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.
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