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RAD50 Hypomorphism as Basis for Response to Chemotherapy

ABSTRACT:

Outlier analyses represent a versatile method to identify predictive biomarkers of response to both targeted agents and chemotherapy. We performed whole genome sequencing (WGS) of tumor and germline blood from a patient with metastatic small cell carcinoma of the ureter who experienced a durable complete response to a combination of irinotecan plus AZD7762, a checkpoint kinase inhibitor. The patient initially had resection of the ureter followed by metastatic recurrence within the kidney and lymph nodes and underwent nephrectomy with lymph node dissection. Through WGS of tissue from the second surgery, we detected a hypomorphic L1237F mutation within RAD50, a component of the Mre11 double strand break repair complex, which resulted in heightened sensitivity to the combination of checkpoint inhibition and clastogenic chemotherapy. We validated the WGS findings using a combination of an exon capture assay and validation in model systems. The tumor samples sequenced by exon capture were derived from tissue taken from both the initial and second surgeries.

PROVIDER: phs000706 | dbGaP |

SECONDARY ACCESSION(S): PRJNA236153PRJNA236152

REPOSITORIES: dbGaP

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			Action	DRS
	GapExchange_phs000706.v1.p1.xml	Xml
	dbGaPEx2.1.5.xsd	Other
	Study_Report.phs000706.RAD50_Hypomorphism.v1.p1.MULTI.pdf	Pdf
	manifest_phs000706.RAD50_Hypomorphism.v1.p1.c1.GRU-MDS.pdf	Pdf
	datadict_v2.xsl	Other

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