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Blood. 2016 May 26;127(21):2598-606. doi: 10.1182/blood-2015-11-680199. Epub 2016 Feb 22.

Exome sequencing reveals recurrent germ line variants in patients with familial Waldenström macroglobulinemia.

Author information

1
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;
2
Dana-Farber Cancer Institute, Department of Medical Oncology, Harvard Medical School, Boston, MA;
3
Department of Biostatistics and Computational Biology, Dana-Farber Cancer Institute, Boston, MA; and.
4
Department of Hematology, Centro per la Ricerca Emato-oncologica AIL, Spedali Civili di Brescia, Brescia, Italy;
5
Department of Biostatistics, Harvard School of Public Health, Boston, MA.

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.

PMID:
26903547
DOI:
10.1182/blood-2015-11-680199
[Indexed for MEDLINE]
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