Abstract 1300: Exploration of rare variants from exome sequencing in families with Waldenstrom macroglobulinemia (WM)

Proceedings: AACR Annual Meeting 2014; April 5-9, 2014; San Diego, CA In spite of progress in the identification of the somatic events associated with Waldenstrom macroglobulinemia (WM), the genetic determinants of WM susceptibility have not been identified. We have conducted exome sequencing in 32 individuals from 9 well-characterized families at high risk for WM. We sequenced 3 or more patients or obligate carriers from each family. We used Nimblegen v2.0 and v3.0 for exome capture followed by sequencing on the Illumina HiSeq2000. Among quality control measures, we required 80% of coding sequences to achieve 15x coverage. To eliminate other possible sequencing artifacts, variants found in more than 1% of samples sequenced in our laboratory from other studies were excluded. Novoalign v.2.07.14 was used for alignment and GATK was used for local re-alignment and variant calling. A large number of rare (<1% frequency in European populations) non-synonymous variants were shared among patients in each family. To prioritize variants for further validation and follow-up, we first searched for variants shared in more than one family; variants in highly conserved regions; those predicted to be damaging by one or more in silico functional models; and variants in genes known to be related to B-cell function and/or disease. We used Ingenuity Variant Analysis to facilitate annotation. We then applied a semi-quantitative scoring algorithm based on these variables to prioritize genes for further evaluation. Although no single gene met all criteria when analyzed across families using this method, we are currently conducting targeted sequencing of 17 highest-scoring genes in an additional 2 WM patients and 92 relatives from these families and 272 other subjects (95 familial WM, 28 nonfamilial WM and 149 informative relatives). Susceptibility gene discovery in this complex disease remains challenging. Citation Format: Mary L. McMaster, Lynn R. Goldin, Melissa Rotunno, Ji He, Laurie Burdette, Amy Hutchinson, Joseph Boland, Meredith Yeager, Margaret A. Tucker, Stephen J. Chanock, Neil E. Caporaso. Exploration of rare variants from exome sequencing in families with Waldenstrom macroglobulinemia (WM). [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 1300. doi:10.1158/1538-7445.AM2014-1300