Genomic Determinants of Early Recurrences in Low-Stage, Low-Grade Endometrioid Endometrial Carcinoma

Abstract

Low-stage, low-grade endometrioid endometrial carcinoma (EEC), the most common histologic type of endometrial cancer, typically has a favorable prognosis. A subset of these cancers, however, displays an aggressive clinical course with early recurrences, including distant relapses. All statistical tests were 2-sided. Using a combination of whole-exome and targeted capture sequencing of 65 FIGO stage IA and IB grade 1 EECs treated with surgery alone, we demonstrate that chromosome 1q gain (odds ratio [OR] = 8.09, 95% confidence interval [CI] = 1.59 to 54.6; P = .02), PIK3CA mutation (OR = 9.16, 95% CI = 1.95 to 61.8; P = .01), and DNA mismatch repair-deficient molecular subtype (OR = 7.92, 95% CI = 1.44 to 87.6; P = .02) are independent predictors of early recurrences within 3 years in this patient population. Chromosome 1q gain was validated in an independent dataset of stage I grade 1 EECs subjected to whole-exome sequencing. Our findings expand on the repertoire of genomic parameters that should be considered in the evaluation of patients with low-stage, low-grade EEC.

Figure 1.

Molecular landscape of stage I, grade 1 endometrioid endometrial cancers with and without recurrences within 36 months. A) Representative hematoxylin and eosin-stained sections of stage I, grade 1 endometrioid endometrial carcinomas (EECs). Scale bars = 200 µm. B) Recurrent nonsynonymous somatic mutations in nonrecurrent stage I, grade 1 EECs (n = 38, left) and stage I, grade 1 EECs from patients who developed recurrences within 36 months (n = 27, right). Mutation types and molecular subtype information are color coded to the legend. C) Copy number alterations identified in stage I, grade 1 EECs from patients who developed recurrent disease within 36 months (n = 27, top) and who were disease free at 36 months (bottom). Information on the molecular subtypes, CTNNB1, and TP53 mutation status, are provided in the phenobar. CN = copy number; MMR = mismatch repair; SNV = single nucleotide variants.