Mutations in a gene encoding a midbody kelch protein in familial and sporadic classical Hodgkin lymphoma lead to binucleated cells
- Stephen J. Salipantea,
- Matthew E. Mealiffeb,1,
- Jeremy Wechslerc,
- Maxwell M. Kremd,
- Yajuan Liub,
- Shinae Namkoongb,
- Govind Bhagate,
- Tomas Kirchhofff,
- Kenneth Offitf,
- Henry Lynchg,
- Peter H. Wiernikh,
- Mikhail Roshali,
- Mary Lou McMasterj,
- Margaret Tuckerj,
- Jonathan R. Frommi,
- Lynn R. Goldinj and
- Marshall S. Horwitzc,2
- aDepartment of Genome Sciences,
- bDivision of Medical Genetics, Department of Medicine,
- cDepartment of Pathology,
- dMedical Oncology Program,
- iDepartment of Laboratory Medicine, University of Washington School of Medicine, Seattle, WA 98195;
- eDepartment of Pathology, College of Physicians and Surgeons of Columbia University, New York, NY 10032;
- fMemorial Sloan-Kettering Cancer Center, Clinical Cancer Genetics Laboratory, New York, NY 10065;
- gDepartment of Preventive Medicine, Creighton University School of Medicine, Omaha, NE 68178;
- hOur Lady of Mercy Cancer Center, New York Medical College, Bronx, NY 10466; and
- jGenetic Epidemiology Branch, Division of Cancer Epidemiology and Genetics, National Cancer Institute, Bethesda, MD 20892
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Edited by Mary-Claire King, University of Washington, Seattle, WA, and approved July 2, 2009 (received for review April 16, 2009)
Abstract
Classical Hodgkin lymphoma (cHL) is a malignancy of B-cell origin in which the neoplastic cells, known as “Reed-Sternberg” (RS) cells, are characteristically binucleated. Here we describe a family where multiple individuals developing cHL have inherited a reciprocal translocation between chromosomes 2 and 3. The translocation disrupts KLHDC8B, an uncharacterized gene from a region (3p21.31) previously implicated in lymphoma and related malignancies, resulting in its loss of expression. We tested KLHDC8B as a candidate gene for cHL and found that a 5′-UTR polymorphism responsible for decreasing its translational expression is associated with cHL in probands from other families with cHL and segregates with disease in those pedigrees. In one of three informative sporadic cases of cHL, we detected loss of heterozygosity (LOH) for KLHDC8B in RS cells, but not reactive T lymphocytes, purified from a malignant lymph node. KLHDC8B encodes a protein predicted to contain seven kelch repeat domains. KLHDC8B is expressed during mitosis, where it localizes to the midbody structure connecting cells about to separate during cytokinesis, and it is degraded after cell division. Depletion of KLHDC8B through RNA interference leads to an increase in binucleated cells, implicating its reduced expression in the formation of cHL's signature RS cell.
Footnotes
- 2To whom correspondence should be addressed. E-mail: horwitz{at}u.washington.edu
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Author contributions: S.J.S., M.E.M., J.W., M.M.K., J.R.F., L.R.G., and M.S.H. designed research; S.J.S., M.E.M., J.W., M.M.K., Y.L., S.N., M.R., J.R.F., and M.S.H. performed research; G.B., T.K., K.O., H.L., P.H.W., M.R., M.L.M., M.T., J.R.F., and L.R.G. contributed new reagents/analytic tools; S.J.S., M.E.M., J.W., M.M.K., Y.L., S.N., L.R.G., and M.S.H. analyzed data; and M.S.H. wrote the paper.
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The authors declare no conflict of interest.
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This article is a PNAS Direct Submission.
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This article contains supporting information online at www.pnas.org/cgi/content/full/0904231106/DCSupplemental.
