Genomic progression of precancerous actinic keratosis to squamous cell carcinoma

The mechanism underlying the progression of actinic keratosis (AK) and cutaneous squamous cell carcinoma in situ (SCCIS) to squamous cell carcinoma (SCC) remains unclear. To investigate this, we performed regional microdissection and targeted deep sequencing in SCC (N=10) and paired adjacent SE (sun-damaged epidermis)/AK/SCCIS (N=13) samples to detect mutations and copy number alterations (CNAs). Most (11/13) SE/AK/SCCIS tissues harbored ≥ 1 driver alterations, indicating their precancerous nature. All pairs except one showed genome architectures representing genomic progression of SE/AK/SCCIS to SCC with common trunks and unique branches (7 parallel and 5 linear progression cases). SE/AK/SCCIS tissues tended to harbor lower mutation/CNA burdens than SCC tissues, but most of them had driver mutations, including NOTCH1 and TP53 mutations. SCC-specific genomic alterations included TP53, PIK3CA, FBXW7, and CDKN2A mutations and a MYC copy-number gain, but they were heterogeneous among cases, suggesting that a single gene or pathway does not explain the progression of AK to SCC. In multiregion analyses of AK lesions, only some AK samples were related to SCC. In conclusion, the SE/AK/SCCIS genomes may have previously acquired truncal driver alterations, such as NOTCH1 and TP53 mutations, which promote parallel or linear progression to SCC upon acquisition of additional genomic alterations.