Homozygous deletion of CDKN2A by fluorescence in situ hybridization is prognostic in grade 4, but not grade 2 or 3, IDH-
- PDF / 1,116,887 Bytes
- 12 Pages / 595.276 x 790.866 pts Page_size
- 17 Downloads / 171 Views
pen Access
RESEARCH
Homozygous deletion of CDKN2A by fluorescence in situ hybridization is prognostic in grade 4, but not grade 2 or 3, IDH‑mutant astrocytomas Daniel F. Marker and Thomas M. Pearce*
Abstract IDH-mutant astrocytomas have a more indolent natural history and better prognosis than their IDH-wild type counterparts, but are still graded according to schemes developed prior to the recognition of this type of neoplasm as a distinct entity. Homozygous deletion of CDKN2A has been proposed as a molecular correlate of aggressive behavior in these tumors, and may be incorporated into future grading systems in an effort to improve prognostic stratification. Fluorescence in situ hybridization (FISH) is a common ancillary testing modality used to assess CDKN2A status, but the specifics of how to best interpret FISH results for prognostication of gliomas have not been clearly defined in the literature. To address this issue, we performed a retrospective analysis of prospectively collected CDKN2A FISH data from 108 primary and 43 recurrent IDH-mutant astrocytomas diagnosed between 2007–2020 at the University of Pittsburgh Medical Center. High level CDKN2A homozygous deletion was rare in primary tumors and was identified more frequently in recurrent tumors. Multivariate Cox Proportional-Hazards analysis demonstrated that histologic grade and CDKN2A status are independent predictors of survival, and the prognostic value of CDKN2A is maximized by applying a threshold of ≥ 30% of tumor cells with homozygous deletion by FISH to define a positive result. At this threshold, CDKN2A deletion significantly stratified survival of histologic grade 4 tumors, but grade 2 and 3 tumors rarely exceeded this cutoff value and did not show worse survival. Lower thresholds identified additional lower grade tumors, but were not prognostically useful. Compared to prior studies, the lack of prognostic significance of CDKN2A homozygous deletion by FISH in grade 2–3 IDH-mutant astrocytomas may reflect differences in cohort populations or technical differences between testing modalities. Definitive criteria for determining CDKN2A homozygous deletion by various methodologies will be critical if this is to be included in future grading schemes. Keywords: CDKN2A, IDH, Astrocytoma, FISH Introduction Incorporation of somatic molecular alterations into the classification and grading of brain tumors continues to drive an ongoing revolution in the field of *Correspondence: [email protected] Department of Pathology, Division of Neuropathology, University of Pittsburgh Medical Center, S701 Scaife Hall, 3550 Terrace Street, Pittsburgh, PA 15261, USA
neuro-oncology. Among diffusely infiltrating gliomas, the mutational status of isocitrate dehydrogenase (IDH1 or IDH2 genes) is a fundamental determinant of biologic behavior, which, in combination with additional molecular features, is now a defining criterion of the diagnostic category of IDH-mutant (IDHm) astrocytoma [1]. Segregating IDHm astrocytic tumors from their more aggressive IDH-wild type (ID
Data Loading...
