Abstract
The low 5-year survival rate of women with high-grade serous epithelial ovarian cancer (HGS-EOC) is related to its late diagnosis; thus, improvement in diagnosis constitutes a crucial step to increase the curability of this disease. To determine whether the presence of the clonal pathogenic TP53 variant detected in matched primary tumor biopsies can be identified in DNA purified from Papanicolaou test samples collected from women with HGS-EOC years before the diagnosis. This cohort study was conducted among a single-center cohort of women with histologically confirmed diagnosis of HGS-EOC recruited at San Gerardo Hospital, Monza, Italy, from October 15, 2015, to January 4, 2019. Serial dilutions of DNA derived from tumor samples and DNA extracted from healthy women's Papanicolaou test samples were analyzed to define the sensitivity and specificity of droplet digital polymerase chain reaction assays designed to detect the TP53 variants identified in tumors. All available brush-based Papanicolaou test slides performed up to 6 years before diagnosis were investigated at the Mario Negri Institute, Milano, Italy. Data were analyzed from October 2018 to December 2019. The presence of tumor pathogenic TP53 variants was assessed by the droplet digital polymerase chain reaction approach in DNA purified from Papanicolaou test samples obtained from the same patients before diagnosis during cervical cancer screenings. Among 17 included patients (median [interquartile range] age at diagnosis, 60 [53-69] years), Papanicolaou tests withdrawn before diagnosis presented tumor-matched TP53 variants in 11 patients (64%). In 2 patients for whom longitudinal Papanicolaou tests were available, including 1 patient with Papanicolaou tests from 25 and 49 months before diagnosis and 1 patient with Papanicolaou tests from 27 and 68 months before diagnosis, the TP53 clonal variant was detected at all time points. These findings suggest that noninvasive early molecular diagnosis of HGS-EOC is potentially achievable through detection of TP53 clonal variants in the DNA purified from Papanicolaou tests performed during cervical cancer screening.
Highlights
High-grade serous epithelial ovarian cancer (HGS-EOC) is characterized by a clonal pathogenic variant in the TP53 (OMIM 191170) gene, which represents one of the early events in the etiopathogenetic process.[1,2] It has been demonstrated that the same TP53 clonal variant detected in the primary tumor site can be detected in precancerous lesions in the Fallopian tube, known as serous tubal intraepithelial carcinomas.[3]
In 2 patients for whom longitudinal Papanicolaou tests were available, including 1 patient with Papanicolaou tests from 25 and 49 months before diagnosis and 1 patient with Papanicolaou tests from 27 and 68 months before diagnosis, the TP53 clonal variant was detected at all time points
These findings suggest that noninvasive early molecular diagnosis of HGS-EOC is potentially achievable through detection of TP53 clonal variants in the DNA purified from Papanicolaou tests performed during cervical cancer screening
Summary
High-grade serous epithelial ovarian cancer (HGS-EOC) is characterized by a clonal pathogenic variant in the TP53 (OMIM 191170) gene, which represents one of the early events in the etiopathogenetic process.[1,2] It has been demonstrated that the same TP53 clonal variant detected in the primary tumor site can be detected in precancerous lesions in the Fallopian tube, known as serous tubal intraepithelial carcinomas.[3]. Experimental evidence in support of this theoretical prediction is lacking,[3] which hampers the potential development of a test for the early diagnosis of ovarian cancer.[3]. Clonal pathogenic variants in the TP53 gene are suitable candidates to identify early steps in the neoplastic transformation toward HGS-EOC at the molecular level. Several studies[5,6,7] have shown the feasibility of detecting somatic variants in DNA from endometrial and ovarian cancers retrieved from various types of vaginal samples collected at the time of diagnosis. The aim of this study was to explore the possibility of exploiting the Papanicolaou test conducted for cervical cancer screening years before diagnosis as a source of material to detect clonal variants in the TP53 gene as a basis to develop assays for the early diagnosis of HGS-EOC
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