Abstract 1766: CREBBP, NOTCH2 and GNASmutational profile in uterine sarcomas
Authors: Anjos Laura Gonzalez dos , Quevedo Giovanna , Baracat Edmund , Carvalho Katia C. 
Published: March 2024

Abstract
Background: Uterine sarcomas (US) present clinical challenges due to their dynamic behavior and limited treatment options. Representing 1-3% of uterine cancer cases, these tumors exhibit rapid growth, high recurrence rates, and resistance to the standard treatments. The present study aimed to validate several Loss-of-function mutations (LOF), obtained by NGS analysis in the CREBBP, NOTCH2, and GNAS sequences, in US through Sanger sequencing. Methods: Twenty-five samples of US were collected between 2000 and 2015 for genomic DNA extraction. An initial genetic screening of the samples by NGS method was followed by Sanger sequencing validation. Bioinformatics analysis through SnapGene confirmed the results. Results: A c.4063G&gt;A mutation was confirmed in uterine leiomyosarcomas (ULMS), in the both strands. Notable variations in the forward strand, such as a C&gt;G substitution at position 38 of the alignment and a degenerate base S at position 113, differentiated ULMS from uterine sarcomas (US). Two ULMSs exhibited the highest substitution rates: one with 18 and another with 6 substitutions. Despite the absence of the c.5527T&gt;C CREBBP mutation, ULMS displayed increased insertions and deletions. Assessing the NOTCH2 gene in US revealed a complex genetic landscape, with a unique SU-specific duplication in the forward strand. The reverse strand maintained high genetic stability. Mutation c.6094C&gt;A was exclusive to one US sample. Notably, the c.7223T&gt;A mutation in NOTCH2 was not identified. Shared mutations between ULMS and US suggest genomic similarities in these regions. In the GNAS analysis, the c.2381A&gt;C mutation was not found. However, in the forward sequence of one US sample, a deletion at the expected substitution site was detected, suggesting a specific genetic alteration. The c.706G&gt;A mutation was consistently present in sample ULMS, indicating genetic stability in this sample. US exhibited a G&gt;C substitution in the reverse sequence, hinting at a unique pattern of genetic variation. These findings underscore the complexity of genetic alterations in these critical gene regions. Conclusion: Our analysis identified specific alterations in ULMS and US. ULMS showed the c.4063G&gt;A CREBBP mutation and unique variations, while US had a specific c.6094C&gt;A NOTCH2 mutation. The absence of the c.2381A&gt;C GNAS mutation in both ULMS and US, along with distinct genetic patterns (c.706G&gt;A in ULMS and G&gt;C substitution in US), underscores significant mutational differences in these critical gene regions. These findings enhance our understanding of uterine sarcoma genetics, prompting further exploration for potential diagnosis, prognosis and therapeutic advancements.
Citation Format: Laura Gonzalez dos Anjos, Giovanna Quevedo, Edmund Baracat, Katia C. Carvalho. CREBBP, NOTCH2 and GNASmutational profile in uterine sarcomas [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 1766.