RNA sequencing in a penile cancer cohort: an investigation of biomarkers of cisplatin resistance and potential therapeutic drug targets

• Published in: Clinical genitourinary cancer Vol. 20; no. 3; pp. 219 - 226
• Main Authors: Ibilibor, Christine, Watson, Amanda L., Wang, Hanzhang, Gonzalez, Gabriela, Liang, Sitai, Alonzo, David, Rodriguez, Ronald
• Format: Journal Article
• Language: English
• Published: United States Elsevier Inc 01.06.2022
• Subjects: Antineoplastic Combined Chemotherapy Protocols - therapeutic use; Biomarkers; Biomarkers, Tumor - genetics; Biomarkers, Tumor - metabolism; Cisplatin; Cisplatin - pharmacology; Cisplatin - therapeutic use; Endonucleases - metabolism; High-throughput nucleotide sequencing; Humans; Male; Penile neoplasms; Penile Neoplasms - drug therapy; Penile Neoplasms - genetics; Penile Neoplasms - pathology; Retrospective Studies; RNA - therapeutic use; RNA sequence analysis; Sequence Analysis, RNA; Squamous cell carcinoma; PSqCC; Squamous cell carcinoma; ILND; Cisplatin; High-throughput nucleotide sequencing; Penile neoplasms; RNA sequence analysis
• ISSN: 1558-7673; 1938-0682
• DOI: 10.1016/j.clgc.2022.01.002

Chemoresistance in distant micrometastatic lesions may account for diminished durable response rates in advanced penile cancer. However, there are limited studies on new therapeutic targets and the identification of biomarkers that predict chemotherapy response in this population. Thus, we examine the expression of candidate biomarkers of cisplatin resistance, ERCC1 and E2F1, and perform next-generation sequencing on the cancer transcriptome in a penile cancer cohort. In this retrospective cohort study, we identified 71 patients treated for penile squamous cell carcinoma between 2009 and 2019. Immunohistochemistry staining for ERCC1 and E2F1 was performed. H-scores were measured for patient specimens obtained from adjacent normal skin, primary tumor and metastatic lymph node specimens and correlated with RNA expression data obtained through next-generation sequencing. Of the 71 patients identified, 51 and 8 had available surgical specimens for immunohistochemistry and RNA sequencing, respectively. Median H-scores for ERCC1 in adjacent normal skin, primary and metastatic tumors were 17.04, 3.15, and 7.9 respectively compared to E2F1 (43.95, 15.54, 7.9). The median H-score for E2F1 was higher in poorly differentiated primary tumors (24.86) compared to well (7.62) and moderately differentiated (9.55, p = 0.055). Next generation sequencing showed no difference in RNA expression of E2F1 nor ERCC1 between primary tumors and metastatic lesions however did demonstrate elevated RNA expression of genes such as MMP1, and MMP10 in primary tumors compared to adjacent normal skin. We identify potential drug targets for metastatic penile cancer through next-generation RNA sequencing. There are limited innovative drug targets and biomarkers of chemotherapeutic response in penile cancer. In 51 patients, we performed immunohistochemistry staining and next-generation RNA sequencing for ERCC1 and E2F1, biomarkers of cisplatin resistance. We found elevated expression of E2F1 and elevated RNA expression of potential drug targets. Our findings are relevant because these drug targets are currently being developed for clinical use.