Mutational landscape of radiation-associated angiosarcoma of the breast
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Bryan J. Thibodeau1, Vincent Lavergne2, Nayana Dekhne3, Pamela Benitez3, Mitual Amin4, Samreen Ahmed1, Jean L. Nakamura2, Philip R. Davidson5, Alice O. Nakamura5, Inga S. Grills6, Peter Y. Chen6, Jessica Wobb6 and George D. Wilson1,6
1Beaumont BioBank, Beaumont Health, Royal Oak, MI, USA
2Department of Radiation Oncology, University of California, San Francisco, CA, USA
3Department of Surgery, Beaumont Health, Royal Oak, MI, USA
4Department of Pathology, Beaumont Health, Royal Oak, MI, USA
5Department of Finance and Statistical Analysis, University of Alberta, Edmonton, Alberta, Canada
6Department of Radiation Oncology, Beaumont Health, Royal Oak, MI, USA
George D. Wilson, email: [email protected]
Keywords: angiosarcoma; radiation-associated; breast; mutational signature; next generation sequencing
Received: September 15, 2017 Accepted: October 13, 2017 Published: January 19, 2018
Purpose: Radiation-associated breast angiosarcomas are a rare complication of radiation therapy for breast carcinoma. With relatively little is known about the genetic abnormalities present in these secondary tumors, we examined genomic variation in biospecimens from radiation-associated breast angiosarcomas.
Experimental Design: Patients were identified that had a previous breast cancer diagnosis, received radiation therapy, and developed angiosarcoma in the ipsilateral breast as the earlier cancer. Tumor regions were isolated from archival blocks using subsequent laser capture microdissection. Next generation sequencing was performed using a targeted panel of 160 cancer-related genes. Genomic variants were identified for mutation and trinucleotide-based mutational signature analysis.
Results: 44 variants in 34 genes were found in more than two thirds of the cases; this included 12 variants identified as potentially deleterious. Of particular note, the BRCA1 DNA damage response pathway was highly enriched with genetic variation. In a comparison to local recurrences, 14 variants in 11 genes were present in both the primary and recurrent lesions including variants in genes associated with the DNA damage response machinery. Furthermore, the mutational signature analysis shows that a previously defined IR signature is present in almost all of the current samples characterized by predominantly C→T substitutions.
Conclusions: While radiation-associated breast angiosarcomas are relatively uncommon, their prognosis is very poor. These data demonstrate a mutational pattern associated with genes involved in DNA repair. While important in revealing the biology behind these tumors, it may also suggest new treatment strategies that will prove successful.
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