PIK3CA mutations are frequent in esophageal squamous cell carcinoma associated with chagasic megaesophagus and are associated with a worse patient outcome

Abstract

BackgroundChronic diseases such as chagasic megaesophagus (secondary to Chagas’ disease) have been suggested as etiological factors for esophageal squamous cell carcinoma; however, the molecular mechanisms involved are poorly understood.ObjectiveWe analyzed hotspot PIK3CA gene mutations in a series of esophageal squamous cell carcinomas associated or not with chagasic megaesophagus, as well as, in chagasic megaesophagus biopsies. We also checked for correlations between the presence of PIK3CA mutations with patients’ clinical and pathological features.MethodsThe study included three different groups of patients: i) 23 patients with chagasic megaesophagus associated with esophageal squamous cell carcinoma (CM/ESCC); ii) 38 patients with esophageal squamous cell carcinoma not associated with chagasic megaesophagus (ESCC); and iii) 28 patients with chagasic megaesophagus without esophageal squamous cell carcinoma (CM). PIK3CA hotspot mutations in exons 9 and 20 were evaluated by PCR followed by direct sequencing technique.ResultsPIK3CA mutations were identified in 21.7% (5 out of 23) of CM/ESCC cases, in 10.5% (4 out of 38) of ESCC and in only 3.6% (1 case out of 28) of CM cases. In the CM/ESCC group, PIK3CA mutations were significantly associated with lower survival (mean 5 months), when compared to wild-type patients (mean 2.0 years). No other significant associations were observed between PIK3CA mutations and patients’ clinical features or TP53 mutation profile.ConclusionThis is the first report on the presence of PIK3CA mutations in esophageal cancer associated with chagasic megaesophagus. The detection of PIK3CA mutations in benign chagasic megaesophagus lesions suggests their putative role in esophageal squamous cell carcinoma development and opens new opportunities for targeted-therapies for these diseases.

PIK3CA Gene Mutations in Solid Malignancies: Association with Clinicopathological Parameters and Prognosis

“…Mutations in PIK3CA gene were associated with improved outcomes among metastatic HPV-positive oropharyngeal cancer [97], with similar results reported in HPV-negative oropharyngeal cancer [98]. Moreover, the combination of temsirolimus, carboplatin, and paclitaxel resulted in tumor regression in head and neck squamous cell carcinomas [99].…”

Role of PI3K/AKT pathway in cancer: the framework of malignant behavior

“…In general, the genetic alterations of PIK3CA (24%), and PTEN (7%) are observed in ESCA (Table 1), especially the somatic mutations of PIK3CA (7.2% vs 12.5%), PIK3C2A (0.7% vs. 0), PIK3CG (2.9% vs. 4.2%) and PIK3C2G (0 vs. 37.5%) are observed respectively in 139 paired ESCC cases and 24 cell lines [98]. Even more, PIK3CA mutations are frequent in ESCC associated with chagasic megaesophagus and are associated with a worse patient outcome [99]. HERG1, LSD1, CEP55, CACNA2D3, CircVRK1 and lncRNA GAS5 affect the proliferation, migration, invasion or radioresistance of ESCC cells via the PI3K/AKT pathway [100][101][102][103][104][105].…”

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

“…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.…”

“…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.…”

“…These changes lead to the buildup of food, resulting in the development of megaesophagus 17 . Importantly, about 2-10% of individuals with chagasic megaesophagus will develop esophageal squamous cell carcinoma 19, 20 ; however, due to the scarcity of studies regarding the carcinogenic environment, the neoplastic mechanism leading to ESCC remains uncertain 21 . Nevertheless, it is believed that in ammation and chronic esophagitis may play an important role in the development of epithelial dysplasia and, subsequently in cancer 22,23 .…”