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J Mol Diagn. 2018 Dec 31. pii: S1525-1578(18)30172-7. doi: 10.1016/j.jmoldx.2018.11.003. [Epub ahead of print]

Structural Variation Detection by Proximity Ligation from Formalin-Fixed, Paraffin-Embedded Tumor Tissue.

Author information

1
Dovetail Genomics, LLC, Santa Cruz.
2
Department of Pathology, Stanford University School of Medicine, Stanford.
3
Department of Biomedical Data Science, Stanford University School of Medicine, Stanford; Department of Genetics, Stanford University School of Medicine, Stanford.
4
Department of Biomolecular Engineering, University of California Santa Cruz, Santa Cruz, California. Electronic address: ed@soe.ucsc.edu.
5
Department of Pathology, Stanford University School of Medicine, Stanford; Department of Biomedical Data Science, Stanford University School of Medicine, Stanford. Electronic address: ed@soe.ucsc.edu.

Abstract

The clinical management and therapy of many solid tumor malignancies is dependent on detection of medically actionable or diagnostically relevant genetic variation. However, a principal challenge for genetic assays from tumors is the fragmented and chemically damaged state of DNA in formalin-fixed, paraffin-embedded (FFPE) samples. From highly fragmented DNA and RNA there is no current technology for generating long-range DNA sequence data as is required to detect genomic structural variation or long-range genotype phasing. We have developed a high-throughput chromosome conformation capture approach for FFPE samples that we call "Fix-C", which is similar in concept to Hi-C. Fix-C enables structural variation detection from archival FFPE samples. This method was applied to 15 clinical adenocarcinoma and sarcoma positive control specimens spanning a broad range of tumor purities. In this panel, Fix-C analysis achieves a 90% concordance rate with FISH assays - the current clinical gold standard. Additionally, novel structural variation undetected by other methods could be identified and long-range chromatin configuration information recovered from these FFPE samples harboring highly degraded DNA. This powerful approach will enable detailed resolution of global genome rearrangement events during cancer progression from FFPE material and inform the development of targeted molecular diagnostic assays for patient care.

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