Transcriptome sequencing reveals a profile that corresponds to genomic variants in Waldenström macroglobulinemia.

Whole-genome sequencing has identified highly prevalent somatic mutations including MYD88, CXCR4, and ARID1A in Waldenström macroglobulinemia (WM). The impact of these and other somatic mutations on transcriptional regulation in WM remains to be clarified. We performed next-generation transcriptional profiling in 57 WM patients and compared findings to healthy donor B cells. Compared with healthy donors, WM patient samples showed greatly enhanced expression of the VDJ recombination genes DNTT, RAG1, and RAG2, but not AICDA Genes related to CXCR4 signaling were also upregulated and included CXCR4, CXCL12, and VCAM1 regardless of CXCR4 mutation status, indicating a potential role for CXCR4 signaling in all WM patients. The WM transcriptional profile was equally dissimilar to healthy memory B cells and circulating B cells likely due increased differentiation rather than cellular origin. The profile for CXCR4 mutations corresponded to diminished B-cell differentiation and suppression of tumor suppressors upregulated by MYD88 mutations in a manner associated with the suppression of TLR4 signaling relative to those mutated for MYD88 alone. Promoter methylation studies of top findings failed to explain this suppressive effect but identified aberrant methylation patterns in MYD88 wild-type patients. CXCR4 and MYD88 transcription were negatively correlated, demonstrated allele-specific transcription bias, and, along with CXCL13, were associated with bone marrow disease involvement. Distinct gene expression profiles for patients with wild-type MYD88, mutated ARID1A, familial predisposition to WM, chr6q deletions, chr3q amplifications, and trisomy 4 are also described. The findings provide novel insights into the molecular pathogenesis and opportunities for targeted therapeutic strategies for WM.

Family history of non-hematologic cancers among Waldenstrom macroglobulinemia patients: a preliminary study.

BACKGROUND: Little is known about the epidemiology and etiology of Waldenstrom macroglobulinemia (WM). Despite several studies of the relation between family history and B-cell disorders and WM, family history of non-hematologic cancers has not been systematically investigated. We thus examined associations of family history of breast, colorectal, lung, ovarian, and prostate cancers with WM. METHODS: All probands aged 20-79 years with bone marrow biopsy-confirmed diagnosis of WM between May 1, 1999 and January 1, 2010 at the Bing Center for Waldenstrom Macroglobulinemia were eligible for inclusion in our analysis. We reviewed medical records for eligible probands to determine family history of cancer (defined as a cancer diagnosis for ≥1 first-degree relative(s) of the proband). Using expected values constructed from the United States National Health Interview Survey, we estimated age- and race-standardized rate ratios (RRs) for family history of breast, colorectal, lung, ovarian, and prostate cancers by WM subtype. RESULTS: Family history of prostate cancer had the largest overall rate ratio (RR=1.4, 95% confidence limits [CL]: 1.1, 1.7), and among sporadic cases, family history of prostate and breast cancer had the largest rate ratios (prostate: RR=1.3, 95% CL: 1.1, 1.7; breast: RR=1.3, 95% CL: 1.2, 1.6). CONCLUSION: Our study suggests that it may be worthwhile to pursue these associations in a case-control study with uniform selection and data collection for cases and controls, and at least some record-based information on family history.

Associated malignancies in patients with Waldenström's macroglobulinemia and their kin.

We examined the incidence of other malignancies in 924 Waldenström's Macroglobulinemia (WM) patients and their kin. A total of 225 (24.3%) patients had ≥1 additional malignancy, with 63% predating the WM diagnosis. The most common gender-adjusted malignancies were prostate (9.4%), breast (8.0%), non-melanoma skin (7.1%), hematologic (2.8%), melanoma (2.2%), lung (1.4%) and thyroid 1.1%). Among hematologic malignancies, all 13 cases of diffuse large B-cell lymphoma and 4 cases of acute myelogenous leukemia were diagnosed after WM, and were therapy-related. Familial WM subgroup analysis showed a higher incidence of prostate cancer (P=.046) in sporadic WM patients, while patients with familial WM had a higher incidence of lung cancer (P=.0043). An increased incidence of myeloid leukemias (P<.0001) was reported among kin of familial WM patients. These data reveal specific cancer associations with WM, and provide a basis for exploratory studies aimed at delineating a common genetic basis. Additionally, these studies suggest specific cancer clustering based on familial predisposition to WM.