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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., Competing Interests: The following represents disclosure information provided by authors of this manuscript. All relationships are considered compensated unless otherwise noted. Relationships are self-held unless noted. I = Immediate Family Member, Inst = My Institution. Relationships may not relate to the subject matter of this manuscript. For more information about ASCO's conflict of interest policy, please refer to www.asco.org/rwc or ascopubs.org/po/authors/author-center. Open Payments is a public database containing information reported by companies about payments made to US-licensed physicians (Open Payments). Erik A. WilliamsEmployment: Foundation Medicine, Inc. Stock and Other Ownership Interests: F. Hoffmann-La RocheRadwa SharafEmployment: Foundation Medicine Stock and Other Ownership Interests: RocheBrennan DeckerStock and Other Ownership Interests: Avidea Technologies Consulting or Advisory Role: Foundation Medicine, Avidea TechnologiesMeagan MontesionStock and Other Ownership Interests: RocheEthan S. SokolEmployment: Foundation Medicine Stock and Other Ownership Interests: Roche (Parent of FMI)Dean C. PavlickStock and Other Ownership Interests: RocheNikunj ShahEmployment: Foundation MedicineKevin Jon WilliamsStock and Other Ownership Interests: Hygieia, Gemphire Therapeutics Consulting or Advisory Role: Gemphire Therapeutics Research Funding: Novo NordiskJeffrey M. VenstromEmployment: Genentech, Foundation Medicine Leadership: Genentech Stock and Other Ownership Interests: Genentech Research Funding: Genentech, Roche, Foundation Medicine Travel, Accommodations, Expenses: GenentechBrian M. AlexanderEmployment: Foundation Medicine Leadership: Foundation Medicine Stock and Other Ownership Interests: Roche Research Funding: Eli Lilly (Inst), Puma (Inst), Celgene (Inst) (OPTIONAL) Open Payments Link: https://openpaymentsdata.cms.gov/physician/854258/summaryJeffrey S. RossEmployment: Foundation Medicine Leadership: Foundation Medicine Stock and Other Ownership Interests: Foundation Medicine Consulting or Advisory Role: Celsius Therapeutics Research Funding: Foundation MedicineLee A. AlbackerEmployment: Foundation Medicine Stock and Other Ownership Interests: RocheDouglas I. LinEmployment: Foundation MedicineShakti H. RamkissoonEmployment: Foundation Medicine Stock and Other Ownership Interests: Foundation MedicineJulia A. ElvinEmployment: Foundation Medicine No other potential conflicts of interest were reported., (© 2020 by American Society of Clinical Oncology.)

Purpose: Vulvar squamous cell carcinoma (vSCC) encompasses two predominant variants: one associated with detectable high-risk strains of human papillomavirus (hrHPV) and a second form often occurring in the context of chronic dermatitis in postmenopausal women. Genomic assessment of a large-scale cohort of patients with aggressive vSCC may identify distinct mutational signatures., Materials and Methods: Tumor samples from a total of 280 patients with vSCC underwent hybridization capture with analysis of up to 406 cancer-related genes. Human papillomavirus (HPV) sequences were detected by de novo assembly of nonhuman sequencing reads and aligned to the RefSeq database. Immunohistochemistry for programmed death-ligand 1 (PD-L1) was assessed., Results: One hundred two of 280 vSCCs (36%) contained hrHPV sequences, predominantly HPV 16 (88%). The HPV-positive (HPV+) group was significantly younger (median age, 59 v 64 years; P = .001). Compared with HPV-negative (HPV-) vSCCs, HPV+ tumors showed more frequent pathogenic alterations in PIK3CA (31% v 16%; P = .004), PTEN (14% v 2%; P < .0001), EP300 (14% v 1%; P < .0001), STK11 (14% v 1%; P < .0001), AR (5% v 0%; P = .006), and FBXW7 (10% v 3%; P = .03). In contrast, HPV- vSCCs showed more alterations in TP53 (83% v 6%; P < .0001), TERTp (71% v 9%; P < .0001), CDKN2A (55% v 2%; P < .0001), CCND1 amplification (22% v 2%; P < .0001), FAT1 (25% v 4%; P < .0001), NOTCH1 (19% v 6%; P = .002), and EGFR amplification (11% v 0%; P < .0001), as well as a higher rate of 9p24.1 ( PDL1/PDL2) amplification (5% v 1%) and PD-L1 immunohistochemistry high-positive tumor staining (33% v 9%; P = .04)., Conclusion: Comprehensive molecular profiles of vSCC vary considerably with hrHPV status and may inform patient selection into clinical trials. Sixty-one percent of HPV+ vSCCs had a pathogenic alteration in the PI3K/mTOR pathway, whereas HPV- vSCCs showed alterations in TP53 , TERTp , CDKN2A , CCND1 , and EGFR , and biomarkers associated with responsiveness to immunotherapy., Competing Interests: The following represents disclosure information provided by authors of this manuscript. All relationships are considered compensated unless otherwise noted. Relationships are self-held unless noted. I = Immediate Family Member, Inst = My Institution. Relationships may not relate to the subject matter of this manuscript. For more information about ASCO's conflict of interest policy, please refer to www.asco.org/rwc or ascopubs.org/po/author-center. Open Payments is a public database containing information reported by companies about payments made to US-licensed physicians (Open Payments). Erik A. WilliamsEmployment: Foundation Medicine Stock and Other Ownership Interests: F. Hoffmann-La RocheRadwa SharafEmployment: Foundation Medicine Stock and Other Ownership Interests: RocheMeagan MontesionStock and Other Ownership Interests: RocheEthan S. SokolEmployment: Foundation Medicine Stock and Other Ownership Interests: Roche (Parent of FMI)Dean C. PavlickStock and Other Ownership Interests: RocheMolly McLaughlin-DrubinEmployment: Foundation Medicine Employment: PatientsLikeMe (I), Precision for Medicine (I) Stock and Other Ownership Interests: Roche Travel, Accommodations, Expenses: Foundation MedicineRachel ErlichEmployment: Foundation Medicine Stock and Other Ownership Interests: Foundation MedicineKevin Jon WilliamsStock and Other Ownership Interests: Hygieia Stock and Other Ownership Interests: Gemphire Therapeutics Consulting or Advisory Role: Gemphire Therapeutics, Inc. Research Funding: Novo NordiskJeff M. VenstromEmployment: Genentech, Foundation Medicine Leadership: Genentech Stock and Other Ownership Interests: Genentech Research Funding: Genentech, Foundation Medicine Travel, Accommodations, Expenses: GenentechBrian M. AlexanderEmployment: Foundation Medicine Leadership: Foundation Medicine Stock and Other Ownership Interests: Roche Research Funding: Eli Lilly (Inst), Puma (Inst), Celgene (Inst) Open Payments Link: https://openpaymentsdata.cms.gov/physician/854258/summaryNikunj ShahEmployment: Foundation MedicineNatalie DanzigerEmployment: Foundation MedicineAmanda C. HemmerichEmployment: Foundation Medicine Stock and Other Ownership Interests: Foundation Medicine (Inst)Eric A. SeversonEmployment: Foundation Medicine, Partners Healthcare Stock and Other Ownership Interests: Foundation MedicineJonathan Keith KillianEmployment: Foundation Medicine Stock and Other Ownership Interests: Foundation MedicineDouglas I. LinEmployment: Foundation MedicineJeffrey S. RossEmployment: Foundation Medicine Leadership: Foundation Medicine Stock and Other Ownership Interests: Foundation Medicine Consulting or Advisory Role: Celsius Therapeutics Research Funding: Foundation MedicineJulie Y. TseEmployment: Foundation Medicine, Pathology Watch Travel, Accommodations, Expenses: Foundation MedicineShakti H. RamkissoonEmployment: Foundation Medicine Stock and Other Ownership Interests: Foundation MedicineJulia A. ElvinEmployment: Foundation Medicine No other potential conflicts of interest were reported., (© 2020 by American Society of Clinical Oncology.)

Competing Interests: Disclosure of Potential Conflicts of Interest PKS is a member of the Scientific Advisory Board of RareCyte Inc., which manufactures the CyteFinder slide scanner used in this study. PKS is also co-founder of Glencoe Software, which contributes to and supports the open-source OME/OMERO image informatics software used in this paper. SS has consulted for RareCyte Inc..Other authors have no competing financial interests to disclose.