Molecular and immunophenotypic characterization of anal squamous cell carcinoma reveals distinct clinicopathologic groups associated with HPV and TP53 mutation status

Zhu, Xiaoqin; Jamshed, Sarah; Zou, Jian; Azar, Azniv; Meng, Xiuling; Bathini, Venu; Dresser, Karen; Strock, Cara; Yalamarti, Bhargavi; Yang, Michelle; Tomaszewicz, Keith; Tjionas, George; Mochel, Mark C.; Hutchinson, Lloyd; Bledsoe, Jacob R.

doi:10.1038/s41379-020-00729-y

Cited by 21 publications

(25 citation statements)

References 55 publications

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“…One study (n=119) found 4% of SCCA expressed exon 5 TP53 mutations (30). Another recent study (n=106) confirmed the correlation with HPV-negativity, p53 staining, and TP53 mutation in SCCA are associated with inferior OS as well as reduced recurrence-free survival (19). Our study discovered TP53 mutations in 12% of NGS samples (25/208) and 5% of NGS hot spot samples (3/60).…”

Section: Discussionsupporting

confidence: 78%

“…J Gastrointest Oncol 2021 | https://dx.doi.org/10.21037/jgo-20-610 other HPV driven malignancies such as head and neck cancer, cervical cancer and other gynecologic cancers utilize p16 overexpression as a confirmation for HPV infection as well as a prognostic marker related to PFS and OS [8][9][10][11]. The prognostic value of HPV-DNA and p16 expression in SCCA has also been explored, with results revealing that patients testing positively for both HPV-DNA and p16 overexpression have longer OS [18][19]. Newer unlike other gastrointestinal malignancies such as colon or pancreatic adenocarcinomas, SCCA rarely harbors KRAS mutations, with an incidence of 3% or less, which is confirmed in this comprehensive analysis (27,28).…”

Section: Discussionmentioning

confidence: 99%

“…PD-L1 expression was found to be high in SCCA, which is likely related to the immune response to HPV oncoproteins (62). A recently published study preformed PD-L1 staining on 62 SCCA tumors and found expression (CPS ≥1) in 32% of cases (19). Amongst those who were HPV-negative with PD-L1 expression, there was a trend toward shorter OS (9.8 vs. 40.6 months; P=0.064).…”

Section: Immunotherapymentioning

confidence: 95%

“…Second, by understanding the differences between profiles of primary and metastatic SCCA, pathways affecting metastasis can be identified. Third, there is recent data evaluating the molecular characteristics of the difference between TP53-WT versus TP53-MT tumors and our cohort adds to this growing field (19,20). Thus, continued knowledge expansion of molecular pathways that confer this resistance to standard therapy would help guide the selection of alternative treatments.…”

Section: Introductionmentioning

confidence: 91%

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Molecular characterization of squamous cell carcinoma of the anal canal

Armstrong

Malley

Wang

et al. 2021

J Gastrointest Oncol

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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.

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Section: Discussionsupporting

confidence: 78%

Section: Discussionmentioning

confidence: 99%

Section: Immunotherapymentioning

confidence: 95%

Section: Introductionmentioning

confidence: 91%

See 2 more Smart Citations

Molecular characterization of squamous cell carcinoma of the anal canal

Armstrong

Malley

Wang

et al. 2021

J Gastrointest Oncol

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“…In contrast, the frequency of TP53 mutations in HPV-HNSCC is high (84%) [ 75 ]. TP53 mutations in HPV-negative squamous cell carcinoma are reproducible events in other organs [ 79 , 80 , 81 , 82 ]. In addition, aberrant p53 expression has been reported in several premalignant lesions [ 83 , 84 , 85 , 86 ].…”

Section: Diversity Of Tumor Virusesmentioning

confidence: 99%

Virus-Driven Carcinogenesis

Hatano

Ideta

Hirata

et al. 2021

Cancers

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Cancer arises from the accumulation of genetic and epigenetic alterations. Even in the era of precision oncology, carcinogens contributing to neoplastic process are still an important focus of research. Comprehensive genomic analyses have revealed various combinations of base substitutions, referred to as the mutational signatures, in cancer. Each mutational signature is believed to arise from specific DNA damage and repair processes, including carcinogens. However, as a type of carcinogen, tumor viruses increase the cancer risk by alternative mechanisms, including insertional mutagenesis, viral oncogenes, and immunosuppression. In this review, we summarize virus-driven carcinogenesis to provide a framework for the control of malignant cell proliferation. We first provide a brief overview of oncogenic viruses and describe their implication in virus-related tumors. Next, we describe tumor viruses (HPV, Human papilloma virus; HBV, Hepatitis B virus; HCV, Hepatitis C virus; EBV, Epstein–Barr virus; Kaposi sarcoma herpesvirus; MCV, Merkel cell polyoma virus; HTLV-1, Human T-cell lymphotropic virus, type-1) and tumor virus-related cancers. Lastly, we introduce emerging tumor virus candidates, human cytomegalovirus (CMV), human herpesvirus-6 (HHV-6) and adeno-associated virus-2 (AAV-2). We expect this review to be a hub in a complex network of data for virus-associated carcinogenesis.

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Utility ofCYP2D6copy number variants as prognostic biomarker in localized anal squamous cell carcinoma

Trilla-Fuertes

Gámez‐Pozo

Nogué

et al. 2023

Cancer

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Background: Anal squamous cell carcinoma (ASCC) is an infrequent tumor whose treatment has not changed since the 1970s. The aim of this study is the identification of biomarkers allowing personalized treatments and improvement of therapeutic outcomes.Methods: Forty-six paraffin tumor samples from ASCC patients were analyzed by whole-exome sequencing. Copy number variants (CNVs) were identified and their relation to disease-free survival (DFS) was studied and validated in an independent retrospective cohort of 101 ASCC patients from the Multidisciplinary Spanish Digestive Cancer Group (GEMCAD). GEMCAD cohort proteomics allowed assessing the biological features of these tumors.Results: On the discovery cohort, the median age was 61 years old, 50% were males, stages I/II/III: 3 (7%)/16 (35%)/27 (58%), respectively, median DFS was 33 months, and overall survival was 45 months. Twenty-nine genes whose duplication was related to DFS were identified. The most representative was duplications of the CYP2D locus, including CYP2D6, CYP2D7P, and CYP2D8P genes. Patients with CYP2D6 CNV had worse DFS at 5 years than those with two CYP2D6 copiesThis is an open access article under the terms of the Creative Commons Attribution-NonCommercial License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited and is not used for commercial purposes.

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Molecular and immunophenotypic characterization of anal squamous cell carcinoma reveals distinct clinicopathologic groups associated with HPV and TP53 mutation status

Cited by 21 publications

References 55 publications

Molecular characterization of squamous cell carcinoma of the anal canal

Molecular characterization of squamous cell carcinoma of the anal canal

Virus-Driven Carcinogenesis

Utility ofCYP2D6copy number variants as prognostic biomarker in localized anal squamous cell carcinoma

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