CDKN2A loss-of-function genetic alterations in uterine sarcoma: prognostic implications and potential therapeutic target

Objectives: Uterine sarcomas frequently harbor non-actionable oncogenic mutations, limiting the use of targeted therapies. Alterations in the potentially targetable CDK4/6 pathway have recently been described. We explored clinicopathologic differences between uterine sarcomas with CDKN2A loss-of-function genetic alterations and TP53 loss-of-function mutations and sought to determine whether these molecularly defined uterine sarcomas differ in prognosis among early stage patients. Methods: Patients with uterine sarcoma were consented to a prospective study of tumor-normal targeted massively parallel sequencing of up to 468 cancer-related genes. Clinicopathologic data were abstracted from the medical record. Fisher's exact tests and Mann-Whitney-U tests were employed to compare categorical and continuous variables, respectively. Kaplan-Meier curves were used to estimate survival, compared using log-rank test. Results: A total of 229 patients with uterine leiomyosarcoma (LMS; n=191) or undifferentiated uterine sarcoma (UUS; n=38) were identified. The most common genomic alterations were TP53 (62%, n=142) and RB1 (41%, n=94) mutations/homozygous deletions. Furthermore, 10% (n=23) harbored CDKN2A loss-of-function mutations or homozygous deletions, which were mutually exclusive with both TP53 and RB1 alterations (p Download : Download high-res image (93KB) Download : Download full-size image Conclusions: CDKN2A loss-of-function alterations, found in 10% of uterine sarcomas, are mutually exclusive with TP53 and RB1 alterations commonly present in this malignancy. CDKN2A altered uterine sarcoma may be a genomically and morphologically distinct tumor. We demonstrate poor survival outcomes for patients with early stage disease harboring these CDKN2A alterations. Identifying uterine sarcomas with CDKN2A loss-of-function alterations provides rationale for testing cyclin-dependent kinase inhibitors in this molecular subset.