title: Exome sequencing reveals recurrent germ line variants in patients with familial Waldenström macroglobulinemia.
abstract: Familial aggregation of Waldenström macroglobulinemia (WM) cases, and the clustering of B-cell lymphoproliferative disorders among first-degree relatives of WM patients, has been reported. Nevertheless, the possible contribution of inherited susceptibility to familial WM remains unrevealed. We performed whole exome sequencing on germ line DNA obtained from 4 family members in which coinheritance for WM was documented in 3 of them, and screened additional independent 246 cases by using gene-specific mutation sequencing. Among the shared germ line variants, LAPTM5(c403t) and HCLS1(g496a) were the most recurrent, being present in 3/3 affected members of the index family, detected in 8% of the unrelated familial cases, and present in 0.5% of the nonfamilial cases and in <0.05 of a control population. LAPTM5 and HCLS1 appeared as relevant WM candidate genes that characterized familial WM individuals and were also functionally relevant to the tumor clone. These findings highlight potentially novel contributors for the genetic predisposition to familial WM and indicate that LAPTM5(c403t) and HCLS1(g496a) may represent predisposition alleles in patients with familial WM.
authors.affiliation: Dana-Farber Cancer Institute, Department of Medical Oncology, Harvard Medical School, Boston, MA; Department of Hematology, Centro per la Ricerca Emato-oncologica AIL, Spedali Civili di Brescia, Brescia, Italy;
authors.forename: Aldo M
authors.identifier: 0000-0002-1872-5128
authors.initials: AM
authors.lastname: Roccaro
authors.affiliation: Dana-Farber Cancer Institute, Department of Medical Oncology, Harvard Medical School, Boston, MA;
authors.forename: Antonio
authors.initials: A
authors.lastname: Sacco
authors.affiliation: Department of Biostatistics and Computational Biology, Dana-Farber Cancer Institute, Boston, MA; and.
authors.forename: Jiantao
authors.initials: J
authors.lastname: Shi
authors.affiliation: Dana-Farber Cancer Institute, Department of Medical Oncology, Harvard Medical School, Boston, MA; Department of Hematology, Centro per la Ricerca Emato-oncologica AIL, Spedali Civili di Brescia, Brescia, Italy;
authors.forename: Marco
authors.initials: M
authors.lastname: Chiarini
authors.affiliation: Dana-Farber Cancer Institute, Department of Medical Oncology, Harvard Medical School, Boston, MA;
authors.forename: Adriana
authors.initials: A
authors.lastname: Perilla-Glen
authors.affiliation: Dana-Farber Cancer Institute, Department of Medical Oncology, Harvard Medical School, Boston, MA;
authors.forename: Salomon
authors.initials: S
authors.lastname: Manier
authors.affiliation: Dana-Farber Cancer Institute, Department of Medical Oncology, Harvard Medical School, Boston, MA;
authors.forename: Siobhan
authors.initials: S
authors.lastname: Glavey
authors.affiliation: Dana-Farber Cancer Institute, Department of Medical Oncology, Harvard Medical School, Boston, MA;
authors.forename: Yosra
authors.initials: Y
authors.lastname: Aljawai
authors.affiliation: Dana-Farber Cancer Institute, Department of Medical Oncology, Harvard Medical School, Boston, MA;
authors.forename: Yuji
authors.initials: Y
authors.lastname: Mishima
authors.affiliation: Dana-Farber Cancer Institute, Department of Medical Oncology, Harvard Medical School, Boston, MA;
authors.forename: Yawara
authors.initials: Y
authors.lastname: Kawano
authors.affiliation: Dana-Farber Cancer Institute, Department of Medical Oncology, Harvard Medical School, Boston, MA;
authors.forename: Michele
authors.initials: M
authors.lastname: Moschetta
authors.affiliation: Dana-Farber Cancer Institute, Department of Medical Oncology, Harvard Medical School, Boston, MA;
authors.forename: Mick
authors.initials: M
authors.lastname: Correll
authors.affiliation: Dana-Farber Cancer Institute, Department of Medical Oncology, Harvard Medical School, Boston, MA;
authors.forename: Ma Reina
authors.initials: MR
authors.lastname: Improgo
authors.affiliation: Dana-Farber Cancer Institute, Department of Medical Oncology, Harvard Medical School, Boston, MA;
authors.forename: Jennifer R
authors.initials: JR
authors.lastname: Brown
authors.affiliation: Department of Hematology, Centro per la Ricerca Emato-oncologica AIL, Spedali Civili di Brescia, Brescia, Italy;
authors.forename: Luisa
authors.initials: L
authors.lastname: Imberti
authors.affiliation: Department of Hematology, Centro per la Ricerca Emato-oncologica AIL, Spedali Civili di Brescia, Brescia, Italy;
authors.forename: Giuseppe
authors.initials: G
authors.lastname: Rossi
authors.affiliation: Dana-Farber Cancer Institute, Department of Medical Oncology, Harvard Medical School, Boston, MA;
authors.forename: Jorge J
authors.initials: JJ
authors.lastname: Castillo
authors.affiliation: Dana-Farber Cancer Institute, Department of Medical Oncology, Harvard Medical School, Boston, MA;
authors.forename: Steven P
authors.initials: SP
authors.lastname: Treon
authors.affiliation: Dana-Farber Cancer Institute, Department of Medical Oncology, Harvard Medical School, Boston, MA;
authors.forename: Matthew L
authors.initials: ML
authors.lastname: Freedman
authors.affiliation: Dana-Farber Cancer Institute, Department of Medical Oncology, Harvard Medical School, Boston, MA;
authors.forename: Eliezer M
authors.initials: EM
authors.lastname: Van Allen
authors.affiliation: Department of Biostatistics, Harvard School of Public Health, Boston, MA.
authors.forename: Winston
authors.initials: W
authors.lastname: Hide
authors.affiliation: Dana-Farber Cancer Institute, Department of Medical Oncology, Harvard Medical School, Boston, MA;
authors.forename: Elaine
authors.initials: E
authors.lastname: Hiller
authors.affiliation: Dana-Farber Cancer Institute, Department of Medical Oncology, Harvard Medical School, Boston, MA;
authors.forename: Irene
authors.initials: I
authors.lastname: Rainville
authors.affiliation: Dana-Farber Cancer Institute, Department of Medical Oncology, Harvard Medical School, Boston, MA;
authors.forename: Irene M
authors.initials: IM
authors.lastname: Ghobrial
mesh_terms: D048868:Adaptor Proteins, Signal Transducing; D001798:Blood Proteins / Q000235:genetics*; D059472:Exome; D005190:Family; D005260:Female; D020022:Genetic Predisposition to Disease; D018095:Germ-Line Mutation; D059014:High-Throughput Nucleotide Sequencing; D006801:Humans; D008297:Male; D008565:Membrane Proteins / Q000235:genetics*; D008258:Waldenstrom Macroglobulinemia / Q000235:genetics*
chemical_list: D048868:Adaptor Proteins, Signal Transducing; D001798:Blood Proteins; C061909:HCLS1 protein, human; D008565:Membrane Proteins; C100848:LAPTM5 protein, human