Dramatic response of metastatic cutaneous angiosarcoma to an immune checkpoint inhibitor in a patient with Xeroderma Pigmentosum: whole genome sequencing aids treatment decision in end-stage disease.

Published: 19 September 2019| Version 1 | DOI: 10.17632/7cxt72pckw.1
Serena Nik-Zainal


"Mutational signatures" are patterns of mutations that report DNA damage and subsequent repair processes that have occurred. Whole genome sequencing (WGS) can provide additional information to standard diagnostic techniques and can identify therapeutic targets. A 32-year-old male with Xeroderma Pigmentosum developed metastatic angiosarcoma which was unresponsive to three lines of conventional sarcoma therapies. WGS was performed on his primary cancer revealing a hypermutated tumor, including clonal ultraviolet radiation-induced mutational patterns (Signature 7) and subclonal signatures of mutated DNA Polymerase-epsilon (POLE) (Signature 10). These signatures are associated with response to immune-checkpoint blockade. Immunohistochemistry confirmed high PD-L1 expression in metastatic deposits. The anti-PD-1 monoclonal antibody Pembrolizumab was commenced off-label given the POLE mutation and high mutational load. After four cycles, there was significant reduction in his disease with almost complete resolution of the metastatic deposits. This case highlights the importance of WGS in the analysis, interpretation and treatment of cancers. We anticipate that as WGS becomes integral to the cancer diagnostic pathway, treatments will be stratified to the individual based upon their unique genomic and/or transcriptomic profile, enhancing classical approaches of histologically-driven treatment decisions.



University of Cambridge


Xeroderma pigmentosum, Genome Sequencing