Perfil molecular do gene NOTCH1 em tumores de pênis

Abstract

Penile cancer (CaPe) is a rare but common neoplasm in developing countries with high socioeconomic vulnerability. The state of Maranhão has the highest global incidence ever recorded, making it a serious public health problem. Recent research has identified the NOTCH1 gene as one of the most frequently mutated genes in CaPe, which can significantly impact its expression. NOTCH1 can perform different functions, promoting or suppressing tumor growth and proliferation, depending on the cellular context. The aim of this study was to identify genomic alterations in the NOTCH1 gene in samples of primary tumor and lymph node metastasis of CaPe. This was a retrospective study with samples from patients over 18 years of age diagnosed with CaPe who underwent surgical procedures at three referral hospitals in São Luís, MA. Clinical and histopathological data were obtained through histological reviews, and NOTCH1 copy number and gene expression were analyzed by qPCR using the comparative ΔCt method. Sixty-four cases of penile tumors were analyzed (30 with metastasis and 34 without lymph node metastasis). Most of the patients were over 60 years old, had little schooling, a low income, lived in rural areas and had poor hygiene. Phimosis was observed in 40% of the cases with metastasis and 38.2% of those without. The lesions were predominantly on the glans (40% in the group with metastasis) and on the glans and foreskin (41.2% in the cases without metastasis), with a G3 degree of differentiation in 90% of the cases with metastasis and 61.8% of the cases without, and lymphocytic infiltration in 96.6% of the cases with metastasis and 96.9% of the cases without metastasis. There was a high frequency of HPV, present in 62.5% of cases, and the high-risk genotype (16, 18 and 31) was the most frequent in both groups. Smoking was directly associated with a higher occurrence of mutations in the NOTCH1 gene (P=0.010), and the relationship between NOTCH1 status and extranodal extension was statistically significant (p = 0.048). NOTCH1 gene expression in the primary tumor was significantly lower compared to healthy tissue (p = 0.0006), as well as in lymph node metastasis tissue (p = 0.008). This decrease was associated with worse disease-free survival (Log rank p = 0.03725) and the presence of sarcomatoid transformation, both in the primary tumor tissue (p = 0.011) and in the lymph node metastasis tissue (p = 0.006). This is the first study to analyze the NOTCH1 gene in CaPe, revealing unprecedented results. The results show that smoking was associated with an increase in the number of NOTCH1 gene copies, and that NOTCH1 gene expression was reduced in both primary tumor tissue and lymph node metastasis, compared to healthy tissue. This reduction in expression was related to the presence of sarcomatoid transformation and worse disease-free survival, suggesting that this gene is involved in the tumor progression of CaPe and is a potential biomarker