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

• Published in: Human pathology 2018-10, Vol.80, p.1-10
• Main Authors: Shin, Sun, Park, Hyeon-Chun, Kim, Min Sung, Han, Mi-Ryung, Lee, Sung Hak, Jung, Seung Hyun, Lee, Sug Hyung, Chung, Yeun-Jun
• Format: Article
• Language: English
• Subjects: Adult; Algorithms; Anal Canal - pathology; Anus; Anus Neoplasms - genetics; Anus Neoplasms - pathology; Biomarkers, Tumor - genetics; Cancer; Cancer therapies; Carcinoma, Squamous Cell - pathology; Carcinoma, Squamous Cell - virology; Chemotherapy; Copy number alteration; Deoxyribonucleic acid; DNA; DNA Copy Number Variations - genetics; Female; Genes; HIV; Hospitals; Human immunodeficiency virus; Human papillomavirus; Humans; Infections; Male; Metastasis; Middle Aged; Mutation; Mutation - genetics; Mutation signature; Neoplasm Recurrence, Local - genetics; Neoplasm Recurrence, Local - pathology; Neoplasm Recurrence, Local - virology; Papillomaviridae - genetics; Pathogenesis; Signatures; Software; Squamous cell carcinoma; Surgery; Tumors; Whole Exome Sequencing - methods; Whole-exome sequencing
• ISSN: 0046-8177; 1532-8392
• DOI: 10.1016/j.humpath.2018.03.008

Anal squamous cell carcinoma (ASCC), either with human papillomavirus (+) or (−), is a neoplastic disease with frequent recurrence and metastasis. To characterize ASCC genomes, we attempted to disclose novel alterations of ASCC genomes and 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. Although signatures 1 to 3 have been detected in other SCCs, 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 and for developing clinical strategies for ASCC. •HRAS and ARID1A mutations are drivers in anal squamous cell carcinomas (ASCCs).•There are 4 signature patterns of ASCC mutations including APOBEC and mismatch repair.•ASCCs harbor chromothripsis and copy-neutral losses of heterozygosity.•Genomes of ASCCs are similar to other SCCs, but also have unique features.