Impact of Copy Number Alterations on Human Papillomavirus (HPV)-Induced and HPV-Independent Penile Cancers.

Penile squamous cell carcinomas (SCC) develop via transforming human papillomavirus (HPV) infection or independent of HPV. The association of copy number alterations (CNA) affecting chromosome arms, amplifications or deletions of tumor suppressor/oncogenes with HPV status and somatic mutations is largely unknown. CNA in 121 penile SCC (52% HPV associated, 48% HPV independent) were assessed using shallow whole-genome sequencing and correlated with hotspot mutations in 50 cancer driver genes. CNA were common with frequent complex co-occurrences in both etiologies. Arm-level changes included gains of 3q, 8q (48% each), 1q (36%), 1p (26%), 9q (36%), and 9p (31%) and losses of 19p (48%), 8p (44%), 19q (36%), and 3p (33%). Oncogene amplifications included broad 3q alterations (43%; TP63, SOX2, and PIK3CA) and 8q alterations (40%; MYC, HEY1, and RAD21). MYC amplifications coincided with an increased fraction of genome altered indicating genomic instability (P=.00001). Homozygous deletions affected 8p (29%; WRN, NRG1), and 3p (19%, BAP1, FANCD2, VHL) and 11q22/23 (19%, ARHGEF12, BCL9L, ATM) in both etiologies. CNA affecting TP53, CDKN2A/B, CDKN1A/B, and RB1 occurred in both, HPV-induced (16%) and HPV-independent SCC (24%), while tumor suppressor gene mutations were exclusive to HPV-independent SCC. Further differences included more amplifications on 1p in HPV-induced SCC (adjusted P = .003), compared to more 8q full-arm gains (adjusted P = .00003), amplifications of oncogenes on 8q including MYC (adjusted P = .006), and homozygous deletions of 8p (adjusted P = .03) in HPV-independent SCC. EGFR amplifications dominated in HPV-independent TP53/CDKN2A wild-type SCC without dermatoses. Together with mutations in PIK3CA, HRAS, and FGFR3, CNA represent an alternate RTK/Ras/PI3K-mediated carcinogenesis pathway. Therapeutically interesting targetable CNA such as EGFR, MTAP, and ATM occurred in >50% of advanced SCC irrespective of etiology. CNA are common in penile SCC, mainly independent of HPV-status and somatic mutations and may assist in personalized treatment strategies.