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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.

Author information

Mouw KW1, Cleary JM2, Reardon B2,3, Pike J1, Braunstein LZ1, Kim J3, Amin-Mansour A2,3, Miao D2,3, Damish A1, Chin J4, Ott PA2, Fuchs CS2, Martin NE1, Getz G3, Carter S3,5, Mamon HJ1, Hornick JL6, Van Allen EM7,3, D'Andrea AD8,9,10.

1 Department of Radiation Oncology, Brigham and Women's Hospital, Dana-Farber Cancer Institute, Boston, Massachusetts.

2 Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, Massachusetts.

3 Broad Institute of MIT and Harvard, Cambridge, Massachusetts.

4 Department of Radiation Oncology, Massachusetts General Hospital, Boston, Massachusetts.

5 Center for Cancer Precision Medicine, Dana-Farber Cancer Institute, Boston, Massachusetts.

6 Department of Pathology, Brigham and Women's Hospital, Boston, Massachusetts.

7 Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, Massachusetts. alan_dandrea@dfci.harvard.edu eliezerm_vanallen@dfci.harvard.edu.

8 Department of Radiation Oncology, Brigham and Women's Hospital, Dana-Farber Cancer Institute, Boston, Massachusetts. alan_dandrea@dfci.harvard.edu eliezerm_vanallen@dfci.harvard.edu.

9 Center for DNA Damage and Repair, Dana-Farber Cancer Institute, Boston, Massachusetts.

10 Ludwig Center at Harvard, Boston, Massachusetts.