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Abstract
Introduction/Background Endometrial precancer (endometrioid intraepithelial neoplasia/EIN) diagnosis remains contentious, with variable criteria and frequent disagreements among gynecologic pathologists, potentially leading to under/overtreatment. The endometrium is unique in that diagnostic biopsies do not extirpate neoplastic lesions. Our purpose was to 1) characterize serial genomic alterations along the pre-EIN/EIN/cancer continuum in individual women; 2) determine if genomic analysis adds diagnostic value to histopathological review.
Methodology Inclusion criteria were 1) endometrial cancer diagnosis/hysterectomy 2) preceding serial endometrial biopsies (typically over many years) including for some patients an early biopsy before an EIN diagnosis. A comprehensive panel was designed for genes recurrently mutated in endometrial cancer, including hereditary cancer loci. Formalin-fixed/paraffin-embedded specimens for each cancer, preceding samples, and matched germline DNA were subjected to barcoded massively-parallel sequencing to identify mutations, hereditary and acquired, and track their origin and allelic frequency progression. 147 samples from 29 women (5.1 samples/patient) were analyzed.
Results In all but two patients mutations in the cancer were detectable in preceding EIN(s). Notably, ≥1 mutations were detectable in 15/19 patients where a pre-EIN biopsy was available. Serial analysis provided unique insights into the progression of various endometrial cancers. In most cases, the presence of ≥1 mutation could be confirmed by immunohistochemistry, providing unique views of histologic correlates. Class-defining mutations (e.g. POLE) were identified in several cases. Germline mutations were identified in patients with known cancer predisposition syndromes. Mutations were not identified in 15 age-matched control (normal) endometria, arguing that with appropriate thresholds, age-related endometrial mutations should not confound analyses.
Conclusion Genomic analysis of selected endometrial biopsies has the potential to be a cost-effective and valuable diagnostic adjunct to histology, also replacing in a single assay diverse screening methods to identify cancer predisposition syndromes. Though of considerable promise, further investigations will be required to establish utility and refine diagnostic criteria.
Disclosure The authors have no conflicts of interest to disclose. Funding to DHC was provided by the National Institutes of Health/National Cancer Institute (USA), the Cancer Prevention Research Institute of Texas (State of Texas) and the UT Southwestern Stembridge Distinguished Professorship.
Allelic frequencies for mutations in biopsies up to 8 years prior to cancer dx (single patient)