Citations

BACKGROUND. No laboratory test can predict the risk of nonrelapse mortality (NRM) or severe graft-versus-host disease (GVHD) after hematopoietic cellular transplantation (HCT) prior to the onset of GVHD symptoms. METHODS. Patient blood samples on day 7 after HCT were obtained from a multicenter set of 1,287 patients, and 620 samples were assigned to a training set. We measured the concentrations of 4 GVHD biomarkers (ST2, REG3α, TNFR1, and IL-2Rα) and used them to model 6-month NRM using rigorous cross-validation strategies to identify the best algorithm that defined 2 distinct risk groups. We then applied the final algorithm in an independent test set ( n = 309) and validation set ( n = 358). RESULTS. A 2-biomarker model using ST2 and REG3α concentrations identified patients with a cumulative incidence of 6-month NRM of 28% in the high-risk group and 7% in the low-risk group ( P < 0.001). The algorithm performed equally well in the test set (33% vs. 7%, P < 0.001) and the multicenter validation set (26% vs. 10%, P < 0.001). Sixteen percent, 17%, and 20% of patients were at high risk in the training, test, and validation sets, respectively. GVHD-related mortality was greater in high-risk patients (18% vs. 4%, P < 0.001), as was severe gastrointestinal GVHD (17% vs. 8%, P < 0.001). The same algorithm can be successfully adapted to define 3 distinct risk groups at GVHD onset. CONCLUSION. A biomarker algorithm based on a blood sample taken 7 days after HCT can consistently identify a group of patients at high risk for lethal GVHD and NRM. FUNDING. The National Cancer Institute, American Cancer Society, and the Doris Duke Charitable Foundation.

Abstract Existing antiangiogenic approaches to treat metastatic hepatocellular carcinoma (HCC) are weakly effectual, prompting further study of tumor angiogenesis in this disease setting. Here, we report a novel role for sulfatase 2 (SULF2) in driving HCC angiogenesis. Sulf2-deficient mice (Sulf2 KO) exhibited resistance to diethylnitrosamine-induced HCC and did not develop metastases like wild-type mice (Sulf2 WT). The smaller and less numerous tumors formed in Sulf2 KO mice exhibited a markedly lower microvascular density. In human HCC cells, SULF2 overexpression increased endothelial proliferation, adhesion, chemotaxis, and tube formation in a paracrine fashion. Mechanistic analyses identified the extracellular matrix protein periostin (POSTN), a ligand of αvβ3/5 integrins, as an effector protein in SULF2-induced angiogenesis. POSTN silencing in HCC cells attenuated SULF2-induced angiogenesis and tumor growth in vivo. The TGFβ1/SMAD pathway was identified as a critical signaling axis between SULF2 and upregulation of POSTN transcription. In clinical HCC specimens, elevated levels of SULF2 correlated with increased microvascular density, POSTN levels, and relatively poorer patient survival. Together, our findings define an important axis controlling angiogenesis in HCC and a mechanistic foundation for rational drug development. Cancer Res; 77(3); 632–45. ©2016 AACR.

Background Intracranial aneurysms ( IAs ), abdominal aortic aneurysms ( AAAs ), and thoracic aortic aneurysms ( TAAs ) all have a familial predisposition. Given that aneurysm types are known to co‐occur, we hypothesized that there may be shared genetic risk factors for IAs , AAAs, and TAAs . Methods and Results We performed a mega‐analysis of 1000 Genomes Project‐imputed genome‐wide association study ( GWAS ) data of 4 previously published aneurysm cohorts: 2 IA cohorts (in total 1516 cases, 4305 controls), 1 AAA cohort (818 cases, 3004 controls), and 1 TAA cohort (760 cases, 2212 controls), and observed associations of 4 known IA , AAA , and/or TAA risk loci (9p21, 18q11, 15q21, and 2q33) with consistent effect directions in all 4 cohorts. We calculated polygenic scores based on IA ‐, AAA ‐, and TAA ‐associated SNP s and tested these scores for association to case‐control status in the other aneurysm cohorts; this revealed no shared polygenic effects. Similarly, linkage disequilibrium–score regression analyses did not show significant correlations between any pair of aneurysm subtypes. Last, we evaluated the evidence for 14 previously published aneurysm risk single‐nucleotide polymorphisms through collaboration in extended aneurysm cohorts, with a total of 6548 cases and 16 843 controls ( IA ) and 4391 cases and 37 904 controls ( AAA ), and found nominally significant associations for IA risk locus 18q11 near RBBP 8 to AAA (odds ratio [ OR ]=1.11; P =4.1×10 −5 ) and for TAA risk locus 15q21 near FBN 1 to AAA ( OR =1.07; P =1.1×10 −3 ). Conclusions Although there was no evidence for polygenic overlap between IAs , AAAs , and TAAs , we found nominally significant effects of two established risk loci for IAs and TAAs in AAAs . These two loci will require further replication.

Abstract Purpose: Tamoxifen and raloxifene, are primary prevention strategies for women at high risk of breast cancer (Visvanathan, 2013). Recent advances in genetic studies of breast cancer risk have identified common susceptibility loci that explain 14% of familial risk for breast cancer in the general population (Michailidou, 2013). However, it is not known if these loci are risk factors for breast cancer among high-risk women treated with SERMs for breast cancer prevention. We hypothesized that the large risk reduction associated with SERMs, coupled with the fact that several breast cancer loci correlate with family history, may limit the contribution of these common genetic loci to breast cancer in this high risk population. We present the first report to evaluate 75 established breast cancer susceptibility loci, in the context of a polygenic risk score (PRS), as a risk factor for breast cancer among high risk women taking raloxifene and tamoxifen for breast cancer prevention. Methods: We conducted a matched case-control study of 594 cases (i.e., participants who developed breast cancer while on SERM therapy) and 1,171 matched controls selected from the 33,000 participants enrolled in the NSABP P-1 and P-2 breast cancer prevention trials. Genotypes of 75 single nucleotide polymorphisms (SNPs) were available from a genome-wide association study conducted at the RIKEN Center for Genomic Medicine. We formed a quantitative PRS from reported per-SNP odds ratios (OR) for the 75 susceptibility loci. Conditional logistic regression was used to examine the PRS as a risk factor for breast cancer and to assess whether the PRS and breast cancer association differed by treatment type, family history, or other clinical characteristics. Analyses also examined associations of PRS with invasive vs. in situ cancer and ER-positive vs. ER-negative cancer. Results: The PRS ranged from 3.98 to 7.74, and a one unit change in PRS was associated with a 42% increase in breast cancer (OR=1.42; 95% CI: 1.18-1.70; P = 0.0002). There was evidence of a stronger association of PRS with breast cancer among women with no first-degree family history (OR=1.62, 95% CI: 1.18-2.21) compared to those with a positive family history (OR=1.32, 95% CI: 1.06-1.66) (Pintx&lt;0.05). The PRS also appeared a stronger risk factor for ER-positive (OR=1.59, 95% CI: 1.25-2.02, P &lt; 0.0002) vs. ER-negative (OR=1.05, 95% CI: 0.68-1.62, P=0.84) breast cancer, although differences did not reach statistical significance (Pintx=0.10). PRS and breast cancer associations were similar across tamoxifen and raloxifene treatments, age at trial entry, 5-year predicted Gail model risk, hysterectomy status, BMI, presence of atypical hyperplasia and invasive vs. in situ cancer. Conclusion: A polygenic risk score composed of 75 loci was a risk factor for ER-positive breast cancer, especially in the absence of a first-degree family history of breast cancer. Further, the PRS associations with breast cancer were similar for women taking tamoxifen or raloxifene for prevention. These data suggest that common genetic variation adds information on risk of ER-positive breast cancer in a high-risk population receiving SERMs. Citation Format: Celine M Vachon, Daniel J Schaid, James N Ingle, Matthew P Goetz, Donald L Wickerham, Michiaki Kubo, Erin E Carlson, Soonmyung Paik, Norman Wolmark, Yusuke Nakamura, Liewei Wang, Richard M Weinshilboum, Fergus J Couch. The contribution of common genetic variation to breast cancer risk among women receiving tamoxifen or raloxifene within the National Surgical Adjuvant Breast and Bowel Project (NSABP) P-1 and P-2 trials [abstract]. In: Proceedings of the Thirty-Seventh Annual CTRC-AACR San Antonio Breast Cancer Symposium: 2014 Dec 9-13; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2015;75(9 Suppl):Abstract nr P6-10-03.

In vitro studies have proposed a tumor suppressor role for sulfatase 1 (SULF1) in hepatocellular carcinoma (HCC); however, high expression in human HCC has been associated with poor prognosis. The reason underlying this paradoxical observation remains to be explored. Using a transgenic (Tg) mouse model overexpressing Sulf1 (Sulf1‐Tg), we assessed the effects of SULF1 on the diethylnitrosamine model of liver carcinogenesis. Sulf1‐Tg mice show a higher incidence of large and multifocal tumors with diethylnitrosamine injection compared to wild‐type mice. Lung metastases were found in 75% of Sulf1‐Tg mice but not in wild‐type mice. Immunohistochemistry, immunoblotting, and reporter assays all show a significant activation of the transforming growth factor‐β (TGF‐β)/SMAD transcriptional pathway by SULF1 both in vitro and in vivo . This effect of SULF1 on the TGF‐β/SMAD pathway is functional; overexpression of SULF1 promotes TGF‐β‐induced gene expression and epithelial–mesenchymal transition and enhances cell migration/invasiveness. Mechanistic analyses demonstrate that inactivating mutation of the catalytic site of SULF1 impairs the above actions of SULF1 and diminishes the release of TGF‐β from the cell surface. We also show that SULF1 expression decreases the interaction between TGF‐β1 and its heparan sulfate proteoglycan sequestration receptor, TGFβR3. Finally, using gene expression from human HCCs, we show that patients with high SULF1 expression have poorer recurrence‐free survival (hazard ratio 4.1, 95% confidence interval 1.9‐8.3; P = 0.002) compared to patients with low SULF1. We also found strong correlations of SULF1 expression with TGF‐β expression and with several TGF‐β‐related epithelial–mesenchymal transition genes in human HCC. Conclusion : Our study proposes a novel role of SULF1 in HCC tumor progression through augmentation of the TGF‐β pathway, thus defining SULF1 as a potential biomarker for tumor progression and a novel target for drug development for HCC. (H epatology 2015;61:1269–1283)

PurposeAdvanced systemic mastocytosis (SM), a fatal hematopoietic malignancy characterized by drug resistance, has no standard therapy. The effectiveness of allogeneic hematopoietic stem-cell transplantation (alloHCT) in SM remains unknown.Patients and MethodsIn a global effort to define the value of HCT in SM, 57 patients with the following subtypes of SM were evaluated: SM associated with clonal hematologic non–mast cell disorders (SM-AHNMD; n = 38), mast cell leukemia (MCL; n = 12), and aggressive SM (ASM; n = 7). Median age of patients was 46 years (range, 11 to 67 years). Donors were HLA-identical (n = 34), unrelated (n = 17), umbilical cord blood (n = 2), HLA-haploidentical (n = 1), or unknown (n = 3). Thirty-six patients received myeloablative conditioning (MAC), and 21 patients received reduced-intensity conditioning (RIC).ResultsResponses in SM were observed in 40 patients (70%), with complete remission in 16 patients (28%). Twelve patients (21%) had stable disease, and five patients (9%) had primary refractory disease. Overall survival (OS) at 3 years was 57% for all patients, 74% for patients with SM-AHNMD, 43% for those with ASM, and 17% for those with MCL. The strongest risk factor for poor OS was MCL. Survival was also lower in patients receiving RIC compared with MAC and in patients having progression compared with patients having stable disease or response.ConclusionAlloHCT was associated with long-term survival in patients with advanced SM. Although alloHCT may be considered as a viable and potentially curative therapeutic option for advanced SM in the meantime, given that this is a retrospective analysis with no control group, the definitive role of alloHCT will need to be determined by a prospective trial.

Key Points Tac/Sir prophylaxis provides equivalent GVHD-free survival when compared with Tac/Mtx in MRD transplantation. Tac/Sir is associated with more rapid engraftment and reduced oropharyngeal mucositis after MRD transplantation.

Abstract A newly identified costimulatory molecule, programmed death-1 (PD-1), provides a negative signal that is essential for immune homeostasis. However, it has been suggested that its ligands, B7-H1 (PD-L1) and B7-dendritic cells (B7-DC; PD-L2), could also costimulate T cell proliferation and cytokine secretion. Here we demonstrate the involvement of PD-1/B7-H1 and B7-DC interaction in the development of colitis. We first examined the expression profiles of PD-1 and its ligands in both human inflammatory bowel disease and a murine chronic colitis model induced by adoptive transfer of CD4+CD45RBhigh T cells to SCID mice. Second, we assessed the therapeutic potential of neutralizing anti-B7-H1 and/or B7-DC mAbs using this colitis model. We found significantly increased expression of PD-1 on T cells and of B7-H1 on T, B, and macrophage/DCs in inflamed colon from both inflammatory bowel disease patients and colitic mice. Unexpectedly, the administration of anti-B7-H1, but not anti-B7-DC, mAb after transfer of CD4+CD45RBhigh T cells suppressed wasting disease with colitis, abrogated leukocyte infiltration, and reduced the production of IFN-γ, IL-2, and TNF-α, but not IL-4 or IL-10, by lamina propria CD4+ T cells. These data suggest that the interaction of PD-1/B7-H1, but not PD-1/B7-DC, might be involved in intestinal mucosal inflammation and also show a possible role of interaction between B7-H1 and an as yet unidentified receptor for B7-H1 in inducing T cell activation.