Characterization of familial Waldenström's macroglobulinemia

original article Annals of Oncology 17: 488–494, 2006 doi:10.1093/annonc/mdj111 Published online 15 December 2005 Characterization of familial Waldenström’s macroglobulinemia S. P. Treon1,3*, Z. R. Hunter1, A. Aggarwal2, E. P. Ewen2, S. Masota2, C. Lee2,3, D. Ditzel Santos1,3, E. Hatjiharissi1,3, L. Xu1, X. Leleu1, O. Tournilhac1,3, C. J. Patterson1, R. Manning1, A. R. Branagan1 & C. C. Morton2,3 1 3 Bing Center for Waldenström’s Macroglobulinemia, Dana Farber Cancer Institute, Boston; 2Department of Pathology, Brigham and Women’s Hospital, Boston; Harvard Medical School, Boston MA, USA Received 8 November 2005; accepted 16 November 2005 been reported, though the frequency and any differences in disease manifestation for familial patients remain to be defined. Patients and methods: We therefore analyzed clinicopathological data from 257 consecutive and unrelated WM patients. Forty-eight (18.7%) patients had at least one first-degree relative with either WM (n = 13, 5.1%), or another B-cell disorder including non-Hodgkin’s lymphoma (n = 9, 3.5%), myeloma (n = 8, 3.1%), chronic lymphocytic leukemia (n = 7, 2.7%), monoclonal gammopathy of unknown significance (n = 5, 1.9%), acute lymphocytic leukemia (n = 3, 1.2%) and Hodgkin’s disease (n = 3, 1.2%). Patients with a familial history of WM or a plasma cell disorder (PCD) were diagnosed at a younger age and with greater bone marrow involvement. Results: Deletions in 6q represented the only recurrent structural chromosomal abnormality and were found in 13% of patients, all non-familial cases. Interphase FISH analysis demonstrated deletions in 6q21-22.1 in nearly half of patients, irrespective of familial background. Conclusions: The above results suggest a high degree of clustering for B-cell disorders among first-degree relatives of patients with WM, along with distinct clinical features at presentation based on familial disease cluster patterns. Genomic studies to delineate genetic predisposition to WM are underway. Key words: Waldenström’s macroglobulinemia, B-cell, familial clustering introduction Waldenström’s macroglobulinemia (WM) is a distinct B-cell lymphoproliferative disorder characterized primarily by bone marrow infiltration with lymphoplasmacytic cells, along with demonstration of an IgM monoclonal gammopathy [1]. This condition is considered to be lymphoplasmacytic lymphoma as defined by the REAL and WHO classification systems [2, 3]. Since the report by Massari et al. in 1962 of two brothers with WM and their mother with asymptomatic IgM monoclonal gammopathy, numerous familial cases of WM have been reported, including involvement among siblings (up to four siblings), and offspring over several generations who demonstrated WM or manifested another B-cell disorder [4–17]. Hypergammaglobulinemia involving IgM, IgG, and IgA but without a monoclonal component has also been observed in relatives of patients with WM and may reflect hyper-attenuated antigen signaling [7, 8, 10, 12, 14–16, 18]. *Correspondence to: Dr S. P. Treon, Bing Program for Waldenström’s Macroglobulinemia, Dana Farber Cancer Institute, LG102, 44 Binney St, Boston, MA 02115 USA. Tel: +1 617 632 2681; Fax: +1 617 632 4862; E-mail: ª 2005 European Society for Medical Oncology The occurrence of various B-cell disorders, as well as the finding of different light chain pairings and idiotypic determinants for the IgM monoclonal protein among related patients with WM has suggested that for some patients a generalized predisposition for a B-cell disorder may exist, whereas for others inheritance of a specific genetic defect may predispose to WM, but occur though a different pathway of clonal evolution [13]. While the genetic basis for familial predisposition to WM remains to be clarified, impaired differentiation of peripheral blood (PB) B-cells following mitogenic stimulation has been observed among relatives of WM patients with IgM hypergammaglobulinemia suggesting that in some familial clusters predisposition to WM may involve a defect in the ability of B-cells to differentiate into plasma cells [7]. Moreover, enhanced ex vivo survival of PB B-cells along with overexpression of the anti-apoptotic Bcl-2 protein has also been demonstrated among kindred of WM patients [19]. While the existence of familial WM has been known for the past 40 years, the incidence as well its presenting features in comparison to non-familial WM is not known. Moreover, cytogenetic studies in patients with familial WM are very limited and may hold important clues to the pathogenesis of WM. As original article Background: Familial clustering of B-cell disorders among Waldenström’s macroglobulinemia (WM) patients has original article Annals of Oncology such, we investigated the incidence, presenting features and cytogenetics of familial WM among 257 patients with the consensus panel definition of WM who were evaluated in the WM clinic at our Institution over a 5-year period (1999–2004). The findings of this study are presented in this report. patients and methods cytogenetic analysis Cytogenetic studies of bone marrow specimens including conventional GTG and both metaphase and interphase fluorescence in situ hybridization (FISH) were performed for patients with and without a familial history of a B-cell malignancy. For conventional GTG karyotypes, unselected bone marrow cells were placed in 10% Chang Medium BMC (Irvine Scientific). The culture was incubated for 24 h and 72 h without and with pokeweed respectively. Standard harvesting procedures were used. FISH analyses were performed on cultured unsorted bone marrow specimens using bacterial artificial chromosome (BAC) probes for chromosome 6q including RP11-79L7, RP11-91C23, RP11-171J20 which hybridize to 6q21, 6q21–22, and 6q22.1 respectively and the CEP6 which hybridizes to the centromere of chromosome 6 (Children’s Hospital Oakland Research Institute). Cutoffs for detection of 6q21–22 deletions using these probes were established by use of discarded pellets from bone marrow specimens submitted for analysis that were determined to be karyotypically and histopathologically normal. One hundred cells were counted, and detection of the 6q21–22 deletion was deemed to be positive when ‡5%, and ‡6% of the cells showed loss of hybridization to RP1191C23 and RP11-71J20, and RP11-79L7, respectively. All patients provided written consent for these studies, which were approved by the Institutional Review Board of the Dana Farber Cancer Institute. Eighty-six patients with WM were enrolled in this study, 22 of whom had a family history of a related B-cell disorder in a first degree relative (9 WM, 5 Multiple Myeloma, 5 Non-Hodgkin’s Lymphoma, 1 Hodgkin’s disease, 1 Chronic lymphocytic leukemia, 1 Bence Jones monoclonal gammopathy). Fifteen of 22 (68%) and 18 of 54 (33%) patients with and without a familial background, respectively, had no prior therapy (P = 0.01 by Fisher’s exact probability test). Volume 17 | No (...truncated)