Next-Generation Sequencing-Based Molecular Profiling of Conjunctival Squamous Cell Carcinoma and Its Potential...

Area of Science:

• Ophthalmology
• Oncology
• Genomics

Background:

• Conjunctival squamous cell carcinoma (cSCC) is a rare ocular surface malignancy.
• Understanding the molecular drivers of cSCC is crucial for developing targeted therapies.

Purpose of the Study:

• To perform comprehensive genomic and transcriptomic analyses of invasive cSCC.
• To identify key molecular alterations and potential therapeutic targets in cSCC.

Main Methods:

• Targeted next-generation sequencing of >1700 cancer-related genes.
• Integrative analysis of exome and transcriptome data from tumor and normal samples.
• Molecular characterization including somatic mutations, tumor mutation burden (TMB), structural variations, and gene expression.

Main Results:

• Human papillomavirus (HPV) was detected in only 2 of 20 cSCCs.
• TP53 and CDKN2A alterations were common in HPV-negative tumors; PIK3CA mutations were found in HPV-positive tumors.
• High TMB (>20 Mut/Mb) was observed in 65% of cases, often associated with UV mutational signatures and TERT promoter mutations.
• Recurrent copy number alterations and aberrant TP63 expression were also identified.

Conclusions:

• HPV is not a major driver of cSCC in this cohort.
• TP53 alterations and UV signatures are key in HPV-negative cSCC.
• Chromatin modifiers, Hippo, and Notch pathway genes are frequently altered.
• High TMB and actionable molecular targets suggest immunotherapy and targeted therapies as potential treatment strategies.