Single Nucleotide Polymorphisms That Increase Expression of the Guanosine Triphosphatase RAC1 Are Associated With Ulcerative Colitis

BACKGROUND & AIMS: RAC1 is a GTPase that has an evolutionarily conserved role in coordinating immune defenses, from plants to mammals. Chronic inflammatory bowel diseases (IBD) are associated with dysregulation of immune defenses. We studied the role of RAC1 in IBD using human genetic and functional studies and animal models of colitis. METHODS: We used a candidate gene approach to HapMap-Tag single nucleotide polymorphisms (SNPs) in a discovery cohort; findings were confirmed in 2 additional cohorts. RAC1 mRNA expression was examined from peripheral blood cells of patients. Colitis was induced in mice with conditional disruption of Rac1 in phagocytes by administration of dextran sulphate sodium (DSS). RESULTS: We observed a genetic association between RAC1 with ulcerative colitis (UC) in a discovery cohort, 2 independent replication cohorts, and in combined analysis for the SNPs rs10951982 (Pcombined UC = 3.3 × 10–8, odds ratio [OR]=1.43 [1.26–1.63]) and rs4720672 (Pcombined UC=4.7 × 10–6, OR=1.36 [1.19–1.58]). Patients with IBD who had the rs10951982 risk allele had increased expression of RAC1, compared to those without this allele. Conditional disruption of Rac1 in macrophage and neutrophils of mice protected them against DSS-induced colitis. CONCLUSION: Studies of human tissue samples and knockout mice demonstrated a role for the GTPase RAC1 in the development of UC; increased expression of RAC1 was associated with susceptibility to colitis

The bcl-2 oncogene in Hodgkin\u27s disease arising in the setting of follicular non-Hodgkin\u27s lymphoma

Expression of the bcl-2 proto-oncogene on chromosome 18 is deregulated by the 14;18 chromosomal translocation, an abnormality that is consistently associated with follicular non-Hodgkin\u27s lymphomas (NHL). Because bcl-2 is believed to function by prolonging cell survival rather than by increasing proliferation, the presence of t(14;18) in Hodgkin\u27s disease (HD) would have profound implications for the pathogenesis of this neoplasm. We evaluated 32 cases of HD for t(14;18) by polymerase chain reaction (PCR). These results were correlated with expression of bcl-2 oncogenic protein by Hodgkin cells and with the presence of Epstein-Barr virus (EBV), as determined by immunohistochemistry or in situ hybridization. PCR provided evidence of t(14;18) in only 2 HD cases (6%), both of which were associated with a prior history of follicular lymphoma, and both of which were among the 7 cases (22%) with strong bcl-2 expression in Hodgkin cells. In at least 1 of the cases, the translocation involved identical chromosomal breakpoints in both types of lymphoma. Furthermore, 7 additional cases of combined follicular NHL and HD showed strong bcl-2 staining in Hodgkin cells. Although EBV was detected in 6 of 30 cases, it was not associated with t(14;18) and usually not with strong bcl-2 expression. These results suggest that a small proportion of HD cases might evolve from follicular NHL, possibly through molecular events superimposed on the t(14;18). High-level bcl-2 expression in Hodgkin cells is a potentially useful but not definitive marker for these cases

A novel case of an infantile fibrosarcoma-like tumor with KIAA1549-BRAF translocation and an oncogenic NF2p.Q459* SNV with potential clinical significance

We report a case of a right gluteal mass from the sacroiliac joint to the knee of an infant girl. Biopsy showed histopathological features similar to infantile fibrosarcoma (IFS). However, unlike most IFS, no ETV6-NTRK3 fusion gene abnormality was detected. Molecular analysis with TruSight RNA Pan-Cancer Panel detected the presence of KIAA1549-BRAF translocation and an oncogenic NF2p.Q459* SNV with potential clinical significance. A review revealed that the combination of this patient’s tumor site with the presence of a KIAA1549-BRAF translocation abnormality and an accompanying single nucleotide variant has not been previously described. The detection of this translocation abnormality raises the possibility that the spindle cell tumors in infants with an absence of the ETV6-NTRK3 fusion gene abnormality might have a distinct pathogenetic mechanism different from the previously known IFS and congenital mesoblastic nephroma. Furthermore, the discovery of BRAF translocation and its aberrant signaling of the mitogen-activated protein kinase (MAPK) pathway in this tumor contributes to the promise of clinical benefit of using the MEKi trametinib for the treatment of progressive disease that is refractory to conventional chemotherapy.&nbsp

Rac2-deficiency leads to exacerbated and protracted colitis in response to Citrobacter rodentium infection.

Recent genetic-based studies have implicated a number of immune-related genes in the pathogenesis of inflammatory bowel disease (IBD). Our recent genetic studies showed that RAC2 is associated with human IBD; however, its role in disease pathogenesis is unclear. Given Rac2's importance in various fundamental immune cell processes, we investigated whether a defect in Rac2 may impair host immune responses in the intestine and promote disease in the context of an infection-based (Citrobacter rodentium) model of colitis. In response to infection, Rac2(-/-) mice showed i) worsened clinical symptoms (days 13-18), ii) increased crypt hyperplasia at days 11 and 22 (a time when crypt hyperplasia was largely resolved in wild-type mice; WT), and iii) marked mononuclear cell infiltration characterized by higher numbers of T (CD3(+)) cells (day 22), compared to WT-infected mice. Moreover, splenocytes harvested from infected Rac2(-/-) mice and stimulated in vitro with C. rodentium lysate produced considerably higher levels of interferon-γ and interleukin-17A. The augmented responses observed in Rac2(-/-) mice did not appear to stem from Rac2's role in NADPH oxidase-driven reactive oxygen species production as no differences in crypt hyperplasia, nor inflammation, were observed in infected NOX2(-/-) mice compared to WT. Collectively, our findings demonstrate that Rac2(-/-) mice develop more severe disease when subjected to a C. rodentium-induced model of infectious colitis, and suggest that impaired Rac2 function may promote the development of IBD in humans

Posttransplant lymphoproliferative disorder in pediatric patients: Survival rates according to primary sites of occurrence and a proposed clinical categorization

Posttransplant lymphoproliferative disorder (PTLD) is a devastating complication of organ transplant. In a hospital-based registry, we identified biopsy-proven cases of PTLD among children during a 15-year period and reviewed trends in PTLD rates, the sites of involvement, and the associated survival rates. Cases that were included had at least 1 year of follow-up after the diagnosis of PTLD. We studied 82 patients with first-episode PTLD. Median age at diagnosis was 6.4 years (IQR 3.2-12.3 years). The most frequent PTLD sites were tonsillar/adenoidal (T/A [34%]) and gastrointestinal (32%), followed by miscellaneous (defined as less common sites including central nervous system, kidney, lung, and soft tissue [12%]), lymph node (11%), and multisite (11%). Kaplan-Meier survival curves showed that T/A PTLD was associated with decreased all-cause mortality compared with PTLD at other sites (log-rank 0.004), even after adjustment for histological subtype (P = .047). PTLD-related mortality was also decreased among T/A PTLD (log-rank 0.012) but showed a trend toward significance only after adjustment for histological subtype (P = .09). Among first episodes of PTLD, T/A PTLD was associated with a survival advantage compared with PTLD at other sites, even after adjustment for potential confounders. Based on our observations, we propose a clinical categorization of PTLD according to anatomical site of occurrence

Posttransplant Lymphoproliferative Disorder in Pediatric Patients: Characteristics of Disease in EBV-seropositive Recipients

Patients at greatest risk of posttransplant lymphoproliferative disorder (PTLD) are those who acquire primary Epstein-Barr virus (EBV) infection after solid organ transplantation. The incidence of PTLD among patients who are EBV-seropositive before transplant is lower, and little is known about the differences in presentation and outcome of this population. We describe the characteristics of EBV-seropositive transplant recipients (R+) who developed PTLD and compare survival outcomes with EBV-seronegative recipients (R-)