Clinical and mutational profile of AT-rich interaction domain 1A-mutated cancers

Rosa Falcone; Marco Filetti; Pasquale Lombardi; Valeria Altamura; Francesco Paroni Sterbini; Giovanni Scambia; Gennaro Daniele

doi:10.37349/etat.2023.00163

Clinical and mutational profile of AT-rich interaction domain 1A-mutated cancers

Explor Target Antitumor Ther. 2023;4(4):716-726. doi: 10.37349/etat.2023.00163. Epub 2023 Aug 31.

Authors

Rosa Falcone¹, Marco Filetti¹, Pasquale Lombardi¹, Valeria Altamura¹, Francesco Paroni Sterbini¹, Giovanni Scambia^{2

3}, Gennaro Daniele^{1

2}

Affiliations

¹ Phase 1 Unit, Fondazione Policlinico Universitario A. Gemelli IRCCS, 00168 Rome, Italy.
² Scientific Directorate, Fondazione Policlinico Universitario A. Gemelli IRCCS, 00168 Rome, Italy.
³ Department of Life Science and Public Health, Università Cattolica del Sacro Cuore, 00168 Rome, Italy.

Abstract

Aim: AT-rich interaction domain 1A (ARID1A) encodes a key component of the SWItch/Sucrose Non-Fermentable (SWI/SNF) chromatin remodeling complex that participates in gene expression. ARID1A alterations are quite common among cancer patients, although their role remains debated. The aim of this article was to study ARID1A-mutated cancer patients.

Methods: Molecular and clinical data of cancer patients evaluated at Phase 1 Unit of Fondazione Policlinico Universitario A. Gemelli IRCCS were collected. Molecular analyses were performed using FoundationOne^® CDx (Foundation Medicine Inc., Cambridge, MA, United States). Cancer patients with at least one molecular alteration in ARID1A gene were identified as ARID1A⁺.

Results: Among the 270 patients undergoing molecular analysis, we found 25 (9%) with at least one pathogenic alteration in ARID1A. The vast majority of these patients were female (84%). The median age at diagnosis was 59; most of the cancers (15, 60%) were gynecological (especially endometrioid endometrial cancers and clear cell ovarian cancers), diagnosed at an early stage. Frameshift alterations in ARID1A were the most common (19/31, 61%) alterations. The median number of mutations in ARID1A⁺ population was higher compared to ARID1A^- population (6 vs. 4), as well as tumor mutational burden (TMB) [20 mutations/megabase (mut/Mb) vs. 1.26 mut/Mb]. Phosphatidylinositol-4,5-bisphosphate 3-kinase catalytic subunit alpha (PIK3CA), phosphatase and tensin homolog (PTEN), catenin beta 1 (CTNNB1), and lysine methyltransferase 2D (MLL2) mutations were enriched in ARID1A⁺ population. In this cohort, ARID1A did not display any relation with response to platinum chemotherapy. Cancers with double alterations in ARID1A (ARID1A²⁺) were all gynecological cancers (83% endometrioid endometrial cancers).

Conclusions: This analysis provides clinical and molecular details about the phenotypes of ARID1A⁺ cancers, in particular the subgroup of gynecologic cancers. The high frequency of concurrent mutations in the phosphoinositide 3-kinase (PI3K) pathway among endometrioid endometrial cancers may support the proposal of a new treatment strategy based on the combination of ataxia telangiectasia and Rad3-related (ATR) inhibitor and PIK3CA inhibitor.

Keywords: AT-rich interaction domain 1A; cancer; mutation; target.