期刊
MODERN PATHOLOGY
卷 33, 期 11, 页码 2280-2294出版社
SPRINGERNATURE
DOI: 10.1038/s41379-020-0571-7
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资金
- NIH [K08EY026654, P30CA046592]
- Research to Prevent Blindness
- A. Alfred Taubman Medical Research Institute Leslie and Abigail Wexner Emerging Scholar Program
- A. Alfred Taubman Medical Research Institute A. Alfred Taubman Emerging Scholar Program
- Grossman Research Fund
- Leonard G. Miller Professorship and Ophthalmic Research Fund at the Kellogg Eye Center
- Barbara Dunn Research Fund
- Roz Greenspon Research Fund
- Beatrice & Reymont Paul Foundation
- March Hoops to Beat Blindness
- NIH/NEI [5K08EY027464-02]
- Research to Prevent Blindness Career Development Award
- AMC [R35CA231996]
- Howard Hughes Medical Institute Investigator
- A. Alfred Taubman Scholar
- American Cancer Society
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 involvingSOX2, and highly recurrent mutations and/or loss of heterozygosity events affecting tumor suppressorsTP53andCDKN2A. Additionally, we identify a novel molecular subclass of CIS withRB1mutations. AmongTP53wild-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, includingMMP1,MMP3,MMP9,LAMC2,LGALS1, andTNFRSF12A. 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.
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