Frequency and impact of a genome-wide homologous recombination deficiency signature (HRDsig+) on the genomic landscape of clinically advanced penile squamous cell carcinoma (CAPSCC).
Authors: Spiess Philippe E. , Necchi Andrea , Li Roger , Kamat Ashish M. , Grivas Petros , Gupta Shilpa , Agarwal Neeraj , Cheng Liang , Pavlick Dean , Sokol Ethan , Graf Ryon P , Lin Douglas I , Ross Jeffrey S. , Schrock Alexa Betzig , Quintanilha Julia , Li Gerald , Mitchell Jerry W. , Jacob Joseph M , Basnet Alina , Bratslavsky Gennady 
Published: February 2025

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Background:
CAPSCC is a challenging disease with significant need for improvements in effective systemic therapies for patients with surgically incurable disease.
Methods:
373 cases of CAPSCC underwent comprehensive genomic profiling to examine all classes of genomic alterations (GA). MSI high status, tumor mutation burden (TMB) levels, genomic ancestry and trinucleotide mutational signatures were determined from the sequencing data. HRDsig status was calculated using a broad set of genome-wide copy number features (PMID 37769224). PD-L1 was determined by IHC using the Dako 22C3 tumor proportional score (TPS) system. Results were compared using the Fisher exact system.
Results:
13 (3.5%) of the CAPSCC cases featured a positive HRDsig status (HRDsig+). The PSCC HRDsig+ patients were older than the PSCC HRDsig+ patients (median ages 67 vs 62; NS). The GA/tumor frequencies were higher in the PSCC HRDsig- cases (5 v3 3; NS). Genomic ancestry distribution was similar with 68-77% of patients featuring EUR ancestry. 9.4% of PSCC HRDsig- featured AFR ancestry compared with 0% PSCC HRDsig+ (NS). MSI-high status was extremely low in both HRDsig- vs HRDsig+ PSCC groups (1.4% vs 0.0%; NS). Although the median TMB was higher in the HRDsig+ (6.3 vs 3.8; NS); the frequency of TMB > 10 mutations/Mb was similar in both groups (13.3% vs 17.7%; NS). Trinucleotide mutational signature distribution was similar in both cohorts. PD-L1 low (1-49% TPS) expression was similar in both groups and ranged from 43% to 52%. Only 1 (7.7%) of the 13 PSCC HRDsig+ cases featured a
BRCA1
inactivating mutation and 0 (0%) had a
BRCA2
mutation. In the HRDsig- group, 66.7%/75.0% of
BRCA1
/
BRCA2
mutated CAPSCC were mono-allelic likely non-driver GA respectively. Other HRD associated mutations in the PSCC HRDsig+ cases included 2 (15.4%) ATM and 1 (7.7%)
PALB2
mutation. The
PALB2
mutation was a bi-allelic homozygous deletion which has been linked to prolonged benefit from PARP inhibitor-based treatments. GA in both
TERT
(51.1% vs 0.0%; P=.009) and
TP53
(53.3% vs 23.1%) were more frequent in the PSCC HRDsig- cases whereas GA in
MAP2K1
(15.4% vs .0%; P=.025),
KRAS
(15.4% vs 1.1%); NS) and
NF1
(15.4% vs 1.4%; NS) were more frequent in the PSCC HRDsig+ cases.
NOTCH1
GA were similar in both groups (range 16.4% to 15.4%). There was no difference in the frequencies of HPV+ status between the 2 groups.
Conclusions:
With a 3.5% frequency, HRDsig+ status is a relatively uncommon biomarker in CAPSCC. However, HRDsig+ status appears to occur in PSCC in the absence of
BRCA1
/
2
mutations and may include homozygous deletions in HRD-associated genes such as
PALB2
that been associated with substantial benefit from PARPi regimens in other tumor types. These findings may impact the future development of PARP inhibitor-based treatment regimens for PSCC patients.