What's new?

Breast cancer screening can lead to better survival, but it also increases the risk of overdiagnosis. Significant variability in overdiagnosis estimates has been disconcerting to both experts and women considering their screening participation. Here, the authors reproduced the analyses made in several previous studies to estimate overdiagnosis using a single recent data source. Estimates ranged widely, from 1% to 55%. However, high estimates were more than halved when accounting for changes in background risk, and further decreased when excluding never-screened birth cohorts. Thus, considering underlying study assumptions is important to produce more informative overdiagnosis estimates, and potentially avoid unwarranted confusion.

What's new?

Costa Rica has one of the highest incidence rates of childhood leukemia worldwide. Pesticide use is widespread there, raising questions about whether pesticide exposure is in part responsible for the country's elevated childhood leukemia incidence. Here, acute lymphoblastic leukemia (ALL) in Costa Rican boys was associated with maternal insecticide use in the home as well as with pesticide spraying on nearby farms before and after the child's birth. Among both boys and girls, ALL risk increased in association with frequency of maternal in-home insecticide use. The results offer insight into possible areas of intervention to reduce childhood leukemia risk.

What's new?

Exposure to ultraviolet radiation (UVR) is a leading cause of melanoma. However, while reducing UVR exposure can potentially prevent melanoma, determining the extent to which exposure-limiting interventions are effective requires a better understanding of preventable melanoma burden. Here, preventable melanoma burden was estimated for countries worldwide using incidence estimates obtained from GLOBOCAN 2012. The data show that, of new melanoma cases diagnosed in 2012, about three-quarters could be attributed to UVR exposure. More than 1 percent of new cancers cases overall were associated with UVR. The findings underpin the need for continuing targeted prevention efforts, especially in high-incidence populations.

What's new?

Due to the importance of acidic microenvironment for cancer progression, proton pump inhibitors (PPIs), which are commonly prescribed for treating gastroesophageal reflux and peptic ulcer, are also increasingly used as a supplement to cancer therapy. Yet, their effect on cancer mortality is largely unknown. This large retrospective cohort study among Danish cancer patients found a association between postdiagnostic use of PPIs and increased cancer mortality. Furthermore, PPI-induced acceleration of tumor growth was observed in mouse models. These data raise concerns about the increasing use of PPIs and calls for further studies addressing their safety among cancer patients, in particular.

What's new?

Polymorphisms of transforming growth factor beta (TGF-β) and infection with high-risk human papilloma virus (HPV) types individually modify cancer risk, but the combined effect of both is largely unknown. The authors determined the genotype of a specific TGF-β1 variant that also affects the binding site of miRNA-187 in patients with oral squamous cell carcinoma, a cancer often associated with HPV type 16 infection. They find that this variant combined with HPV16 seropositivity increased oral cancer susceptibility, particularly in young and risk-free individuals, and propose that it could serve as a biomarker for risk of HPV16-associated oral cancer.

What's new?

B-cell lymphomas (BCL) are frequent in immunocompromised individuals, but most BCL cases are thought to occur as a consequence of minor immune perturbations in otherwise immunocompetent individuals. Here the authors prospectively examined a panel of immune markers in the blood from 268 patients afflicted with BCL and paired controls. The data uncover a functional role for growth factors (i.e. FGF-2, TGF-alpha) in the incidence and progression of multiple myeloma, a BCL subtype, and underscore the importance of chemokine and cytokine regulation in diffuse large B-cell lymphoma and chronic lymphocytic leukemia.

What's new?

Human immunodeficiency virus (HIV) infection is linked to the development of certain cancers of infectious origin. The incidence and character of these malignancies have likely been impacted by widespread access to antiretroviral therapy. This study, involving patients in Rwanda, confirms associations between HIV and Kaposi sarcoma, non-Hodgkin lymphoma, Hodgkin lymphoma (HL) and cervical, anal and conjunctival cancers and further describes associations with lymphoma subtypes. In particular, HIV infection was associated with plasmablastic lymphoma and with certain HL subtypes. The findings show that despite access to antiretroviral therapy, there is ongoing need for monitoring and control of HIV-associated cancers.

What's new?

Relative to other aspects of the Mediterranean diet, such as the intake of alcohol and processed meats, little is known about the relationship between the consumption of dairy products or their fat content and colorectal cancer (CRC) risk. Here, potential relationships were assessed among older Mediterranean individuals at high risk of cardiovascular disease. The data suggest that CRC incidence is inversely related to high total dairy product consumption. Of particular importance was the intake of low-fat milk, which was the primary driver behind the inverse association. Other dairy products were not significantly associated with CRC risk.

What's new?

Chimeric genes formed by fusion of previously separate genes are associated with many malignant tumors, but rare in ovarian cancer. Here the authors performed transcriptome sequencing of different types of ovarian tumors and identify novel fusion genes, involving cyclin genes, the master regulators of the cell cycle. As most of these fusions were found in ovarian cancer of the endometroid type, which represent about 10% of all ovarian cancers, the data point to a novel role of cyclin deregulation in this specific cancer subtype.

What's new?

The post-translational modification of histones through acetylation serves an important role in the regulation of gene expression. Histone deacetylases (HDACs) are a critical component of this system. This study sheds light on regulatory mechanisms of HDAC5 transcription and shows that sulforaphane, an HDAC inhibitor, suppresses HDAC5 expression through downregulation of upstream transcription factor 1 (USF1). USF1 downregulation in turn destabilizes lysine-specific demethylase 1 (LSD1) protein in breast cancer cells. The findings suggest that targeting the HDAC5–LSD1 axis through combined sulforaphane and LSD1 inhibitor treatment could be an effective approach to enhancing antineoplastic efficacy of epigenetic agents against breast cancer.

What's new?

Fish oil and dietary fiber have a chemoprotective effect against colon cancer. How these dietary components influence mechanisms modulating epigenetic programming remains unclear. Our study describes how combined exposure to fish oil and fermentable fiber during malignant transformation of colonocytes uniquely induces global transcriptional and epigenetic modifications linked to chemoprotective genes. Thus, combined dietary chemoprevention upregulates lipid catabolism and beta-oxidation associated genes. These genes are linked to activated ligand-dependent nuclear receptors associated with n-3 polyunsaturated fatty acids, and to enhanced metabolic oxidation via fiber fermentation. The data provide novel insight in the chemotherapeutic properties of fish oil and fiber.

What's new?

Cancer can change patterns of DNA methylation, with widespread loss of methylation but also localized increases in methylation. Here, the authors analyzed blood cells, looking for differences in methylation between breast cancer patients and healthy persons. They developed a deep bisulfite sequencing assay to specifically test the promoter regions of 8 tumor suppressor genes, plus the estrogen receptor gene, along with reduced tumor suppressor gene expression. They found that breast cancer patients showed increased methylation changes in multiple tumor suppressor genes, reduced tumor suppressor gene expression. Thus, epigenetic abnormalities could indicate disruptions in the mechanisms that maintain proper methylation, and could signal increased tumor risk.

What's new?

Human papillomavirus type 16 (HPV16) is a major risk factor for development of oropharyngeal squamous cell carcinoma (OPSCC). Interestingly, although HPV16⁺ OPSCC metastasize faster than HPV⁻ tumors, they have a better prognosis. The molecular and cellular alterations underlying the pathobiology of HPV⁺ OPSCC remain elusive, however. Here, the authors found that HPV16-E6E7 oncogene expression can modify the phenotype of infected tissue stem cells, thereby increasing the number of migratory cancer stem cells. Additionally, miR-1281 and miR-3194-5p were identified as potential biomarkers for migratory cancer stem cells and invasive HPV16⁺ OPSCC, thus representing promising targets for blocking metastatic spread of OPSCC.

What's new?

Cyclooxygenase-2 (COX-2) inhibitors block prostaglandin E₂ synthesis and are associated with reduced tumor frequency and progression. Nonetheless, they can have limiting side effects, and their utility in the treatment of established cancers remains uncertain. Here, COX-2-expressing human breast cancer cells were found to exhibit characteristics similar to those of chemotherapy-resistant cancer stem cells (CSCs). Selective inhibition of PGE₂ receptor 4 (EP₄) triggered the release of extracellular vesicles containing CSC proteins, resulting in a loss of stem cell properties. The findings suggest that direct EP₄ inhibition could enhance chemotherapeutic approaches without evoking the side effects of broader COX-2 inhibition.

What's new?

Compared to other ovarian cancer histotypes, ovarian clear cell carcinoma (OCCC) is highly resistant to conventional chemotherapeutic agents. While mechanisms remain unclear, OCCC chemoresistance likely is linked to elevated expression of iASPP, an inhibitory member of the otherwise apoptosis-stimulating ASPP protein family. Here, expression of both iASPP and polo-like kinase 1 (PLK1) was correlated with OCCC chemoresistance, while high iASPP expression alone was associated with poor survival in OCCC patients. Sensitivity to cisplatin increased in vitro and in vivo following iASPP knockdown. Further in vitro studies demonstrated a critical role for iASPP and PLK1 in the maintenance of autophagy.

What's new?

The skeletal system is a primary site for breast cancer metastasis but no humanized mouse model can currently faithfully mimic unique niche properties of human bone. Here the authors generated a complex tissue engineered human bone (hTEB) to recapitulate hematopoietic and metastatic features of a physiological human bone. They show that the hTEB attracted hematopoietic and cancer cells in the context of a humanized mouse model. Expression of human cytokines (GM-CSF, IL-7 and IL-15) inhibited tumor growth in the hematochimeric mice, underscoring the potential for the new model to serve as a developmental platform for new therapeutic anti-cancer agents.

What's new?

Monocytes and macrophages rely on colony stimulating factor-1 (CSF-1) and its receptor, CSF-1R, for recruitment and survival in the tumor microenvironment. Moreover, CSF-1 expression is associated with poor prognosis in certain cancer types. This work shows that after treatment with the chemotherapeutic agent topotecan, neuroblastoma cells increase CSF-1 release. In immunodeficient mice with neuroblastomas induced by co-injection of human neuroblastoma cells and human monocytes, BLZ945, a small molecule inhibitor of CSF-1R, enhanced the chemotherapeutic effects, inhibiting neuroblastoma growth and improving survival. The findings could have implications for the treatment of neuroblastoma and other cancers with limited cancer-fighting T-lymphocyte responses.

What's new?

Tumor cells employ various immunosuppressive mediators to evade immune detection and thereby escape mechanisms for tumor elimination. While cancer immunotherapeutic agents have been developed to counter this, some patients fail to respond, necessitating the development of alternative immunosuppressive approaches. Here, immune profiling in a head and neck squamous cell carcinoma (HNSCC) mouse model revealed high expression of the ecto-5-nucleotidase CD73 on CD4+ and CD8+ T cells. Treatment with an anti-CD73 antibody suppressed tumor growth and restored T-cell effector function. CD73 expression was further found to be upregulated in human HNSCC tissues, where it was prognostic for poor outcome.

What's new?

Exposure to ionizing radiation during medical procedures or following nuclear accidents can increase breast cancer risk by inducing DNA double-strand breaks that potentially lead to DNA copy number alterations. In this study, the authors identified a genomic copy number signature associated with radiation exposure in breast cancers in women who were exposed to ionizing radiation as Chernobyl clean-up workers or accident evacuees. The signature, composed of nine genomic copy number regions, enabled the calculation of a breast cancer radiation-exposure risk score, which was independent of clinical characteristics. The findings cast light on a new approach to radiation-induced breast cancer detection.

What's new?

Indoleamine 2,3-dioxygenase 1 (IDO) catabolizes tryptophan through the kynurenine (kyn) pathway, whose activity has been correlated with impaired clinical outcome in colorectal cancer (CRC). The function of IDO activity in CRC, however, remains unclear. Here, the authors demonstrated the chemopreventive effects of the canonical IDO inhibitor 1-L-MT on colitis-associated cancer, which were independent of adaptive immunity. IDO inhibition in colon cancer cells suppressed CDC20 transcription, thus inducing mitotic death, which was mediated by decreased Kyn production. The authors thus identified the IDO/Kyn pathway as a promising preventive target for colorectal cancer, and possibly other malignancies.

What's new?

Chemotherapy is the main therapeutic option for alimentary tract (AT) cancer patients, but intrinsic or acquired drug resistance remains an issue. Preclinical and phase I trials have shown the potential re-sensitivity property to chemo- and immunotherapy of low-dose decitabine. In this phase Ib/II trial, low-dose decitabine-primed chemotherapy with/without cytokine-induced killer cells treatment was assessed in patients with drug-resistant relapsed/refractory AT cancers. The epi- chemoimmunotherapy exhibited high response rates and prolonged the progression-free survival (PFS), compared to the pre-resistant unprimed PFS. The regimen was generally well tolerated. The safety and efficacy of decitabine-primed re-sensitization to chemoimmunotherapy make it a promising treatment strategy.

What's new?

While HPV testing is increasingly being used for cervical-cancer screening, there is a problem with this approach: Most HPV infections won't progress to (pre)malignant disease, which results in a significant number of unnecessary colposcopy referrals and over-diagnoses. A better triage test is needed to discern which HPV+ women have clinically relevant disease. In this longitudinal study, the authors found that a methylation test may provide adequate predictive power. Low cervical-cancer incidence after a negative FAM19A4/mir124-2 methylation test among HPV+ women supports use of this methylation assay as safe, objective triage tool.