0.030 (d vs. b 0.021) |
Trunk b | 41 (39.1%) | 16 (27.6%) | 5 (33.3%) | 20 (62.5%) | ||
Upper extremities c | 12 (11.4%) | 8 (13.8%) | 2 (13.4%) | 2 (6.2%) | ||
Lower extremities d | 36 (34.3%) | 26 (44.8%) | 3 (20.0%) | 7 (21.9%) | ||
Histotype | Nodular | 16 (15.2%) | 8 (13.8%) | 4 (26.7%) | 4 (12.5%) | 0.407 |
Other | 89 (84.8%) | 50 (86.2%) | 11 (73.3%) | 28 (87.5%) | ||
Breslow | mm ± DS | 3.7 ± 2.8 | 4.0 ± 2.8 | 4.8 ± 2.8 | 2.7 ± 1.9 | 0.005 (C vs. B p = 0.04) |
Ulceration | Absent | 59 (56.2%) | 33 (56.9%) | 4 (26.7%) | 22 (68.7%) | 0.025 (C vs. B p = 0.02) |
Present | 46 (43.8%) | 25 (43.1%) | 11 (73.3%) | 10 (38.3%) | ||
SLNB | Not performed | 64 (60.9%) | 39 (67.2%) | 11 (73.3%) | 14 (43.7%) | 0.052 |
Negative | 41 (39.1%) | 19 (32.8%) | 4 (26.7%) | 18 (56.2%) | ||
AJCC 2017 | IB | 24 (22.9%) | 9 (15.5%) | 2 (13.3%) | 13 (40.6%) | <0.001 (C vs. A p = 0.03 C vs. B p = 0.12) |
IIA | 31 (29.5%) | 19 (32.8%) | 5 (33.3%) | 7 (21.9%) | ||
IIB | 29 (27.6%) | 18 (31.0%) | 0 (0.0%) | 11 (34.4%) | ||
IIC | 21 (20.0%) | 12 (20.7%) | 8 (53.4%) | 1 (3.1%) | ||
Mutational status (Sequenom) | WT* | 32 (30.5%) | 15 (25.9%) | 6 (40.0%) | 11 (34.4%) | 0.470 |
BRAF MUT | 44 (41.9%) | 25 (43.1%) | 8 (53.3%) | 11 (34.4%) | ||
NRAS MUT | 27 (25.7%) | 17 (29.3%) | 1 (6.7%) | 9 (28.1%) | ||
KRAS MUT | 1 (0.9%) | 1 (1.7%) | 0 (0%) | 0 (0%) | ||
PIK3CA MUT | 1 (0.9%) | 0 (0%) | 0 (0%) | 1 (3.1%) | ||
Mutational status site | Primary | 42 (40.0%) | 14 (24.1%) | 8 (53.4%) | 20 (62.5%) | <0.001 (B vs. A, C vs. B <0.001) |
Regional mts | 46 (43.8%) | 39 (67.3%) | 5 (33.3%) | 2 (6.3%) | ||
Distant mts | 17 (16.2%) | 5 (8.6%) | 2 (13.3%) | 10 (31.2%) | ||
TERT promoter mutations | WT | 31 (29.5%) | 20 (34.5%) | 4 (26.7%) | 7 (21.9%) | 0.440 |
−146 or −124 C > T | 74 (70.5%) | 38 (65.5%) | 11 (73.3%) | 25 (78.1%) | ||
TERT rs2853669 | Absent | 51 (48.6%) | 28 (48.3%) | 8 (53.3%) | 15 (46.9%) | 0.916 |
Present | 54 (51.4%) | 30 (51.7%) | 7 (46.7%) | 17 (53.1%) | ||
TERT/Trunk site | WT/no trunk a | 24 (22.9%) | 15 (25.9%) | 3 (20.0%) | 6 (18.8%) | 0.0045 (D vs. B p = 0.01) |
−146 or −124 C > T mut/no trunk b | 40 (38.1%) | 27 (46.5%) | 7 (46.7%) | 6 (18.8%) | ||
WT/trunk c | 7 (6.7%) | 5 (8.6%) | 1 (6.7%) | 1 (3.1%) | ||
−146 or −124 C > T mut/trunk d | 34 (32.4%) | 11 (18.9%) | 4 (26.7%) | 19 (59.4%) |
Patients | Total (105) | Other Site of Progression (73; 55.4%) | Only Visceral (32; 44.6%) | |
---|---|---|---|---|
TERT Promoter mutations | −124 C > T | 37 | 24 (32.9%) | 13 (40.6%) |
−146 C > T | 37 | 25 (34.2%) | 12 (37.5%) | |
−57 A > C | 2 | 2 (2.7%) | 0 (0%) | |
−125_124 CC > TT | 2 | 2 (2.7%) | 0 (0%) | |
−139_138 CC > TT | 2 | 1 (1.4%) | 1 (1.4%) | |
WT | 25 | 19 (26.0%) | 6 (18.8%) |
Patients | TERT Promoter | p ** | |||
---|---|---|---|---|---|
Total | WT or Minor Mutations (31) | −146 or −124 C>T Mutation (74) | |||
Gender | F | 42 (40%) | 13 (41.9%) | 29 (39.2%) | 0.793 |
M | 63 (60%) | 18 (58.1%) | 45 (60.8%) | ||
Age at diagnosis | Median (interval) | 70 (22–88) | 72 (22–85) | 68 (26–88) | 0.950 |
Primary site | Head/neck a | 16 (15.2%) | 5 (16.1%) | 11 (14.9%) | 0.010 (d vs. b 0.014 c vs. d 0.010) |
Trunk b | 41 (39.0%) | 7 (22.6%) | 34 (45.9%) | ||
Upper extremities c | 12 (11.4%) | 1 (3.2%) | 11 (14.9%) | ||
Lower extremities d | 36 (34.3%) | 18 (58.1%) | 18 (24.3%) | ||
Histotype | Nodular | 16 (15.2%) | 3 (9.7%) | 13 (17.6%) | 0.305 |
Other | 89 (84.8%) | 28 (90.3%) | 61 (82.4%) | ||
Breslow | mm ± DS | 3.7 ± 2.8 | 4.1 ± 3.2 | 3.6 ± 2.6 | 0.362 |
Ulceration | Absent | 59 (56.2%) | 16 (51.6%) | 43 (58.1%) | 0.541 |
Present | 46 (43.8%) | 15 (48.4%) | 31 (41.9%) | ||
SLNB | Not performed | 64 (60.9%) | 19 (61.3%) | 45 (60.8%) | 0.963 |
Negative | 41 (39.1%) | 12 (38.7%) | 29 (39.2%) | ||
AJCC 2017 | IB | 24 (22.8%) | 3 (9.7%) | 21 (28.4%) | 0.175 |
IIA | 31 (29.5%) | 12 (38.7%) | 19 (25.7%) | ||
IIB | 29 (27.6%) | 10 (32.3%) | 19 (25.7%) | ||
IIC | 21 (20.0%) | 6 (19.3%) | 15 (20.3%) | ||
Mutational status (Sequenom) | WT * | 32 (30.5%) | 12 (38.7%) | 20 (27.0%) | 0.187 |
BRAF MUT | 44 (41.9%) | 8 (25.8%) | 36 (48.7%) | ||
NRAS MUT | 27 (25.7%) | 11 (35.5%) | 16 (21.6%) | ||
KRAS MUT | 1 (0.95%) | 0 (0%) | 1 (1.35%) | ||
PIK3CA MUT | 1 (0.95%) | 0 (0%) | 1 (1.35%) | ||
Mutational status site | Primary | 42 (40%) | 13 (41.9%) | 29 (39.2%) | 0.496 |
Regional mts | 46 (43.8%) | 15 (48.4%) | 31 (41.9%) | ||
Distant mts | 17 (16.2%) | 3 (9.7%) | 14 (18.9%) | ||
TERT rs2853669 | Absent | 51 (48.6%) | 16 (51.6%) | 35 (47.3%) | 0.687 |
Present | 54 (51.4%) | 15 (48.4%) | 39 (52.7%) |
Variable | Only Visceral Site | |||
---|---|---|---|---|
OR | CI | p | ||
Age (linear) | 0.98 | 0.95–1.00 | 0.141 | |
Gender (F vs. M) | 3.28 | 1.26–8.55 | 0.015 | |
Breslow (linear) | 0.74 | 0.57–0.94 | 0.015 | |
Ulceration (absent vs. present) | 0.46 | 0.19–1.12 | 0.089 | |
AJCC 2017 (IB vs. IIA, IIB, IIC) | 0.26 | 0.09–0.67 | 0.006 | |
NM versus other histotype | 0.72 | 0.21–2.45 | 0.606 | |
Trunk vs. other site | 3.41 | 1.43–8.11 | 0.006 | |
Mutational status (Mut vs. WT) | 0.77 | 0.32–1.87 | 0.566 | |
SLNB status (negative vs. not performed) | 2.79 | 1.18–6.57 | 0.019 | |
−146 or −124 C > T TERT promoter mutations | 1.75 | 0.66–4.61 | 0.259 | |
TERT rs2853669 | 1.10 | 0.48–2.53 | 0.818 | |
TERT status and trunk association only in primary lesions | WT/no trunk | 1 | ||
−146 or −124 C > T mut/no trunk | 1.52 | 0.25–9.29 | 0.648 | |
WT/trunk | 2.67 | 0.12–57.6 | 0.532 | |
−146 or −124 C > T mut/trunk | 5.33 | 1.02–27.7 | 0.047 | |
TERT status and trunk association in all | WT/no trunk | 1 | ||
−146 or −124 C > T mut/no trunk | 0.68 | 0.21–2.28 | 0.538 | |
WT/trunk | 0.50 | 0.05–5.03 | 0.556 | |
−146 or −124 C > T mut/trunk | 3.64 | 1.14–11.66 | 0.029 | |
TERT mut + trunk site vs. other only in primary | 4.00 | 1.09–14.62 | 0.036 | |
TERT mut + trunk site vs. other | 4.78 | 1.93–11.8 | 0.001 |
Multivariable | Only Visceral Site | ||
---|---|---|---|
OR | CI | p | |
Age (linear) | 0.99 | 0.96–1.03 | 0.684 |
Gender (F vs. M) | 3.44 | 1.12–10.6 | 0.031 |
AJCC 2017 (IB vs. IIA, IIB, IIC) | 0.22 | 0.07–0.67 | 0.008 |
SLNB status (negative vs. not performed) | 3.05 | 1.06–8.78 | 0.039 |
TERT mut + trunk site vs. other | 3.78 | 1.35–10.6 | 0.011 |
Patients | Total (83) | Other Site of Progression (46; 55.4%) | Only Visceral (37; 44.6%) | p | |
---|---|---|---|---|---|
Gender | F | 31 (37.3%) | 21 (45.6%) | 10 (27.0%) | 0.081 |
M | 52 (62.7%) | 25 (54.4%) | 27 (73.0%) | ||
Age at diagnosis | Median (interval) | 64 (21–87) | 65 (26–87) | 60 (21–84) | 0.404 |
Primary site | Head/neck | 22 (26.5%) | 9 (19.6%) | 13 (35.1%) | 0.059 |
Trunk | 25 (30.1%) | 5 (44.0%) | 20 (37.8%) | ||
Upper extremities | 9 (10.8%) | 2 (13.0%) | 2 (8.1%) | ||
Lower extremities | 27 (32.5%) | 3 (43.5%) | 7 (18.9%) | ||
SLNB | Not performed | 18 (21.7%) | 10 (21.7%) | 8 (21.6%) | 0.990 |
Negative | 65 (78.3%) | 4 (78.3%) | 18 (78.4%) | ||
AJCC 2017 | IB | 24 (28.9%) | 15 (32.6%) | 9 (24.3%) | 0.408 |
IIA, IIB, IIC | 59 (71.1%) | 31 (67.4%) | 28 (75.7%) | ||
TERT/Trunk site | WT/no trunk | 34 (40.9%) | 20 (43.5%) | 14(37.8%) | 0.149 |
−146 or −124 C > T mut/no trunk | 24 (28.9%) | 15 (32.6%) | 9 (24.3%) | ||
WT/trunk | 13 (15.7%) | 8 (17.4%) | 5 (13.5%) | ||
−146 or −124 C > T mut/trunk | 12 (14.5%) | 3 (6.5%) | 9 (24.3%) |
Multivariable Logistic Regression | Only Visceral Site | ||
---|---|---|---|
OR | CI | p | |
Age (linear) | 0.99 | 0.97–1.02 | 0.856 |
Gender (F vs. M) | 2.49 | 0.92–6.70 | 0.071 |
AJCC 2017 (IB vs. IIA, IIB, IIC) | 0.99 | 0.32–3.07 | 0.997 |
SLNB status (negative vs. not performed) | 1.26 | 0.41–3.86 | 0.682 |
TERT mut + trunk site vs. other | 4.80 | 1.01–22.9 | 0.049 |
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Osella-Abate, S.; Bertero, L.; Senetta, R.; Mariani, S.; Lisa, F.; Coppola, V.; Metovic, J.; Pasini, B.; Puig S, S.; Fierro, M.T.; et al. TERT Promoter Mutations are Associated with Visceral Spreading in Melanoma of the Trunk. Cancers 2019, 11, 452. https://doi.org/10.3390/cancers11040452
Osella-Abate S, Bertero L, Senetta R, Mariani S, Lisa F, Coppola V, Metovic J, Pasini B, Puig S S, Fierro MT, et al. TERT Promoter Mutations are Associated with Visceral Spreading in Melanoma of the Trunk. Cancers. 2019; 11(4):452. https://doi.org/10.3390/cancers11040452
Chicago/Turabian StyleOsella-Abate, Simona, Luca Bertero, Rebecca Senetta, Sara Mariani, Francesco Lisa, Vittoria Coppola, Jasna Metovic, Barbara Pasini, Susana Puig S, Maria Teresa Fierro, and et al. 2019. "TERT Promoter Mutations are Associated with Visceral Spreading in Melanoma of the Trunk" Cancers 11, no. 4: 452. https://doi.org/10.3390/cancers11040452
APA StyleOsella-Abate, S., Bertero, L., Senetta, R., Mariani, S., Lisa, F., Coppola, V., Metovic, J., Pasini, B., Puig S, S., Fierro, M. T., Manrique-Silva, E., Kumar, R., Nagore, E., Cassoni, P., & Ribero, S. (2019). TERT Promoter Mutations are Associated with Visceral Spreading in Melanoma of the Trunk. Cancers, 11(4), 452. https://doi.org/10.3390/cancers11040452