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Invasive squamous cell carcinomas and precursor lesions on UV-exposed epithelia demonstrate concordant genomic complexity in driver genes.
- Source :
-
Modern pathology : an official journal of the United States and Canadian Academy of Pathology, Inc [Mod Pathol] 2020 Nov; Vol. 33 (11), pp. 2280-2294. Date of Electronic Publication: 2020 May 27. - Publication Year :
- 2020
-
Abstract
- 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 (ocular) studied SCCs. We assessed 56 formalin-fixed paraffin-embedded (FFPE) cutaneous lesions (n = 8 actinic keratosis, n = 30 carcinoma in situ [CIS], n = 18 invasive) and 43 FFPE ocular surface lesions (n = 2 conjunctival/corneal intraepithelial neoplasia, n = 20 CIS, n = 21 invasive), from institutions in the US and Brazil. An additional seven cases of advanced cutaneous SCC were profiled by hybrid capture-based NGS of >1500 genes. The cutaneous and ocular squamous neoplasms displayed a predominance of UV-signature mutations. Precursor lesions had highly similar somatic genomic landscapes to SCCs, including chromosomal gains of 3q involving SOX2, and highly recurrent mutations and/or loss of heterozygosity events affecting tumor suppressors TP53 and CDKN2A. Additionally, we identify a novel molecular subclass of CIS with RB1 mutations. Among TP53 wild-type tumors, human papillomavirus transcript was detected in one matched pair of cutaneous CIS and SCC. Amplicon-based whole-transcriptome sequencing of select 20 cutaneous lesions demonstrated significant upregulation of pro-invasion genes in 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.
- Subjects :
- Aged
Carcinoma in Situ genetics
Carcinoma, Squamous Cell genetics
Conjunctival Neoplasms genetics
Eye Neoplasms genetics
Female
High-Throughput Nucleotide Sequencing
Humans
Keratosis, Actinic genetics
Keratosis, Actinic pathology
Male
Middle Aged
Skin Neoplasms genetics
Carcinoma in Situ pathology
Carcinoma, Squamous Cell pathology
Conjunctival Neoplasms pathology
Eye Neoplasms pathology
Mutation
Skin pathology
Skin Neoplasms pathology
Subjects
Details
- Language :
- English
- ISSN :
- 1530-0285
- Volume :
- 33
- Issue :
- 11
- Database :
- MEDLINE
- Journal :
- Modern pathology : an official journal of the United States and Canadian Academy of Pathology, Inc
- Publication Type :
- Academic Journal
- Accession number :
- 32461624
- Full Text :
- https://doi.org/10.1038/s41379-020-0571-7