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Mutations in a Gene Encoding a Midbody Kelch Protein in Familial and Sporadic Classical Hodgkin Lymphoma Lead to Binucleated Cells

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Mutations in a Gene Encoding a Midbody Kelch Protein in Familial and Sporadic Classical Hodgkin Lymphoma Lead to Binucleated Cells 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 Edited by Mary-Claire King, University of Washington, Seattle, WA, and approved July 2, 2009 (received for review April 16, 2009) Classical Hodgkin lymphoma (cHL) is a malignancy of B-cell origin is situated in a region (3p21.31) where frequent somatic cyto- in which the neoplastic cells, known as ‘‘Reed-Sternberg’’ (RS) cells, genetic rearrangements have been observed for both cHL and are characteristically binucleated. Here we describe a family where nonHodgkin lymphoma (7). Additionally, genetic linkage anal- multiple individuals developing cHL have inherited a reciprocal ysis (8), chromosome transfer experiments (9), and loss of translocation between chromosomes 2 and 3. The translocation heterozygosity (LOH) studies (10) have also implicated 3p21.31 disrupts KLHDC8B, an uncharacterized gene from a region in nasopharyngeal carcinoma, which shares an association with (3p21.31) previously implicated in lymphoma and related malig- EBV. Moreover, 3p21.31 LOH is common in breast cancer (11), nancies, resulting in its loss of expression. We tested KLHDC8B as and breast cancer occurs more often among first degree relatives GENETICS a candidate gene for cHL and found that a 5؅-UTR polymorphism of cHL patients than in the general population (3). We therefore responsible for decreasing its translational expression is associated proceeded to molecularly define the translocation to determine with cHL in probands from other families with cHL and segregates if it disrupts a gene that may contribute to development of cHL with disease in those pedigrees. In one of three informative and other forms of cancer. sporadic cases of cHL, we detected loss of heterozygosity (LOH) for KLHDC8B in RS cells, but not reactive T lymphocytes, purified from Results a malignant lymph node. KLHDC8B encodes a protein predicted to Description of the Family. In this pedigree (Fig. 1A), cHL has contain seven kelch repeat domains. KLHDC8B is expressed during occurred in conjunction with a constitutional chromosomal mitosis, where it localizes to the midbody structure connecting abnormality. The proband developed the nodular sclerosis type cells about to separate during cytokinesis, and it is degraded after of cHL at age 39. Two siblings also developed nodular sclerosis cell division. Depletion of KLHDC8B through RNA interference cHL as adults. Their mother died shortly after presenting with leads to an increase in binucleated cells, implicating its reduced a mediastinal tumor (which is compatible with cHL, based on its expression in the formation of cHL’s signature RS cell. location), for which she declined workup. A maternal first cousin succumbed to a brainstem tumor (which was probably not cHL, cancer ͉ cytokinesis because it is only rarely found here). Individuals with cancer for whom genetic material is available or for whom karyotype can be lassical Hodgkin lymphoma (cHL) (1) is a lymph node inferred inherited a t(2,3) (q11.2;p21.31) translocation (Fig. 1B). Ccancer of germinal center B-cell origin. cHL tumors consist of a minority of malignant ‘‘Reed-Sternberg’’ (RS) cells mixed Mapping the 3p21.31 Translocation Breakpoint within KLHDC8B. We with reactive lymphocytes and other benign inflammatory cells. initially used fluorescence in situ hybridization (FISH) to map A defining feature of RS cells is the presence of two nuclei. cHL, bacterial artificial chromosomes (BACs) spanning the break- along with nasopharyngeal carcinoma and a few other malig- points, as revealed by ‘‘split’’ signals appearing on both normal nancies, is associated with Epstein-Barr virus (EBV) exposure and derivative chromosomes. Metaphase FISH of lymphoblas- (2), but genetic factors also contribute to risk. toid cells derived from a t(2,3)-carrying family member localized In fact, the familial risk for cHL is very high. The risk in first breakpoints to a segment on chromosome 3 containing two degree relatives of cases is elevated 3- to 4-fold compared with genes and to a region on chromosome 2 lacking apparent genes the general population; the risk is greater still when onset of cHL (Fig. 2A and B). We next hybridized Southern blots containing in the proband is under age 40 (3). A recent genome-wide scan restriction digested genomic DNA with probes from each of the detected multiple loci possibly linked to familial cHL (4), indicating that genetic heterogeneity may pose a challenge for the identification of cHL susceptibility genes through a linkage- 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; based strategy. Chance ascertainment of rare families cosegre- 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/ gating chromosomal abnormalities remains an established par- 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 adigm for disease gene identification, however, and was the M.S.H. wrote the paper. approach that initially led to discovery of tumor suppressor The authors declare no conflict of interest. genes responsible for retinoblastoma (5) and familial adenoma- This article is a PNAS Direct Submission. tous polyposis (6), among other types of cancer. 1Present address: Perlegen Sciences, Mountain View, CA 94043. Here we report a family where several individuals carrying a 2To whom correspondence should be addressed. E-mail: [email protected]. constitutional translocation involving chromosomes 2 and 3 have This article contains supporting information online at www.pnas.org/cgi/content/full/ developed cHL. Intriguingly, the breakpoint on chromosome 3 0904231106/DCSupplemental. www.pnas.org͞cgi͞doi͞10.1073͞pnas.0904231106 PNAS Early Edition ͉ 1of6 Downloaded by guest on September 29, 2021 No Cancer 68 RP11-73L7 RP11-299H21 A Mediastinal B A Chr3/Der3 ()+ Tumor 62 ()+ No Cancer 80 No Cancer Der3 70 Der2 Chr3 ? ++ + ? Der3 No Cancer 45 HL 28 HL 39 HL 42 No Cancer Brainstem Der2 46 Tumor 13 Der3 Trisomy 21 Chr3 Twin Miscarriage Chr2 No Cancer 18 Der2 Chr2 Fig. 1. Family inheriting cHL in association with constitutional, reciprocal Chr3 Breakpoint Chr2 Breakpoint t(2,3) chromosomal translocation. (A) Pedigree. Filled-in symbols represent B individuals with cancer. Plus and minus signs denote those carrying, not carrying, (or inferred to carry), respectively, the translocation. For individuals 3p21.31: ~6.7 Mb 2q11.2: ~6.8 Mb with cancer, age of diagnosis (in years) is indicated; for those without cancer, present age is shown. Slash indicates individual is deceased. Question mark RP11-73L7 (186 kB) RP11-299H21 (208 kB) means translocation carrying status was not known before death and that RP11-97O1 Split BACS CTD-2119F11 CTD-3055A11 CTD-226P22 archival material was unavailable. Arrow denotes proband. (B) Peripheral 48 Kb 58 Kb blood karyotype demonstrating translocation. Genes C2orf29 RNF149 KLHDC8B QARS USP19 LAMB2 FLJ12800 LOC339834 STGC3 FLJ43654 USP4 two genes from 3p21.31. One of them (KLHDC8B) yielded extra bands absent in an unaffected family member lacking the EcoRI NdeI XbaI Probe NdeI SexAI EcoR1 translocation (Fig. 2C), thus narrowing the interval to a region 4.5 Kb 6.7 Kb short enough to amplify by long-range PCR (Fig. 2D). We then 8.5 Kb progressively refined the interval by PCR (Fig. 2E) and used 10.1 Kb DNA sequencing to define precise breakpoints (Fig. 2F). The EcoRI EcoRI EcoRI chromosome 3 breakpoint resides in the first intron of C EcoRI +XbaI +SexA1 +NdeI KLHDC8B. The chromosome 2 breakpoint is not located near known or hypothetical genes. Chromosomes 2 and 3 exhibit four t(2;3) t(2;3) Control t(2;3) t(2;3) Control base pairs of microhomology at the Der3 junction, and there is t(2;3) t(2;3) Control t(2;3) t(2;3) Control a four base pair nonhomologous insertion at the Der2 junction. We additionally excluded possible cryptic rearrangements by ** ** 10.1 Kb array-based comparative genomic hybridization. In sum, the 8.5 Kb translocation disrupts KLHDC8B and replaces sequences up- stream of and including its first exon and part of its first intron * * 6.7 Kb with an intergenic region from chromosome 2, thus deleting its 5Ј-UTR and probable promoter sequences. Accordingly, quan- titative real-time (QR) reverse transcription (RT)-PCR in lym- 4.5 Kb phoblastoid cells shows that a translocation-carrying individual expresses only about half as much KLHDC8B as a family member without the translocation (Fig. 2G). Western blot confirms D E t(2;3) control G ntrol correspondingly reduced expression of protein, see below (Fig. o MW 2>3 N P 2>3 N P MW MW t(2;3) C 3C).
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