Introduction. Endometrial cancer (EC) is the most common oncogynecological malignancy worldwide, while ovarian cancer (OC) is the deadliest malignancy[1]. The high incidence and mortality rates are attributed to lack of specific symptoms or effective screening techniques resulting in late diagnosis. OC is mostly diagnosed at stages III or IV, when the 5-year survival rates are only 3-19% [2]. However, even when the cancer is detected early, as is often with EC, disease recurrence rate is 10-15% and there is no available genetic biomarkers with a potential to predict the most aggressive cases with a high risk of relapse [3]. Both EC and OC are often characterized by genomic alterations. ARID1A, a subunit of SWI/SNF chromatin remodeling complex, is often mutated in both endometriosis-associated OC and EC. ARID1A participates in nucleosome repositioning, thus loss of function mutations in this tumor suppressor gene could lead to global impact on transcription and gene expression [4]. Although currently biopsies are regarded as the gold standard for diagnosis, staging and genetic analysis that may suggest targeted treatment, they are invasive and not suitable for long-term disease monitoring [5]. Both OC and EC shed cells into uterine cavity, which can be sampled non-invasively by uterine lavage, a simple sampling technique that can be performed in a gynecologist' office [6]. Sequencing of uterine lavage fluid from EC patients has been shown to detect mutations in up to 100% of malignancies, proving that uterine lavage could be useful in gynecological cancer diagnosis [7].
The Aim of this study was to use targeted sequencing to asses ARID1A mutations in OC and EC patient's uterine lavage fluid and tissue samples and determine ARID1A SNP association with clinical features.
Methods. 34 uterine lavage and 21 tissue samples from 54 patients (24 high grade serous ovarian cancer, 8 non-serous ovarian cancer, 11 endometrial cancer and 11 patients with benign conditions) were analyzed by targeted next generation sequencing using Ion AmpliSeqTM On-Demand Panel targeting ARID1A mutations. Pathogenicity of uncertain significance mutations were predicted using online database VarSome [8].
Results. 14 ARID1A SNPs were detected in 26% (14/54) patients. 64% (9/14) of these were determined to be pathogenic and the rest were of uncertain significance. ARID1A mutations were primarily detected in early stage (pT1, G1) endometrioid EC and mucinous OC, 8/9 pathogenic SNPs were detected in non-serous malignancies. 43% (3/7) mutations were detected in both tissue and uterine lavage samples.
In conclusion, ARID1A mutations in uterine lavage samples could be a useful tool to non-invasively detect early stage gynecological malignancies.