Vulvar Squamous Cell Carcinoma: Comprehensive Genomic Profiling of HPV+ Versus HPV- Forms Reveals Distinct Sets of Potentially Actionable Molecular Targets

Erik A Williams; Adrienne J Werth; Radwa Sharaf; Meagan Montesion; Ethan S Sokol; Dean C Pavlick; Molly McLaughlin-Drubin; Rachel Erlich; Helen Toma; Kevin Jon Williams; Jeff M Venstrom; Brian M Alexander; Nikunj Shah; Natalie Danziger; Amanda C Hemmerich; Eric A Severson; Jonathan Keith Killian; Douglas I Lin; Jeffrey S Ross; Julie Y Tse; Shakti H Ramkissoon; Mark C Mochel; Julia A Elvin

doi:10.1200/PO.19.00406

Vulvar Squamous Cell Carcinoma: Comprehensive Genomic Profiling of HPV+ Versus HPV- Forms Reveals Distinct Sets of Potentially Actionable Molecular Targets

JCO Precis Oncol. 2020 Jun 16:4:PO.19.00406. doi: 10.1200/PO.19.00406. eCollection 2020.

Authors

Erik A Williams¹, Adrienne J Werth², Radwa Sharaf¹, Meagan Montesion¹, Ethan S Sokol¹, Dean C Pavlick¹, Molly McLaughlin-Drubin¹, Rachel Erlich¹, Helen Toma², Kevin Jon Williams³, Jeff M Venstrom¹, Brian M Alexander¹, Nikunj Shah¹, Natalie Danziger¹, Amanda C Hemmerich¹, Eric A Severson¹, Jonathan Keith Killian¹, Douglas I Lin¹, Jeffrey S Ross^{1

4}, Julie Y Tse^{1

5}, Shakti H Ramkissoon^{1

6}, Mark C Mochel⁷, Julia A Elvin¹

Affiliations

¹ Foundation Medicine, Cambridge, MA.
² Department of Obstetrics and Gynecology, Christiana Hospital, Newark, DE.
³ Lewis Katz School of Medicine at Temple University, Department of Physiology, Department of Medicine, Philadelphia, PA.
⁴ Department of Pathology, State University of New York Upstate Medical University, Syracuse, NY.
⁵ Department of Pathology and Laboratory Medicine, Tufts University School of Medicine, Boston, MA.
⁶ Wake Forest Comprehensive Cancer Center and Department of Pathology, Wake Forest School of Medicine, Winston-Salem, NC.
⁷ Departments of Pathology and Dermatology, Virginia Commonwealth University School of Medicine, Richmond, VA.

Abstract

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.