Abstract 4708: Comprehensive analysis of 71 VHL germline deletions and rearrangements

Abstract

Abstract An estimated 35% of von Hippel-Lindau (VHL) disease patients possess a gross germline deletion of one, two, or all three exons of VHL. In this study, 71 germline deletions have been extensively characterized, including 59 partial deletions (PD) and 12 complete VHL deletions (CD). VHL patients possessing germline VHL deletions were enrolled on an IRB-approved protocol. An Agilent custom high-definition comparative genomic hybridization array (aCGH) including 21 probes within the VHL gene at an average probe density of 2 probes per kb was used to map most VHL deletions; 4 patients were evaluated using CLIA-approved VHL deletion/duplication analysis. Primers were designed adjacent to the estimated deletion boundaries, and the breakpoints were mapped by Sanger bidirectional sequencing. Fifty eight deletions (55 PD and 3 CD) have been mapped to the exact breakpoint. Nearly all (55 of 58) deletions involve Alu repeats at both breakpoints. Several novel observations have been made in this cohort, including two cases that have complex rearrangements involving both deletion and inversion, two cases that have inserted extra Alu-like sequences, three cases that involve breakpoints in Alu repeats situated in opposite orientations, and a “hotspot” PD of exon 3 involving the same pair of Alu repeats that is observed in 12 families. In conclusion, this is the largest study to date of germline deletions in VHL patients. Deletions almost always involve Alu repeats, which are enriched in and near the VHL gene. In two cases, both a deletion and an inversion are observed, implying that it may be possible for an inversion to occur in the absence of deletion. Citation Format: Cathy D. Vocke, Christopher J. Ricketts, Laura S. Schmidt, Mark W. Ball, James Peterson, Lindsay A. Middelton, W Marston Linehan. Comprehensive analysis of 71 VHL germline deletions and rearrangements [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr 4708.