Submitted March 23, 2006
Accepted September 13, 2006
Identification of a novel chromosome region 13q21.33-q22.2 for susceptibility genes in familial chronic lymphocytic leukemia
David Ng, Ousmane Toure, Ming-Hui Wei, Diane C Arthur, Fatima Abbasi, Laura Fontaine, Gerald E Marti, Joseph F Fraumeni Jr, Lynn R. Goldin, Neil Caporaso, and Jorge R. Toro*
Genetic Epidemiology Branch, Division of Cancer Epidemiology & Genetics, National Cancer Institute, NIH, DHHS, Rockville, MD
Program of Division of Cancer Epidemiology & Genetics, SAIC-Frederick, Inc., Frederick, MD
Laboratory of Pathology, Center for Cancert Research, National Cancer Institute, NIH, DHHS, Bethesda, MD
Flow & Image Cytometry Laboratory, Cellular Therapy & Tissues Branch, Division of Gene & Cell Therapy, FDA/CBER, Bethesda, MD
Westat Inc., Rockville, MD
Office of the Director, Division of Cancer Epidemiology & Genetics, National Cancer Institute, NIH, DHHS, Rockville, MD
* Corresponding author; email: toroj{at}mail.nih.gov.
Chronic lymphocytic leukemia (CLL) is the most prevalent form of leukemia in adults in western countries. A genome scan of CLL-prone families found a lod score of one in band 13q22.1. To investigate this finding, we selected six CLL families consisting of 65 individuals (CLL affected n=19, unaffected n=46) for genotyping and fine mapped a 23 megabase region in 13q14.2-q22.2. Interphase FISH revealed 13q14 deletion in 85% (11/13) of CLL patients. Four CLL families shared a 3.68 Mb minimal region in 13q21.33-q22.2. Two asymptomatic siblings who shared the 13q21.33-q22.2 at risk haplotype exhibited CD5+ monoclonal B-cell lymphocytosis (MBL) on flow cytometry. One of these individuals also had 13q14 deletion by FISH. These two MBL individuals shared the at risk haplotype with their CLL affected relatives providing further evidence of the relationship between CLL and MBL, and the biologic significance of this novel region. Using direct DNA sequencing analysis we screened 13 genes for germline mutations but no frameshift or nonsense mutations were detected. Our studies revealed that 11 of the 13 genes in the candidate region were expressed in immune tissues supporting that they have functional relevance in investigations of familial CLL. In conclusion, we identified a novel candidate region that may predispose to familial CLL.
