The Stat3/5 signaling biosignature in hematopoietic stem/progenitor cells predicts response and outcome in myelodysplastic syndrome patients treated with azacitidine

Purpose:Azacitidine is the mainstay of high-risk myelodysplastic syndromes (MDS) therapy, but molecular predictors of response and the mechanisms of resistance to azacitidine remain largely unidentified. Deregulation of signaling via signal transducer and activator of transcription 3 (Stat3) and Stat5 in acute myeloid leukemia (AML) is associated with aggressive disease. Numerous genes involved in cell signaling are aberrantly methylated in MDS, yet the alterations and the effect of azacitidine treatment on Stat3/5 signaling in high-risk MDS have not been explored. Experimental Design:We assessed longitudinally constitutive and ligand-induced phospho-Stat3/5 signaling responses by multiparametric flow cytometry in 74 patients with MDS and low blast count AML undergoing azacitidine therapy. Pretreatment Stat3/5 signaling profiles in CD34+ cells were grouped by unsupervised clustering. The differentiation stage and the molecular properties of the CD34+ G-CSF-inducible Stat3/5 double-positive subpopulation were performed by flow cytometry and quantitative real-time PCR in isolated MDS progenitors. Results:The pretreatment Stat3/5 signaling profiles in CD34+ cells correlated strongly with response and cytogenetics and independently predicted event-free survival. We further identified a CD34+ G-CSF-inducible Stat3/5 double-positive subpopulation (DP subset) whose pretreatment levels were inversely associated with treatment response and cytogenetics. The kinetics of the DP subset followed the response to azacitidine and the disease course, whereas its molecular characteristics and cellular hierarchy were consistent with a leukemia propagating cell phenotype. Conclusions:Our findings provide a novel link among Stat3/5 signaling and MDS pathobiology and suggest that the Stat3/5 signaling biosignature may serve as both a response biomarker and treatment target.

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ESR1 Mutations in Breast Cancer: Proof of Concept Challenges Clinical Action

Wang and colleagues demonstrate that digital droplet PCR (ddPCR) identified ESR1 mutations in 7% of primary breast cancers. ESR1 mutations were also readily detected in metastatic tissues and circulating tumor DNA in the blood. These results suggest that ddPCR may be amendable for monitoring tumor burden, and to predict relapse.

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Recurrent mutations of chromatin remodeling genes and kinase receptors in pheochromocytomas and paragangliomas

Purpose: Pheochromocytomas and paragangliomas (PPGLs) are genetically heterogeneous tumors of neural crest origin, but the molecular basis of most PPGLs is unknown. Experimental Design: We performed exome or transcriptome sequencing of 43 samples from 41 patients. A validation set of 136 PPGLs was used for amplicon-specific resequencing. In addition, a subset of these tumors was used for microarray-based transcription, protein expression and histone methylation analysis by western blot or immunohistochemistry. In vitro analysis of mutants was performed in cell lines. Results: We detected mutations in chromatin remodeling genes, including histone-methyltransferases, histone-demethylases and histones in 11 samples from 8 patients (20%). In particular, we characterized a new cancer syndrome involving PPGLs and giant cell tumors of bone (GCT) caused by a postzygotic G34W mutation of the histone 3.3 gene, H3F3A. Furthermore, mutations in kinase genes were detected in samples from 15 patients (37%). Among those, a novel germline kinase domain mutation of MERTK detected in a patient with PPGL and medullary thyroid carcinoma was found to activate signaling downstream of this receptor. Recurrent germline and somatic mutations were also detected in MET, including a familial case and sporadic PPGLs. Importantly, in each of these three genes mutations were also detected in the validation group. Additionally, a somatic oncogenic hotspot FGFR1 mutation was found in a sporadic tumor. Conclusions: This study implicates chromatin-remodeling and kinase variants as frequent genetic events in PPGLs, many of which have no other known germline driver mutation. MERTK, MET, and H3F3A emerge as novel PPGL susceptibility genes.

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Award for outstanding contributions to the Chinese Journal of Cancer

Abstract

At the 4th Guangzhou International Symposium on Oncology, Rui-Hua Xu, Chao-Nan Qian, and Wei Zhang—the chairmen and editors of the Chinese Journal of Cancer—announced and presented awards to 14 authors in recognition of their outstanding contributions to the journal.

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Potential anti-cancer effect of N-hydroxy-7-(2-naphthylthio) heptanomide (HNHA), a novel histone deacetylase inhibitor, for the treatment of thyroid cancer

Abstract

Background

Thyroid cancer has been indicated to have a higher global proportion of DNA methylation and a decreased level of histone acetylation. Previous studies showed that histone gene reviser and epigenetic changes role significant parts in papillary and anaplastic thyroid cancer tumorigenesis. The goal of this research was to study the endoplasmic reticulum (ER) stress-mediated actions of the dominant histone deacetylase (HDAC) inhibitor, N-hydroxy-7-(2-naphthylthio) hepatonomide (HNHA), in thyroid cancer and to explore its effects on apoptotic cell death pathways.

Methods

Experiments were achieved to conclude the effects of HNHA in papillary thyroid cancer (PTC) and anaplastic thyroid cancer (ATC) cell lines and xenografts, as compared with two other established HDAC inhibitors (SAHA; suberoylanilide hydroxamic acid and TSA; trichostatin A).

Results

Apoptosis, which was induced by all HDAC inhibitors, was particularly significant in HNHA-treated cells, where noticeable B-cell lymphoma-2 (Bcl-2) suppression and caspase activation were observed both in vitro and in vivo. HNHA increased Ca²⁺ release from the ER to the cytoplasm. ER stress-dependent apoptosis was induced by HNHA, suggesting that it induced caspase-dependent apoptotic cell death in PTC and ATC. PTC and ATC xenograft studies demonstrated that the antitumor and pro-apoptotic effects of HNHA were greater than those of the established HDAC inhibitors. These HNHA activities reflected its induction of caspase-dependent and ER stress-dependent apoptosis on thyroid cancer cells.

Conclusions

The present study indicated that HNHA possibly provide a new clinical approach to thyroid cancers, including ATC.

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Hepatic falciform ligament clear cell myomelanocytic tumor: A case report and a comprehensive review of the literature on perivascular epithelioid cell tumors

Abstract

Background

The objective of the study was to explore the clinical expression, radiological and pathological features, differential diagnosis, and biological behavior of a clear cell myomelanocytic tumor. In a case involving a clear cell myomelanocytic tumor located in the hepatic falciform ligament, we evaluated clinical expression, radiological characteristics, histopathology, immunohistochemistry, and biological behavior; we also reviewed the relevant literature.

Case presentation

Clear cell myomelanocytic tumor is a benign soft-tissue neoplasm that often occurs in women, and is expressed as a painless mass. The falciform ligament is its most frequent site of occurrence. The imaging characteristics of this lesion were uneven enhancement in the arterial phase, continuing to strengthen in the venous phase, and equal density in the balance phase. Histological and immunohistochemical analysis revealed the main transparent epithelioid cells and smooth muscle spindle cells to be HMB-45(+), smooth muscle actin(+), and melan-A (+).

Conclusion

Hepatic vascular epithelioid cell tumors are very rare mesenchymal neoplasms. Few studies have investigated this tumor in the hepatic falciform ligament; consequently, its diagnosis and the selection of an appropriate treatment and follow-up protocol are challenging. Treatment outcome remains unpredictable. Therefore, clear cell myomelanocytic tumor should be viewed as a tumor with uncertain malignant potential requiring long-term follow-up.

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Prevalence of hepatitis B and C and sensibility of a selective screening questionnaire in patients receiving chemotherapy for solid tumors

Abstract

Background

Reactivation of hepatitis B or C virus can occur in patients undergoing chemotherapy. Recommendations for selective or systematic hepatitis B virus testing prior chemotherapy for solid tumors differ. The primary aim was to determine the seroprevalence of hepatitis B or C in a low endemic country. The second objective was to assess the relevance of a questionnaire on hepatitis B/C risk factors to consider a selective screening.

Methods

Patients were prospectively tested for hepatitis B/C markers. HBs antigen positive patients and isolated anti-HBc positive patients with detectable viral load received antiviral preventive treatment. Patients or physicians completed the questionnaire on infection risk factors.

Results

Among the 450 patients included, 388 were tested for all serological markers and had gastrointestinal (63.7 %), lung (31.2 %) and skin (4.6 %) cancers. The prevalence of subjects exposed to hepatitis B virus was 8.5 % (33/388). One patient tested positive for HBs antigen and received preventive treatment. Prevalence of subjects exposed to hepatitis C was 1.3 % (5/388). The questionnaire sensitivity was 45.5 %, 100 % and 50 % for detecting carriers of hepatitis B, C and one or the other, respectively.

Conclusions

Seroprevalence of hepatitis B was low. Selective screening with the questionnaire was insufficiently sensitive. Systematic screening with serological tests prior to chemotherapy in patients with solid tumors is therefore relevant.

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