Feasibility and clinical applicability of genomic profiling based on cervical smear samples in patients with endometrial cancer

Abstract

PurposeCervical smear samples are easily obtainable and may effectively reflect the tumor microenvironment in gynecological cancers. Therefore, we investigated the feasibility of genomic profiling based on tumor DNA analysis from cervical smear samples from endometrial cancer patients.Materials and methodsPreoperative cervical smear samples were obtained via vaginal sampling in 50 patients, including 39 with endometrial cancer and 11 with benign uterine disease. Matched blood samples were obtained simultaneously. Genomic DNA (gDNA) from cervical smear and/or cell-free DNA from whole blood were extracted and sequenced using the Pan100 panel covering 100 endometrial cancer-related genes.ResultsCervical swab-based gDNA analysis detected cancer with 67% sensitivity and 100% specificity, showing a superior performance compared to that of the matched blood or Pap smear tests. Cervical swab-based gDNA effectively identified patients with loss of MSH2 or MSH6 and aberrant p53 expression based on immunohistochemistry. Genomic landscape analysis of cervical swab-based gDNA identified PTEN, PIK3CA, TP53, and ARID1A as the most frequently altered genes. Furthermore, 26 endometrial cancer patients could be classified according to the Proactive Molecular Risk Classifier for Endometrial Cancer.ConclusionCervical swab-based gDNA test showed an improved detection potential and allowed the classification of patients, which has both predictive and prognostic implications.

Evaluation of somatic mutations in cervicovaginal samples as a non-invasive method for the detection and molecular classification of endometrial cancer

“…The sensitivity of the ClassEC test was comparable to that of previous studies that used a NGS panel in cervicovaginal samples and achieved sensitivities ranging from 67% to 81%. 13 , 41 , 42 , 43 However, we obtained relatively low sensitivity compared to epigenomic markers in cervicovaginal samples, 12 , 20 , 21 and it was lower for non-endometrioid histologies. Studies evaluating proteins in cervicovaginal samples are also promising, although based on low sample sizes (22 and 9 cases), 44 , 45 low performance (<60% specificity), 23 or did not provide diagnostic accuracy estimates.…”

“… 14 The specificities of studies using a NGS panel were unclear because the controls of the largest study were considerably younger than endometrial cancer cases (mean age 34 vs. 62 years, respectively) 41 and aging is strongly associated with the accumulation of somatic mutations. 47 The remainder of the NGS studies were based on a small sample size of controls (i.e., 11 and 31) without validation 13 , 42 or no controls at all. 43 We used matched controls and observed 80% specificity using clinician-collected samples.…”

Mismatch repair, p53, and L1 cell adhesion molecule status influence the response to chemotherapy in advanced and recurrent endometrial cancer

“…Since the development of the Proactive Molecular Risk Classi er for Endometrial Cancer (ProMisE) molecular classi cation, classi cation methods using new diagnostic methods besides IHC have garnered attention. One method involves using cervical swab-based genomic DNA (gDNA) of EC through the conventional Pap smear technique [22]. The research team veri ed the loss of MSH2 or MSH6 and aberrant p53 expression using cervical swab-based gDNA and con rmed its value as a tool that can be used to layer ProMisE molecular classi cation based on tests and strati cation.…”

Target-enhanced whole-genome sequencing (TE-WGS) shows clinical validity equivalent to commercially available targeted oncology panel

“…The clinical utility of targeted genomic panels, encompassing both germline susceptibility and known "actionable" somatic mutations (including TSO500), has been welldocumented [27][28][29][30][31][32][33]. For some cancer types, targeted panel sequencing is becoming standard practice [31].…”