Mutational profile of TP53 in esophageal squamous cell carcinoma associated with chagasic megaesophagus

Abstract

Chaga's disease is an important communicable neglected disease that is gaining wider attention due to its increasing incidence worldwide. Achalasia due to chagasic megaesophagus (CM), a complication of this disease, is a known-yet, poorly understood-etiological factor for esophageal squamous cell carcinoma (ESCC) development. In this study, we aimed to perform the analysis of TP53 mutations in a series of Brazilian patients with ESCC that developed in the context CM (ESCC/CM), and to compare with the TP53 mutation profile of patients with benign CM and patients with nonchagasic ESCC. Additionally, we intended to correlate the TP53 mutation results with patient's clinical pathological features. By polymerase chain reaction (PCR) followed by direct sequencing of the hotspot regions of TP53 (exon 5 to 8), we found that TP53 mutations were present in 40.6% (13/32) of the ESCC/CM group, 45% (18/40) of the nonchagasic ESCC group, and in only 3% (1/33) of the benign CM group. Missense mutations were the most common in the three groups, yet, the type and mutated exon mutation varied significantly among the groups. Clinically, the groups exhibited distinct features, with both cancer groups (ESCC and ESCC/CM) been significantly associated higher consumption of alcohol and tobacco, older age, worse Karnofsky performance status, poor outcome than the patients with benign CM. No significant association was found between TP53 mutation profile and clinical-pathological features in any of the three groups. We describe first the time the analysis of TP53 mutations in ESCC that developed in the context of CM, and the observed high frequency of mutations, suggest that TP53 also plays an important role in the tumorigenic process of this unexplored etiological condition.

HPV detection within a case series of chagasic megaesophagus associated or not with esophageal squamous cell carcinoma

“…Clinical-pathological and molecular features of the patients studied are described in Table 1 37 . As previously reported by our group 31 , most of the patients were males and under 60 years. In relation to the principal risk factors for the development of esophageal cancer, patients from groups CM/ESCC and ESCC were statistically associated with higher consumption of tobacco and alcohol (87.5% and 86.5%; 66.7% and 81.0%, respectively).…”

“…We included only patients diagnosed with image or histopathological proven chagasic megaesophagus with or without a positive serologic test for Chagas' disease; we also included patients with esophageal ESCC without chagasic megaesophagus with serologic negative for Chagas' disease whose exams (image and histopathology) confirmed the malignant disease. Clinicalpathological variables, and molecular TP53 and PI3KCA status was achieved from these individuals 31 .…”

Frequency of HPV detection in chagasic megaesophagus associated or not with esophageal squamous cell carcinoma

“…Clinical-pathological and molecular features of the patients studied are described in Table 1 21 . As previously reported by our group 32 , most of the patients were males and under 60 years old. In relation to the principal risk factors for the development of esophageal cancer, patients from groups CM/ESCC and ESCC were statistically associated with higher consumption of tobacco and alcohol (87.5% and 86.5%; 66.7% and 81.0%, respectively).…”

“…Finally, in order to better understand the role of HPV in these patients, we analyzed if there was any correlation between the presence of high-risk HPV DNA and the mutation status of TP53, which was reported previously in our studies 32 . Despite the lack of signi cant associations, we observed that patients who tested positive for HPV were more prone to lack mutation within the TP53 gene (18/25, 72.0%) (Table 4).…”

“…We included only patients diagnosed with an image or histopathological proven chagasic megaesophagus with or without a positive serologic test for Chagas' disease; we also included patients with ESCC without chagasic megaesophagus serologic negative for Chagas' disease whose exams (image and histopathology) con rmed the malignant disease. Clinical-pathological variables of patients, as well as the molecular status of TP53 and PI3KCA hotspot mutations and MSI phenotype, were previously reported from these individuals 21,32,33 . All clinical and pathological information was obtained through medical record´s review.…”