Exome sequencing reveals germline NPAT mutation as a candidate risk factor for Hodgkin lymphoma

• Published in: Blood Vol. 118; no. 3; pp. 493 - 498
• Main Authors: Saarinen, Silva, Aavikko, Mervi, Aittomäki, Kristiina, Launonen, Virpi, Lehtonen, Rainer, Franssila, Kaarle, Lehtonen, Heli J., Kaasinen, Eevi, Broderick, Peter, Tarkkanen, Jussi, Bain, Barbara J., Bauduer, Frédéric, Ünal, Ali, Swerdlow, Anthony J., Cooke, Rosie, Mäkinen, Markus J., Houlston, Richard, Vahteristo, Pia, Aaltonen, Lauri A.
• Format: Journal Article
• Language: English
• Published: Washington, DC Elsevier Inc 21.07.2011; Americain Society of Hematology
• Subjects: Biological and medical sciences; Cell Cycle Proteins - genetics; Cell Line, Tumor; DNA Mutational Analysis; Family Health; Female; Finland - epidemiology; Genetic Linkage; Genetic Predisposition to Disease - epidemiology; Genetic Predisposition to Disease - genetics; Germ-Line Mutation; Hematologic and hematopoietic diseases; Hodgkin Disease - epidemiology; Hodgkin Disease - genetics; Humans; Leukemias. Malignant lymphomas. Malignant reticulosis. Myelofibrosis; Lymphoma, Follicular - epidemiology; Lymphoma, Follicular - genetics; Male; Medical sciences; Nuclear Proteins - genetics; Pedigree; Risk Factors; Young Adult; Finland; Hematology; Lymphoproliferative syndrome; Germ line; Risk factor; Genetics; Hodgkin disease; Malignant hemopathy; Mutation; Lymphoma; Epidemiology; Sequencing; Cancer
• ISSN: 0006-4971; 1528-0020; 1528-0020
• DOI: 10.1182/blood-2011-03-341560

A strong clustering of Hodgkin lymphoma in certain families has been long acknowledged. However, the genetic factors in the background of familial Hodgkin lymphoma are largely unknown. We have studied a family of 4 cousins with a rare subtype of the disease, nodular lymphocyte predominant Hodgkin lymphoma. We applied exome sequencing together with genome-wide linkage analysis to this family and identified a truncating germline mutation in nuclear protein, ataxia-telangiectasia locus (NPAT) gene, which segregated in the family. We also studied a large number of samples from other patients with Hodgkin lymphoma, and a germline variation leading to the deletion of serine 724 was found in several cases suggesting an elevated risk for the disease (odds ratio = 4.11; P = .018). NPAT is thus far the first gene implicated in nodular lymphocyte predominant Hodgkin lymphoma predisposition.