Whole-exome sequencing identified mutational profiles of squamous cell carcinomas of anus

Publication date: Available online 17 March 2018
Source:Human Pathology
Author(s): Sun Shin, Hyeon-Chun Park, Min Sung Kim, Mi-Ryung Han, Sung Hak Lee, Seung Hyun Jung, Sug Hyung Lee, Yeun-Jun Chung
Anal squamous cell carcinoma (ASCC), either with human papillomavirus (HPV) (+) or (−), is a neoplastic disease with frequent recurrence and metastasis. To characterize ASCC genomes, we attempted to disclose novel alterations of ASCC genomes as well as other genetic features including mutation signatures. We performed whole-exome sequencing and copy number alteration (CNA) profiling for 8 ASCC samples from 6 patients (2 cases with primary and recurrent/metastatic tumors). We found known ASCC mutations (TP53, CDKN2A and PIK3CA) and CNAs (gains on 3q and 19q and losses on 11q and 13q). In addition, we discovered novel mutations in HRAS and ARID1A and CNAs (gain on 8q and losses 5q, 9p, 10q and 19p) that had not been reported in ASCCs. We identified 4 signature patterns of the mutations (signatures 1 and 2 with deamination of 5-methyl-cytosin, signature 3 with APOBEC and signature 4 with mismatch repair) in the ASCCs. While the signatures 1–3 have been detected in other SCCs, the signature 4 was first identified in ASCCs. In addition, we first found that ASCCs harbored chromothripsis, copy-neutral losses of heterozygosity and focal amplification of KLF5 super-enhancer. Analyses of primary and recurrent/metastatic pair genomes revealed that driver events in development and progression of ASCC might not be uniform. Our data indicate that ASCCs may have similar mutation and CNA profiles to other SCCs, but that there are unique genomic features of ASCCs as well. Our data may provide useful information for ASCC pathogenesis as well as for developing clinical strategies for ASCC.



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