CDKN2C-Null Leiomyosarcoma: A Novel, Genomically Distinct Class of TP53/ RB1-Wild-Type Tumor With Frequent CIC Genomic Alterations and 1p/19q-Codeletion

Erik A Williams; Radwa Sharaf; Brennan Decker; Adrienne J Werth; Helen Toma; Meagan Montesion; Ethan S Sokol; Dean C Pavlick; Nikunj Shah; Kevin Jon Williams; Jeffrey M Venstrom; Brian M Alexander; Jeffrey S Ross; Lee A Albacker; Douglas I Lin; Shakti H Ramkissoon; Julia A Elvin

doi:10.1200/PO.20.00040

CDKN2C-Null Leiomyosarcoma: A Novel, Genomically Distinct Class of TP53/ RB1-Wild-Type Tumor With Frequent CIC Genomic Alterations and 1p/19q-Codeletion

JCO Precis Oncol. 2020 Sep 1:4:PO.20.00040. doi: 10.1200/PO.20.00040. eCollection 2020.

Authors

Erik A Williams¹, Radwa Sharaf¹, Brennan Decker², Adrienne J Werth³, Helen Toma³, Meagan Montesion¹, Ethan S Sokol¹, Dean C Pavlick¹, Nikunj Shah¹, Kevin Jon Williams⁴, Jeffrey M Venstrom¹, Brian M Alexander¹, Jeffrey S Ross^{1

5}, Lee A Albacker¹, Douglas I Lin¹, Shakti H Ramkissoon^{1

6}, Julia A Elvin¹

Affiliations

¹ Foundation Medicine, Cambridge, MA.
² Department of Pathology, Brigham and Women's Hospital and Harvard Medical School, Boston, MA.
³ Christiana Hospital, Department of Obstetrics and Gynecology, Newark, DE.
⁴ Department of Physiology, Department of Medicine, Lewis Katz School of Medicine at Temple University, Philadelphia, PA.
⁵ Department of Pathology, State University of New York Upstate Medical University, Syracuse, NY.
⁶ Wake Forest Comprehensive Cancer Center and Department of Pathology, Wake Forest School of Medicine, Winston-Salem, NC.

Abstract

Purpose: Leiomyosarcoma (LMS) harbors frequent mutations in TP53 and RB1 but few actionable genomic alterations. Here, we searched for recurrent actionable genomic alterations in LMS that occur in the absence of common untreatable oncogenic drivers.

Methods: Tissues from 276,645 unique advanced cancers, including 2,570 uterine and soft tissue LMS, were sequenced by hybrid-capture-based next-generation DNA and RNA sequencing/comprehensive genomic profiling of up to 406 genes. We characterized clinicopathologic features of relevant patient cases.

Results: Overall, 77 LMS exhibited homozygous copy loss of CDKN2C at chromosome 1p32.3 (3.0% of LMS). Genomic alterations (GAs) in TP53, RB1, and ATRX were rare compared with the remainder of the LMS cohort (11.7% v 73.4%, 0% v 54.5%, 2.6% v 24.5%, respectively; all P < .0001). CDKN2C-null LMS patient cases were significantly enriched for GAs in CIC (40.3% v 1.4%) at 19q13.2, CDKN2A (46.8% v 7.0%), and RAD51B (16.9% v 1.7%; all P < .0001). Chromosome arm-level aneuploidy analysis of available LMS patient cases (n = 1,284) found that 81% (58 of 72) of CDKN2C-null LMS exhibited 1p/19q-codeletion, a significant enrichment compared with 5.1% in the remainder of the LMS cohort (P < .0001). In total, 99% of CDKN2C-null LMS were in women; the median age was 61 years at surgery (range, 36-81 years). Fifty-five patient cases were uterine primary, four were nonuterine, and the remaining 18 were of uncertain primary site. Sixty percent of cases showed at least focal epithelioid variant histology. Most patients had advanced-stage disease, with 62% of confirmed uterine primary LMS at International Federation of Gynecology and Obstetrics stage IVB. We further validated our findings in two publicly available datasets: The Cancer Genome Atlas and the Project GENIE initiative.

Conclusion: CDKN2C-null LMS defines a genomically distinct tumor that may have prognostic and/or therapeutic clinical implications, including possible use of specific cyclin-dependent kinase inhibitors.