Abstract
Purpose: Squamous cell carcinoma of the anal canal (ASCC) accounts for 2% to 4% of gastrointestinal malignancies in the United States and is increasing in incidence; however, genomic features of ASCC are incompletely characterized. Primary treatment of ASCC involves concurrent chemotherapy and radiation (CRT), but the mutational landscape of resistance to CRT is unknown. Here, we aim to compare mutational features of ASCC in the pre- and post-CRT setting.Experimental Design: We perform whole-exome sequencing of primary (n = 31) and recurrent (n = 30) ASCCs and correlate findings with clinical data. We compare genomic features of matched pre- and post-CRT tumors to identify genomic features of CRT response. Finally, we investigate the mutational underpinnings of an extraordinary ASCC response to immunotherapy.Results: We find that both primary and recurrent ASCC tumors harbor mutations in genes, such as PIK3CA and FBXW7, that are also mutated in other HPV-associated cancers. Overall mutational burden was not significantly different in pre- versus post-CRT tumors, and several examples of shared clonal driver mutations were identified. In two cases, clonally related pre- and post-CRT tumors harbored distinct oncogenic driver mutations in the same cancer gene (KRAS or FBXW7). A patient with recurrent disease achieved an exceptional response to anti-programmed death (PD-1) therapy, and genomic dissection revealed high mutational burden and predicted neoantigen load.Conclusions: We perform comprehensive mutational analysis of ASCC and characterize mutational features associated with CRT. Although many primary and recurrent tumors share driver events, we identify several unique examples of clonal evolution in response to treatment. Clin Cancer Res; 23(12); 3214-22. ©2016 AACR.
Highlights
A patient with recurrent disease achieved an exceptional response to anti-Programmed Death (PD-1) therapy, and genomic dissection revealed high mutational burden and predicted neoantigen load
We perform comprehensive mutational analysis of Anal squamous cell cancers (ASCCs) and characterize mutational features associated with chemotherapy and radiation (CRT)
Recent updates of large randomized trials have confirmed that concurrent treatment with 5-fluorouracil, mitomycin C, and ionizing radiation remains the standard of care.[6, 7]
Summary
Anal squamous cell cancers (ASCCs) arise from the squamous lining of the terminal gastrointestinal tract and have distinct clinical and pathologic features from tumors that arise more proximally in the colon and rectum.[1, 2] Historically, radical surgery was the only curative treatment for ASCC; trials of pre-operative chemotherapy and radiation (CRT) in the 1970s revealed high tumor response rate, and CRT subsequently replaced surgery as the preferred treatment.[3,4,5] Recent updates of large randomized trials have confirmed that concurrent treatment with 5-fluorouracil, mitomycin C (or cisplatin), and ionizing radiation remains the standard of care.[6, 7] despite high rates of disease control and functional organ preservation, a subset of patients develop locally recurrent or metastatic disease for which treatment options are limited.Analysis of several large cohorts of ASCCs have shown that the majority of ASCCs harbor human papillomavirus (HPV), and HPV associated ASCCs have increased sensitivity to CRT and improved disease outcomes compared to non-HPV associated tumors.[8, 9] In addition, epigenomic analysis has shown differences in global methylation patterns in high- versus low-risk tumors.[10]. Targeted sequencing of known cancer genes has revealed mutations in EGFR, KRAS, and PIK3CA, and a recent study using a combination of targeted sequencing and immunohistochemistry (IHC) revealed high levels of EGFR expression and frequent mutations in the PIK3CA/AKT pathway.[11,12,13] no exome-wide mutational studies are available and the impact of CRT on genomic evolution is unknown
Sign-in/Register to view highlights & summary Sign-in/Register to access full text options 
Free) 
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a call
