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Author Spotlight: Advancements in Molecular Biomarker Testing for Non-Squamous Non-Small Cell Lung Cancer
Published on: September 8, 2023
Molecular characterization of squamous cell carcinoma of the anal canal
Samantha A Armstrong1, Rita Malley1, Hongkun Wang1
1Ruesch Center for the Cure of Gastrointestinal Cancers, Lombardi Comprehensive Cancer Center, Georgetown University Medical Center, Washington, DC, USA.
Background:
Squamous cell carcinoma of the anal canal (SCCA) is an uncommon malignancy with limited therapeutic options. Nivolumab and pembrolizumab show promising results in patients with SCCA. Human papillomavirus (HPV)-negative tumors are frequently TP53-mutated (TP53-MT) and often resistant to therapy.
Methods:
We present a large molecularly-profiled cohort of SCCA, exploring the underlying biology of SCCA, differences between TP53-wild type (TP53-WT) and TP53-MT tumors, and differences between local and metastatic tumors. SCCA specimens (n=311) underwent multiplatform testing with immunohistochemistry (IHC), in situ hybridization (ISH) and next-generation sequencing (NGS). Tumor mutational burden (TMB) was calculated using only somatic nonsynonymous missense mutations. Chi-square testing was used for comparative analyses.
Results:
The most frequently mutated genes included PIK3CA (28.1%), KMT2D (19.5%), FBXW7 (12%), TP53 (12%) and PTEN (10.8%). The expression of PD-1 was seen in 68.8% and PD-L1 in 40.5% of tumors. High TMB was present in 6.7% of specimens. HER2 IHC was positive in 0.9%, amplification by chromogenic in situ hybridization (CISH) was seen 1.3%, and mutations in ERBB2 were present in 1.8% of tumors. The latter mutation has not been previously described in SCCA. When compared with TP53-WT tumors, TP53-MT tumors had higher rates of CDKN2A, EWSR1, JAK1, FGFR1 and BRAF mutations. PD-1 and PD-L1 expression were similar, and high TMB did not correlate with PD-1 (P=0.50) or PD-L1 (P=0.52) expression.
Conclusions:
Molecular profiling differences between TP53-MT and TP53-WT SCCA indicate different carcinogenic pathways which may influence response to therapy. Low frequency mutations in several druggable genes may provide therapeutic opportunities for patients with SCCA.
Insights
Molecular profiling reveals distinct pathways in anal cancer, with TP53-mutated tumors showing different mutations. These findings may guide new therapeutic strategies for squamous cell carcinoma of the anal canal.
Area of Science:
- Oncology
- Genomics
- Cancer Biology
Background:
- Squamous cell carcinoma of the anal canal (SCCA) is rare with limited treatment options.
- Immunotherapies like nivolumab and pembrolizumab show promise.
- Human papillomavirus (HPV)-negative SCCA often harbors TP53 mutations and exhibits therapy resistance.
Purpose of the Study:
- To perform large-scale molecular profiling of SCCA.
- To investigate biological differences between TP53-mutated (TP53-MT) and TP53-wild type (TP53-WT) tumors.
- To compare local and metastatic SCCA molecular profiles.
Main Methods:
- Multiplatform testing (IHC, ISH, NGS) on 311 SCCA specimens.
- Calculation of tumor mutational burden (TMB).
- Comparative analyses using chi-square testing.
Main Results:
- Frequent mutations in PIK3CA (28.1%), KMT2D (19.5%), FBXW7 (12%), TP53 (12%), and PTEN (10.8%).
- PD-1 expression in 68.8% and PD-L1 in 40.5% of tumors.
- TP53-MT tumors showed increased rates of CDKN2A, EWSR1, JAK1, FGFR1, and BRAF mutations compared to TP53-WT tumors.
Conclusions:
- Distinct molecular profiles in TP53-MT vs. TP53-WT SCCA suggest different carcinogenic origins.
- These differences may impact therapeutic responses.
- Identification of low-frequency mutations in druggable genes presents potential new treatment avenues for SCCA.
