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Oncotarget. 2018 Jan 19;9(11):10042-10053. doi: 10.18632/oncotarget.24273. eCollection 2018 Feb 9.

Mutational landscape of radiation-associated angiosarcoma of the breast.

Author information

1
Beaumont BioBank, Beaumont Health, Royal Oak, MI, USA.
2
Department of Radiation Oncology, University of California, San Francisco, CA, USA.
3
Department of Surgery, Beaumont Health, Royal Oak, MI, USA.
4
Department of Pathology, Beaumont Health, Royal Oak, MI, USA.
5
Department of Finance and Statistical Analysis, University of Alberta, Edmonton, Alberta, Canada.
6
Department of Radiation Oncology, Beaumont Health, Royal Oak, MI, USA.

Abstract

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 Cā†’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.

KEYWORDS:

angiosarcoma; breast; mutational signature; next generation sequencing; radiation-associated

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