Mutational landscape of radiation-associated angiosarcoma of the breast.

Bryan J Thibodeau,Mitual Amin,Pamela Benitez,Jean L Nakamura,Inga S Grills,George D Wilson,Jessica Wobb,Samreen Ahmed,Nayana Dekhne,Peter Y Chen,Vincent Lavergne,Alice O Nakamura,Philip R Davidson

doi:10.18632/oncotarget.24273

Abstract

PurposeRadiation-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 DesignPatients 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.Results44 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.ConclusionsWhile 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.

Highlights

Angiosarcomas are a relatively rare histological subtype of sarcomas and represent approximately 1% of all sarcomas [1]
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
The mutational signature analysis shows that a previously defined ionizing radiation (IR) signature is present in almost all of the current samples characterized by predominantly C→T substitutions

Summary

Introduction

Angiosarcomas are a relatively rare histological subtype of sarcomas and represent approximately 1% of all sarcomas [1]. They display remarkable clinical heterogeneity and can occur anywhere in the body, the breast is a frequent location. Secondary sarcomas are a recognized complication of radiation therapy for breast carcinoma and are associated with poor prognosis [2]. The estimated incidence of treatmentassociated breast angiosarcoma is 0.002–0.05% per year corresponding to ~40% of all radiation-associated www.impactjournals.com/oncotarget sarcomas that develop after radiotherapy [3]. Radiationassociated breast angiosarcomas have poor prognosis and relatively little is known about the genetic abnormalities present in these secondary tumors. High expression of the Myc protein was found to be associated with amplification, suggesting that MYC amplification may be implicated in the pathology of secondary breast angiosarcomas [5]

Methods

Results

Conclusion