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

Abstract

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. 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. 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 <i>v</i> 64 years; <i>P</i> = .001). Compared with HPV-negative (HPV-) vSCCs, HPV+ tumors showed more frequent pathogenic alterations in <i>PIK3CA</i> (31% <i>v</i> 16%; <i>P</i> = .004), <i>PTEN</i> (14% <i>v</i> 2%; <i>P</i> < .0001), <i>EP300</i> (14% <i>v</i> 1%; <i>P</i> < .0001), <i>STK11</i> (14% <i>v</i> 1%; <i>P</i> < .0001), <i>AR</i> (5% <i>v</i> 0%; <i>P</i> = .006), and <i>FBXW7</i> (10% <i>v</i> 3%; <i>P</i> = .03). In contrast, HPV- vSCCs showed more alterations in <i>TP53</i> (83% <i>v</i> 6%; <i>P</i> < .0001), <i>TERTp</i> (71% <i>v</i> 9%; <i>P</i> < .0001), <i>CDKN2A</i> (55% <i>v</i> 2%; <i>P</i> < .0001), <i>CCND1</i> amplification (22% <i>v</i> 2%; <i>P</i> < .0001), <i>FAT1</i> (25% <i>v</i> 4%; <i>P</i> < .0001), <i>NOTCH1</i> (19% <i>v</i> 6%; <i>P</i> = .002), and <i>EGFR</i> amplification (11% <i>v</i> 0%; <i>P</i> < .0001), as well as a higher rate of 9p24.1 (<i>PDL1/PDL2)</i> amplification (5% <i>v</i> 1%) and PD-L1 immunohistochemistry high-positive tumor staining (33% <i>v</i> 9%; <i>P</i> = .04). 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 <i>TP53</i>, <i>TERTp</i>, <i>CDKN2A</i>, <i>CCND1</i>, and <i>EGFR</i>, and biomarkers associated with responsiveness to immunotherapy.