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Testing Targeted Therapies in Cancer using Structural DNA Alteration Analysis and Patient-Derived Xenografts
Published on: July 25, 2020
Next-Generation Sequencing-Based Molecular Profiling of Conjunctival Squamous Cell Carcinoma and Its Potential
Hakan Demirci1, Josh N Vo2, Yi-Mi Wu2
1Department of Ophthalmology and Visual Sciences, Kellogg Eye Center, University of Michigan, Ann Arbor, Michigan.
Objective:
Targeted next-generation sequencing-based genomic and transcriptomic analyses of conjunctival squamous cell carcinoma (cSCC) samples using a panel of >1700 cancer-related genes.
Design:
Prospective case series.
Participants:
Twenty patients with invasive cSCC consecutively managed at an academic ocular oncology setting.
Methods:
Integrative exome and transcriptome analysis of fresh-frozen tumor and matching normal samples.
Main Outcome Measures:
Molecular characterization of invasive cSCCs (for somatic mutations, tumor mutation burden (TMB) and signatures, structural variations, viral transcripts, outlier gene expression) and its potential clinical applications.
Results:
Of the 20 invasive cSCCs, only 2 were positive for human papillomavirus (HPV). All 18 HPV-negative tumors had genetic alterations in TP53 and 16 also had alterations in CDKN2A. The 2 HPV-positive tumors showed no alterations in these cell cycle regulators but harbored mutations in PIK3CA. Other frequently altered genes included KMT2C /D (70%), FAT1/3 (65%), and NOTCH1/2/3 (60%), which were implicated in both the HPV-negative and positive tumors. The average TMB was 58.41 mutations per megabase (Mut/Mb). The TMB was >20 Mut/Mb in 13 cases (65%, range: 49.3-160.8 Mut/Mb), of which 11 had ultraviolet (UV) mutational signature, 3 had APOBEC signature, and 2 had microsatellite instability. Most UV-driven tumors (8 of 11) also harbored TERT promoter mutations. The most recurrent large-scale copy number alterations were the deletions affecting chromosomes 3p, 9p, and 14q. Uncommon but potentially drug-targetable copy number gains were also detected affecting several oncogenes. The most frequent gene expression outlier was the aberrantly expressed TP63 found in 19 tumors.
Conclusions:
In our invasive cSCC cohort, HPV infection was not a major contributor to tumor etiopathogenesis. Our results confirmed the central role of TP53 genetic alterations and the common presence of UV signature in the HPV-negative cSCCs. Irrespective of HPV status, other commonly observed genetic alterations included those affecting chromatin modifiers followed by Hippo or Notch pathway-related genes. Ultraviolet-driven TERT promoter mutations co-occurred with other driver gene alterations. The commonly observed high TMB makes immunotherapy a good treatment choice for invasive cSCC. Moreover, several cSCC-associated molecular alterations represent potentially actionable targets, while further studies are necessary to understand their roles in cSCC development and invasion.
Financial Disclosures:
Proprietary or commercial disclosure may be found in the Footnotes and Disclosures at the end of this article.
Insights
Conjunctival squamous cell carcinoma (cSCC) is primarily driven by TP53 alterations and UV signatures, not HPV. High tumor mutation burden suggests immunotherapy is a viable treatment option for cSCC.
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.
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