ARID1A as a prognostic biomarker in gastroesophageal cancer: A genomic database analysis

In recent years, a steady increase of genomic studies has contributed to reveal the complex molecular landscape of Gastroesophageal Adenocarcinoma (GEA), shedding new light on novel therapeutic options and opening the era of precision oncology in these poor-prognosis tumors. The DNA damage repair (DDR) pathway constitutes an intricate network of effectors involved in DNA repair and cell cycle checkpoint control to preserve genomic integrity. The advent of next-generation sequencing and other genomic technologies has broadened the spectrum of genes impairing the DDR pathway by up to 27% in newly diagnosed GEA patients. One of the leading regulators of DDR is AT-rich interaction domain 1A (ARID1A), a tumor suppressor gene that constitutes a subunit of the Switch/Sucrose Non-fermentable (SWI/SNF) chromatin remodeling complex. ARID1A is frequently mutated in Epstein-Barr virus (EBV)-positive and microsatellite instability (MSI) subtypes/DNA mismatch repair (MMR) protein deficient malignancies, nonetheless the prognostic role of ARID1A alterations is still under investigation in GEA.

In this study, we performed a comprehensive analysis of clinic-molecular features of ARID1A alterations in GEA patients by consulting an open access dataset to increase the current knowledge on the molecular and biological profile of gastroesophageal tumors. Data regarding clinical outcomes, mutational profiles, and copy number alterations in patients affected by GEA were extracted from the cBioPortal for Cancer Genomics Database.

2109 GEA patients from eleven studies in the current database were considered for the analysis. According to our results, ARID1A mutations were identified in 357 of cases (17%). Among these, 101 (28%) patients underwent resection as a primary treatment. TTN, TP53, MUC16, and SYNE1 were the mostly reported co-occurring mutations, which were observed in 63.8%, 53.0%, 39.3%, and 35.6% of cases, respectively. Disease-free survival (DFS) was longer in ARID1A-mutated compared with ARID1A wild-type patients (84.0 vs 31.6 months, respectively; p=0.02), resulting in longer overall survival (OS) in those candidate for radical surgery. R0 resections were more frequent in ARID1A-mutated tumors compared with ARID1A wild-type GEAs (26.8% versus 17.5% of cases, respectively; p=0.01).

Despite our study presents some limitations to acknowledge, these preliminary results confirm that ARID1A has the potential to emerge as a novel positive prognostic biomarker in GEA patients following radical resection. Integrated clinic-molecular profiling of GEA is destined to become a continuing challenge, and further studies are warranted in this direction.

The authors.

Has not received any funding.

All authors have declared no conflicts of interest.