Molecular characterization of squamous cell carcinoma of the anal canal

Abstract

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. Chisquare 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.

Two distinct pathogenic pathways of digital papillary adenocarcinoma — BRAF mutation or low‐risk HPV infection

“…Another study reported that HPV42 in the anogenital region typically exhibited squamous differentiation, which is consistent with the observed squamous differentiation in the BRAF ‐WT DPAs 44 . Finally, NGS studies of typical HPV‐driven cancers tend to be negative or seemingly random for driver mutations typically seen in carcinomas, but may have durable responses to immune checkpoint inhibitors 43,45–47 . The previous cited study of HPV42 in DPA also found that HPV42 DNA not detected in many sweat gland tumors of various histopathologic types including acral hidradenoma 19 …”

“…44 Finally, NGS studies of typical HPV-driven cancers tend to be negative or seemingly random for driver mutations typically seen in carcinomas, but may have durable responses to immune checkpoint inhibitors. 43,[45][46][47] The previous cited study of HPV42 in DPA also found that HPV42 DNA not detected in many sweat gland tumors of various histopathologic types including acral hidradenoma. 19 F I G U R E 4 Two distinct pathogenic pathways of digital papillary adenocarcinoma (DPA).…”

Prognostic role of HPV integration status and molecular profile in advanced anal carcinoma: An ancillary study to the epitopes-HPV02 trial

“…Indeed, it has been shown in Head and Neck Squamous Cell Carcinoma (HNSCC) that APOBEC activity and mutations are concordant between viral genome and host cell genome (43). We also found no TP53 mutations in HPV-positive SCCA, as opposed to HPV-negative SCCA (44). Even if mutations were not associated with PFS and OS in our study, we observed a high number of gene amplifications (39 amplifications on tumors of 23 patients), mostly in PIK3CA.…”

Biomarkers in Anal Cancer: Current Status in Diagnosis, Disease Progression and Therapeutic Strategies

“…Some retrospective studies have evaluated the programmed cell death protein ligand 1 (PD-L1) expression in tumor cells of patients with SCCA. Overall, PD-L1 positivity varied from 56% to 68.8% [ 76 , 77 , 78 , 79 , 80 ]. The prognostic role of the biomarker has been reported in those studies, with conflicting results [ 76 , 77 , 78 , 79 ].…”