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

Ermakov MS, Regauer S, Kashofer K.

Journal ArticleOpen access

AI summary — for doctors, generated from the abstract only

In 121 penile squamous cell carcinomas, copy number alterations were common in both HPV-associated and HPV-independent tumors, with several specific alterations (such as MYC and EGFR amplification) differing by HPV status and potentially representing actionable therapeutic targets.

What was studied

A genomic study of 121 penile squamous cell carcinomas (52% HPV-associated, 48% HPV-independent) using shallow whole-genome sequencing to assess copy number alterations (CNA) affecting chromosome arms and specific tumor suppressor/oncogenes, correlated with HPV status and hotspot mutations in 50 cancer driver genes.

Key findings

Common arm-level changes included gains of 3q and 8q (48% each), 1q (36%), 1p (26%), 9q (36%), and 9p (31%), and losses of 19p (48%), 8p (44%), 19q (36%), and 3p (33%).
MYC amplification (part of frequent 8q alterations, 40%) was associated with an increased fraction of genome altered, indicating genomic instability (P=.00001).
HPV-independent tumors showed significantly more 8q full-arm gains (adjusted P=.00003), MYC/8q oncogene amplifications (adjusted P=.006), and 8p homozygous deletions (adjusted P=.03), while HPV-induced tumors had more 1p amplifications (adjusted P=.003); tumor suppressor gene mutations (TP53, CDKN2A/B, etc.) were exclusive to HPV-independent tumors.
Targetable CNA such as EGFR, MTAP, and ATM occurred in more than 50% of advanced tumors regardless of HPV etiology; EGFR amplification predominated in HPV-independent TP53/CDKN2A wild-type tumors without dermatoses.

Clinical relevance

These findings suggest that copy number alterations, rather than being simply tied to HPV status, define distinct molecular subgroups of penile squamous cell carcinoma and may be relevant to identifying patients for personalized, targeted treatment strategies, though clinical trial validation of targeting these alterations was not reported.

Who should care

Pathology

Limitations

This was a genomic correlative study without reported clinical treatment outcomes; the sample size (121 cases), while sizable for this rare cancer, and the retrospective design limit ability to establish prognostic or predictive significance beyond genomic associations.

Copy number alterations are common and etiology-associated in penile squamous cell carcinoma, highlighting potential targetable pathways independent of HPV status.

This is an AI-generated summary of the published abstract, not a clinical recommendation. It may not reflect the full text or subsequent updates — verify against the original source before acting on it.

Abstract

Purpose

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.

Materials and methods

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.

Results

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.

Conclusions

CNA are common in penile SCC, mainly independent of HPV-status and somatic mutations and may assist in personalized treatment strategies.

DOI

10.1016/j.labinv.2026.106129

PMID

42031074

Research metadata (titles, abstracts, authors, publication dates) is sourced from Europe PMC, which aggregates content from PubMed/MEDLINE, PubMed Central, and other providers under the U.S. National Library of Medicine (NLM/NCBI). NLM does not claim copyright on abstracts; the original journal publishers or authors may hold rights to the full articles. AI-generated summaries are derived only from the abstract, never the full text, and are always labeled as AI-generated.

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