Abstract
Penile squamous cell carcinoma (PSCC) is a rare malignancy with poor survival after standard treatment. Although genomic alterations of PSCC have been characterized in several latest studies, the association between the formation of somatic landscape and regional lymph node metastasis (LNM), an important predictor for patient survival, has not been comprehensively investigated. Here, we collected formalin-fixed paraffin-embedded tumor tissue and matched normal samples of 32 PSCC patients, including 14 LNM patients and 18 clinically node-negative patients, to implement a whole-exome sequencing. Comparison of genomic features among different lymph node status subgroups was conducted after genomic profiling and its effects on patient survival were explored. Top-ranked recurrent gene mutants in our PSCC cohort were TP53 (13/32), NOTCH1 (12/32), CDKN2A (11/32), TTN (9/32) and FAT1 (8/32), mainly identified in the Notch, Hippo, cell cycle, TP53, RTK-RAS and PI3K pathways. While CDKN2A was confirmed to be the driver gene in all PSCC patients, certain gene mutants were significantly enriched in LNM involved patients, including TP53 (9/14 vs. 4/18, p = 0.029) and GBF1 (4/14 vs. 0/18, p = 0.028). Overall survival stratification of PSCC patients were found to be significantly correlated with mutations of three genes, including PIK3CA (Hazard ratio [HR] = 4.15, p = 0.029), CHD7 (HR = 4.82, p = 0.032) and LAMC3 (HR = 15.9, p < 0.001). PIK3CA and LAMC3 held a higher prevalence in patients with LNM compared to those without LNM (PIK3CA: 3/14 vs. 1/18, LAMC3: 2/14 vs. 1/18). Our finding demonstrated that genomic divergence exists across PSCC patients with different lymph node statuses, and it may be correlated with their survival outcome. It helps delineate somatic evolution during tumor progression and perfect potential therapeutic intervention in this disease.
Highlights
Penile squamous cell carcinoma (PSCC) is a rare cancer with a significantly higher incidence in developing countries compared to developed countries [1], mainly attributed to exposure to human papilloma virus (HPV) [2]
8 (25%) of them were diagnosed with low, low-to-moderate or moderate grade cancer while 24 (75%) of them were evaluated as moderate-to-high or high grade cancer. 14 (43.75%) patients were assessed at stage III or higher. 28 (87.5%) patients were tested for HPV genotyping, and 16 (50%) of them were found to be HPV-positive. 7 (21.88%) patients experienced metastases or relapse and 9 (28.13%) patients deceased during follow-up
Risk stratification of lymph node metastasis is essential for both clinical intervention and prognosis prediction of PSCC
Summary
Penile squamous cell carcinoma (PSCC) is a rare cancer with a significantly higher incidence in developing countries compared to developed countries [1], mainly attributed to exposure to human papilloma virus (HPV) [2]. To discover novel diagnostic and prognostic biomarkers that are capable to identify patients sensitive to specific therapy, genomic profiling of penile carcinoma has been examined [8,9,10,11] and a few PSCC cell lines were established [12]. Those studies revealed that somatic alterations are associated with penile carcinogenesis, including frequent mutations in gene TP53, CDKN2A, NOTCH1 and PIK3CA [13, 14]. It is indicated that lymph node metastasis (LNM) could be roughly inferred from lymph node staging, lymph vascular invasion or sentinel lymph node biopsy combined with sonography [22,23,24], accurate prediction of lymph node status is still lacking and the connections between lymphatic metastasis and potential genetic biomarkers remain unclear [25]
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