Invasive squamous cell carcinomas and precursor lesions on UV-exposed epithelia demonstrate concordant genomic complexity in driver genes
| Autor: | Suzana Matayoshi, Hakan Demirci, Charles G. Eberhart, Arul M. Chinnaiyan, Shahzad I. Mian, H. K. Soong, Kevin Hu, Dan R. Robinson, Samantha E. Rahrig, Camilla Duarte Silva, Patricia Picciarelli, Alan Sugar, Scott A. Tomlins, Rajesh C. Rao, Anthony B. Daniels, Nolan Bick, Lorena Lazo de la Vega, Xiaoming Wang, Paul W. Harms, Francis P. Worden |
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| Rok vydání: | 2020 |
| Předmět: |
0301 basic medicine
Male squamous cell carcinoma Pathology medicine.medical_specialty Skin Neoplasms Bowen’s disease MMP1 Somatic cell Context (language use) Conjunctival Neoplasms Biology Article Pathology and Forensic Medicine Loss of heterozygosity 03 medical and health sciences CDKN2A 0302 clinical medicine medicine actinic keratosis Humans TP53 Aged Skin ocular surface squamous neoplasia Carcinoma in situ Eye Neoplasms Actinic keratosis High-Throughput Nucleotide Sequencing carcinoma in situ Amplicon Middle Aged medicine.disease Keratosis Actinic stomatognathic diseases 030104 developmental biology 030220 oncology & carcinogenesis Mutation Carcinoma Squamous Cell intraepithelial neoplasia Female precursors |
| Zdroj: | Modern pathology : an official journal of the United States and Canadian Academy of Pathology, Inc |
| ISSN: | 1530-0285 |
| Popis: | Although squamous cell carcinomas (SCC) are the most frequent human solid tumor at many anatomic sites, the driving molecular alterations underlying their progression from precursor lesions are poorly understood, especially in the context of photodamage. Therefore, we used high-depth, targeted next-generation sequencing (NGS) of RNA and DNA from routine tissue samples to characterize the progression of both well- (cutaneous) and poorly-studied (ocular) SCCs. We assessed 56 formalin-fixed paraffin-embedded (FFPE) cutaneous lesions (n= 8 actinic keratosis [AK], n= 30 carcinoma in situ [CIS], n= 18 invasive) and 43 FFPE ocular surface lesions (n= 2 conjunctival/corneal intraepithelial neoplasia [CIN], n= 20 CIS, n= 21 invasive), from institutions in the US and Brazil. An additional 7 cases of advanced cutaneous SCC were profiled by hybrid-capture-based NGS of >1,500 genes. The cutaneous and ocular squamous neoplasms displayed a predominance of UV signature mutations. Precursor lesions had highly similar somatic genomic landscapes to invasive SCCs, including chromosomal gains of 3q involving SOX2, and highly recurrent mutations and/or loss of heterozygosity events affecting tumor suppressors TP53 and CDKN2A. We identify a novel molecular subclass of CIS with RB1 mutation. Among TP53 wild-type tumors, human papillomavirus (HPV) transcript was detected in one matched pair of cutaneous CIS and invasive SCC. Amplicon-based whole-transcriptome sequencing of select 20 cutaneous lesions demonstrated significant upregulation of pro-invasion genes in invasive cutaneous SCCs relative to precursors, including MMP1, MMP3, MMP9, LAMC2, LGALS1, and TNFRSF12A. Together, ocular and cutaneous squamous neoplasms demonstrate similar alterations, supporting a common model for neoplasia in UV-exposed epithelia. Treatment modalities useful for cutaneous SCC may also be effective in ocular SCC given the genetic similarity between these tumor types. Importantly, in both systems, precursor lesions possess the full complement of major genetic changes seen in SCC, supporting non-genetic drivers of invasiveness. |
| Databáze: | OpenAIRE |
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