Del Bianco Paola, Stagni Camilla, Giunco Silvia, Fabozzi Alessio, Elefanti Lisa, Pellegrini Stefania, Vecchiato Antonella, Pigozzo Jacopo, Zamuner Carolina, De Rossi Anita, De Nicolo Arcangela, Menin Chiara
Clinical Research Unit, Veneto Institute of Oncology IOV - IRCCS, 35128 Padua, Italy.
Immunology and Diagnostic Molecular Oncology Unit, Veneto Institute of Oncology IOV - IRCCS, 35128 Padua, Italy.
Cancers (Basel). 2020 Apr 11;12(4):946. doi: 10.3390/cancers12040946.
Resistance is a major challenge in the management of mitogen-activated protein kinase inhibitor (MAPKi)-treated metastatic melanoma. Tumor genetic alterations can cause MAPK pathway reactivation, leading to lack of response and poor outcome. Characterization of the mutational profile in patients with melanoma might be crucial for patient-tailored treatment choices. Mutations in the promoter region of the telomerase reverse transcriptase gene (TERTprom) lead to increased TERT expression and telomerase activity and are frequent in BRAF mutant melanoma. Reportedly, TERTprom, and BRAF mutations cooperate in driving cancer progression and aggressiveness. We evaluated the effect of the TERTprom status on the clinical outcome in 97 MAPKi-treated melanoma patients. We observed that patients with the c.-146C > T mutation showed a significantly worse progression-free survival (PFS) compared to those carrying the c.-124C > T mutation and a two-fold increased risk of progression (median 5.4 vs. 9.5 months; hazard ratio (HR) 1.9; 95% confidence interval (CI) 1.2-3.2; = 0.013). This trend was also observed for the overall survival (OS); melanoma patients with the c.-146C > T mutation showed a poorer prognosis compared to those with the c.-124C > T mutation (median 13.3 vs. 25.5 months; HR 1.9, 95% CI 1.1-3.3, 0.023). Our results disclose a different correlation of the two TERTprom mutations with MAPKi-treated melanoma patient outcome, highlighting a different impact of the pathway blockade.
耐药性是丝裂原活化蛋白激酶抑制剂（MAPKi）治疗转移性黑色素瘤过程中的一项重大挑战。肿瘤基因改变可导致MAPK通路重新激活，从而导致治疗无反应和预后不良。黑色素瘤患者突变谱的特征描述对于个体化治疗选择可能至关重要。端粒酶逆转录酶基因（TERTprom）启动子区域的突变会导致TERT表达增加和端粒酶活性增强，在BRAF突变型黑色素瘤中很常见。据报道，TERTprom和BRAF突变共同推动癌症进展和侵袭性。我们评估了TERTprom状态对97例接受MAPKi治疗的黑色素瘤患者临床结局的影响。我们观察到，与携带c.-124C>T突变的患者相比，携带c.-146C>T突变的患者无进展生存期（PFS）明显更差，进展风险增加两倍（中位时间5.4个月对9.5个月；风险比（HR）1.9；95%置信区间（CI）1.2 - 3.2；P = 0.013）。总生存期（OS）也观察到了这种趋势；携带c.-146C>T突变的黑色素瘤患者与携带c.-124C>T突变的患者相比，预后更差（中位时间13.3个月对25.5个月；HR 1.9，95%CI 1.1 - 3.3，P = 0.023）。我们的结果揭示了两种TERTprom突变与接受MAPKi治疗的黑色素瘤患者结局的不同相关性，突出了通路阻断的不同影响。
