Blood-related Cancers Research Articles

Sex/gender differences in metabolic syndrome among cancer survivors in the US: an NHANES analysis

BackgroundThe purpose of this study was to assess the association of metabolic syndrome (MetS) and its individual components in cancer survivors (CS) by gender, in comparison to participants without a history of cancer who have at least one chronic disease (CD) and those without a chronic disease diagnosis (NCD).MethodsData from participants 40 years and older (n = 12,734) were collected from the 2011 to 2018 National Health and Nutrition Examination Survey dataset. MetS was defined based on the National Cholesterol Education Program’s Adult Treatment Panel III. Chi-square test and multivariate-adjusted logistic regression was used to assess group comparisons and associations respectively.ResultsCompared to NCD, CS and CD men had increased odds of meeting MetS, OR 2.60 (CI 1.75–3.87) and OR 2.18 (CI 1.59–2.98) respectively. For women, CS and CD participants also had higher odds of meeting MetS criteria compared to their healthy counterparts, OR 2.05 (CI 1.44–2.93) and OR 2.14 (CI 1.63–2.81) respectively. In subgroup analysis by cancer site, CS men with a history of hematologic malignancies (OR 4.88, CI 1.30–18.37) and CS women with cervical cancer (OR 4.25, CI 1.70–10.59) had highest odds of developing MetS, compared to NCD. CS men also showed a strong association with elevated waist circumference, low high density lipoprotein-c, and elevated triglycerides, even by cancer site, but there were no consistent findings among women.ConclusionThis study indicates that CS men have a strong association with MetS, especially among those with blood-related cancers.

Risk factors in people with mold infections that have spread to different parts of the body: a plain language summary.

This is a summary of a study originally published in ClinicoEconomics and Outcomes Research. Mold infections spread from one to other parts of the body and can infect other body parts. We need to understand what makes people more likely to get this type of mold infection (called invasive mold infection). This summary may help doctors to understand the risks that can relate to invasive mold infections. The main risks in people with invasive aspergillosis (shortened to IA) and invasive mucormycosis (shortened to IM) were: ○diabetes (high blood sugar and associated conditions), ○lung disease (such as tuberculosis, chronic obstructive pulmonary disorder), ○blood-related cancers (such as leukemia, lymphoma), and ○solid organ transplant (removing an organ from one person and placing in another person). People with the risks listed above may be more likely to get invasive mold infections. People with these risks should talk to their doctor about invasive mold infections. Being aware of these risks may help doctors to be aware of which people are at risk of invasive mold infections.

Promoter/enhancer-based controllability of regulatory networks

Understanding the mechanisms of tissue-specific transcriptional regulation is crucial as mis-regulation can cause a broad range of diseases. Here, we investigated transcription factors (TF) that are indispensable for the topological control of tissue specific and cell-type specific regulatory networks as a function of their binding to regulatory elements on promoters and enhancers of corresponding target genes. In particular, we found that promoter-binding TFs that were indispensable for regulatory network control regulate genes that are tissue-specifically expressed and overexpressed in corresponding cancer types. In turn, indispensable, enhancer-binding TFs were enriched with disease and signaling genes as they control an increasing number of cell-type specific regulatory networks. Their target genes were cell-type specific for blood and immune-related cell-types and over-expressed in blood-related cancers. Notably, target genes of indispensable enhancer-binding TFs in cell-type specific regulatory networks were enriched with cancer drug targets, while target genes of indispensable promoter-binding TFs were bona-fide targets of cancer drugs in corresponding tissues. Our results emphasize the significant role control analysis of regulatory networks plays in our understanding of transcriptional regulation, demonstrating potential therapeutic implications in tissue-specific drug discovery research.

Abstract 170: Anticancer potential of curcuma and target identification in hematologic malignancies: A focus on mismatch repair

Abstract Introduction- Cancer, an heterogeneous condition, arises through mutations in the tumor suppressors and proto oncogenes which are otherwise involved in numerous cellular processes.These mutations rewire the signaling cascades to promote ‘malignant phenotype'. Under such circumstances the DNA repair system aids in rectifying the mutations and establishing normalcy.Plant derived products have shown promising success in treatment of cancer. In the present study, we make an attempt to screen various curcumin compounds to identify putative targets related to hematologic malignancies which in turn modulate the functionally altered mismatch repair system (MMR) using computational tools. Methods-A total of 536 curcumin compounds, retrieved from peer reviewed literature and black turmeric database, were analyzed for molecular characteristics, biological activities, ADME/Tox and, drug-like properties through Molinspiration and PreADMET. This was followed by prediction of site of metabolism via FAME3SOM tool. Simultaneously, COSMIC database was used for selection of proteins associated to haematologic malignancies. The database helped us to identify 9 proteins viz. abl1, max, myb, myc, pcna, p73, top3a, blm and vbp1; molecular aberrations of which are associated with malignant transformation in blood related cancers. Additionally, STRING identified these proteins having significant interaction with proteins of mismatch repair system. The crystal structures of the proteins were obtained from PDB and their domains and active sites were predicted using scanPROSITE, MOTIF Search, metaPOCKET2 and PrankWeb tools. Finally the proteins and ligands were energy minimized using YASARA and subjected to virtual screening and molecular docking using Autodock Vina and Autodock Tools respectively. Results-The overall results revealed six of the curcuma compounds (two monocarbonyl derivatives, one non-curcuminoid and three black turmeric natural compounds) may have the potential to modulate the identified targets and thus revive the MMR functionality; rescuing the genome from being unstable. Conclusion-With these analyses we predict that curcumin compounds can modulate therapeutic targets identified here and in turn rescue the function of MMR in hematologic malignancies. Citation Format: Priyanjali Bhattacharya, Trupti N. Patel. Anticancer potential of curcuma and target identification in hematologic malignancies: A focus on mismatch repair [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2021; 2021 Apr 10-15 and May 17-21. Philadelphia (PA): AACR; Cancer Res 2021;81(13_Suppl):Abstract nr 170.

Serum lactate dehydrogenase activities as systems biomarkers for 48 types of human diseases

Most human diseases are systems diseases, and systems biomarkers are better fitted for diagnostic, prognostic, and treatment monitoring purposes. To search for systems biomarker candidates, lactate dehydrogenase (LDH), a housekeeping protein expressed in all living cells, was investigated. To this end, we analyzed the serum LDH activities from 172,933 patients with 48 clinically defined diseases and 9528 healthy individuals. Based on the median values, we found that 46 out of 48 diseases, leading by acute myocardial infarction, had significantly increased (p < 0.001), whereas gout and cerebral ischemia had significantly decreased (p < 0.001) serum LDH activities compared to the healthy control. Remarkably, hepatic encephalopathy and lung fibrosis had the highest AUCs (0.89, 0.80), sensitivities (0.73, 0.56), and specificities (0.90, 0.91) among 48 human diseases. Statistical analysis revealed that over-downregulation of serum LDH activities was associated with blood-related cancers and diseases. LDH activities were potential systems biomarker candidates (AUCs > 0.8) for hepatic encephalopathy and lung fibrosis.

A study of deregulated MMR pathways and anticancer potential of curcuma derivatives using computational approach

Plant derived products have steadily gained momentum in treatment of cancer over the past decades. Curcuma and its derivatives, in particular, have diverse medicinal properties including anticancer potential with proven safety as supported by numerous in vivo and in vitro studies. A defective Mis-Match Repair (MMR) is implicated in solid tumors but its role in haematologic malignancies is not keenly studied and the current literature suggests that it is limited. Nonetheless, there are multiple pathways interjecting the mismatch repair proteins in haematologic cancers that may have a direct or indirect implication in progression of the disease. Here, through computational analysis, we target proteins that are involved in rewiring of multiple signaling cascades via altered expression in cancer using various curcuma derivatives (Curcuma longa L. and Curcuma caesia Roxb.) which in turn, profoundly controls MMR protein function. These biomolecules were screened to identify their efficacy on selected targets (in blood-related cancers); aberrations of which adversely impacted mismatch repair machinery. The study revealed that of the 536 compounds screened, six of them may have the potential to regulate the expression of identified targets and thus revive the MMR function preventing genomic instability. These results reveal that there may be potential plant derived biomolecules that may have anticancer properties against the tumors driven by deregulated MMR-pathways.

Expanding the Repertoire for "Large Small Molecules": Prodrug ABBV-167 Efficiently Converts to Venetoclax with Reduced Food Effect in Healthy Volunteers.

Since gaining approval for the treatment of chronic lymphocytic leukemia (CLL), the BCL-2 inhibitor venetoclax has transformed the treatment of this and other blood-related cancers. Reflecting the large and hydrophobic BH3-binding groove within BCL-2, venetoclax has significantly higher molecular weight and lipophilicity than most orally administered drugs, along with negligible water solubility. Although a technology-enabled formulation successfully achieves oral absorption in humans, venetoclax tablets have limited drug loading and therefore can present a substantial pill burden for patients in high-dose indications. We therefore generated a phosphate prodrug (3, ABBV-167) that confers significantly increased water solubility to venetoclax and, upon oral administration to healthy volunteers either as a solution or high drug-load immediate release tablet, extensively converts to the parent drug. Additionally, ABBV-167 demonstrated a lower food effect with respect to venetoclax tablets. These data indicate that beyond-rule-of-5 molecules can be successfully delivered to humans via a solubility-enhancing prodrug moiety to afford robust exposures of the parent drug following oral dosing.

Progression of self-management learning experiences of young adults following an allogeneic hematopoietic stem cell transplantation: A qualitative study.

Hematological diseases are among the most common forms of cancer that can affect young adults. Hematopoietic stem cell transplantation is a common intervention to treat blood-related cancers such as leukemia and lymphoma. Allogeneic stem cell transplants can provoke many acute and chronic symptoms. Young adult cancer survivors are expected to develop expertise to self-manage these symptoms. However, learning self-management can be quite challenging for young adults. This paper aims to describe the symptoms self-management learning experiences of young adults following an allogeneic stem cell transplant. A qualitative descriptive study was conducted to describe self-management learning experiences of young adults (18-39 years old) following an allogeneic stem cell transplant. Semi-structured interviews were conducted (n=7, mean age 26 years old, mean time since allogeneic stem cell transplant was 14,71 months). Iterative qualitative content analysis was performed. Participants who had undergone an allogeneic stem cell transplant described learning self-management as a progressive process, with expertise having to be developed through experience. Certain factors could positively or negatively affect the learning process and hence the development of this self-management expertise. With time, these young adults developed interoceptive ability and body awareness related to their symptoms, which influenced their self-management. Following an allogeneic stem cell transplant, young adults need to be supported during their survivorship to develop self-management expertise. Nurses must adapt care according to patients' level of expertise to promote autonomy, development of interoceptive ability, and acquisition of self-management skills.

Discovery of Anticancer Clinical Candidate, Tosedostat, As an Analgesic Agent.

Tosedostat is an inhibitor of aminopeptidases currently in phase II clinical trials for the treatment of blood-related cancers. In our laboratories, we have discovered that it possesses analgesic properties. Extensive in vivo pharmacological studies for the determination of antinociceptive effects of tosedostat are presented here. These studies have indicated that the observed analgesic effect of tosedostat stems from its action on the peripheral nervous system with minimal contribution from the central nervous system. Additionally, when given in combination with morphine, tosedostat exerts a synergistic analgesic effect resulting in a reduction of effective dosages required to achieve the same analgesic effect. With broad implications in addressing the opioid addiction crisis, these revelations attest to tosedostat being a highly valuable drug candidate with diverse pharmacological functions.

309 - Occupational Therapy's Role in Maximizing Quality of Life in Bone Marrow Transplant

Currently, an estimated 1,290,773 people in the United States are living with or in remission from general blood cancers; a number that has increased by more than 50,000 individuals since last year. Furthermore, an estimated 172,910 people in the United States are expected to be diagnosed with leukemia, lymphoma, or myeloma in 2017 (Leukemia & Lymphoma Society, 2017). As bone marrow transplantation (BMT) is a progressive treatment option for blood-related cancers, side effects lead to challenges across multiple functional domains. These side effects may include difficulty with: endurance, sleep hygiene, exercise and activity engagement, self-concept, psychosocial adjustment, and well-being (Bevans et al., 2008; Bieri et al., 2008; Rischer et al., 2009). It is imperative to assess and address quality of life and psychosocial effects amongst those undergoing transplant. Occupational therapy practitioners are uniquely skilled to address symptom distress, activity engagement, adaptation to the environment, and other issues affecting life satisfaction during one's inpatient stay in the hospital (Christiansen & Matsuka, 2006). Occupation is defined to include all the activities that people do to occupy themselves, including looking after themselves and enjoying life (Townsend & Polatakjo, 2013). Consistent with literature, participation in meaningful occupations promotes occupational performance and contributes to good health and well-being (Hocking, 2009). Evidence based practice within occupational therapy supports providing treatment, including the following areas: modification of daily routines, incorporation of new coping strategies for healthful stress management and sleep hygiene, medication management and tracking symptomatology, fatigue management, and self-management of one's overall quality of life (Bevans et al., 2008; Christiansen & Matsuka, 2006; Demiralp, 2010; Kangas, Bovbjerg, & Montgomery, 2008; Paul, 2011). This presentation will examine the role of occupational therapists in providing supportive care for individuals undergoing bone marrow transplant. Occupational therapy efforts to maximize quality of life and promote psychosocial well being will be highlighted through a general intervention framework and case examples. Occupational therapy can be effective in enhancing patients' experience, self efficacy, and overall well-being throughout their transplant stay in an acute inpatient hospital setting; a process that has been identified to hinder a person's ability to spontaneously engage in activities across their daily routine of life (Paul, 2011). In conclusion, occupational therapy can contribute to the interdisciplinary effort and patient care by maximizing individuals' well being, addressing psychosocial needs, and ultimately enhancing quality of life.

Engineering the hematopoietic stem cell niche: Frontiers in biomaterial science.

Hematopoietic stem cells (HSCs) play a crucial role in the generation of the body's blood and immune cells. This process takes place primarily in the bone marrow in specialized 'niche' microenvironments, which provide signals responsible for maintaining a balance between HSC quiescence, self-renewal, and lineage specification required for life-long hematopoiesis. While our understanding of these signaling mechanisms continues to improve, our ability to engineer them in vitro for the expansion of clinically relevant HSC populations is still lacking. In this review, we focus on development of biomaterials-based culture platforms for in vitro study of interactions between HSCs and their local microenvironment. The tools and techniques used for both examining HSC-niche interactions as well as applying these findings towards controlled HSC expansion or directed differentiation in 2D and 3D platforms are discussed. These novel techniques hold the potential to push the existing boundaries of HSC cultures towards high-throughput, real-time, and single-cell level biomimetic approaches that enable a more nuanced understanding of HSC regulation and function. Their application in conjunction with innovative biomaterial platforms can pave the way for engineering artificial bone marrow niches for clinical applications as well as elucidating the pathology of blood-related cancers and disorders.

Exploring The Relationship Between Autophagy and Mitochondrial Dysfunction In a Mouse Model Of MDS

Although myelodysplastic syndrome (MDS) is uncommon in children, with an annual estimated incidence of 0.5 to 4 cases per million children compared to 20 to 40 cases per million in adults, the incidence of MDS appears to be increasing in the United States with the improvements in survival rates of childhood cancers, at least in part because the intensive chemo- and radiotherapy regimens that cure pediatric patients with cancer may also cause therapy-related MDS. Unlike in other blood-related cancers, the disease-causing mutations in pediatric MDS and t-MDS/AML are unknown. Nevertheless, recent studies have suggested that the mitochondrial dysfunction associated with MDS results from the inability of hematopoietic stem/progenitor cells to appropriately cope with mitochondrial damage andmitochondrial dysfunction appears to be an early event in the development of t-MDS/AML.Autophagy is a catabolic process involved in the sequestration and breakdown of cellular components, including organelles such as mitochondria and long-lived or misfolded proteins. By sequestering and degrading depolarized fragments of mitochondria that result from cycles of mitochondrial fusion and fission, autophagy plays a critical role in the maintenance of healthy pools of mitochondria. Given the importance of autophagy in mitochondrial quality control and increasing evidence that mitochondrial dysfunction plays a role in the pathogenesis of MDS, we sought to explore the role of autophagy in the pathogenesis of MDS associated with mitochondrial dysfunction using the previously established PolgAmt/mt mouse model (a.k.a. mtDNA mutator mice).The mtDNA mutator mice express a proof-reading-deficient mutant of mtDNA polymerase (PolgA-D257A), which results in increased mitochondrial mutation frequencies in multiple tissues, and a decline in respiratory function of mitochondria-encoded complexes. The delayed onset of an MDS-like phenotype in these mice provides a window of time to interrogate the role of autophagy in the progression of disease symptoms. Disruption of autophagy in erythroid progenitors did not cause a significant decrease in hemoglobin or red blood cell count in PolgAwt/wt mice, however, it accelerated the onset of anemia and morbidity significantly in PolgAmt/mt mice, suggesting that autophagy delays the onset of symptoms associated with pathologic mtDNA mutations. Flow cytometric evaluation of peripheral blood of PolgAmt/mt mice and wild-type littermates revealed an unexpected defect in RBC maturation in PolgAmt/mt animals, which became apparent with age or following serial phlebotomy. The defect was similar to that observed in autophagy-defective Ulk1-deficient mice suggesting that pathogenic mtDNA mutations may cause an age-dependent delay in autophagy. Transformed PolgAmt/mt murine embryonic fibroblasts (MEFs) with mitochondrial dysfunction also showed a defect in basal LC3 conversion and p62 accumulation, consistent with impaired flux through the autophagy pathway. Together, our data indicates that although autophagy initially combats accumulation of dysfunctional mitochondria resulting from an increased mtDNA mutation burden, the latter eventually leads to a decline in basal autophagy and impaired clearance of mitochondria, which contributes to the decline in mitochondrial function and progression of MDS-like disease in mice. Disclosures:No relevant conflicts of interest to declare.

Supporting cancer survivors’ participation in peer review: perspectives from NCI’s CARRA program

Including cancer survivors in the peer review of cancer-related research is increasingly valued as a strategy for bringing the "patient perspective" to discussions of research merit and human subject protection. Because integrating lay stakeholders into peer review poses challenges, this qualitative study explored the perspectives of experienced patient advocates to identify programmatic supports for survivors' participation. Semi-structured telephone interviews were conducted with a purposive sample of 19 cancer survivors and 6 administrators involved in the National Cancer Institute's Consumer Advocates in Research and Related Activities program. Audio-recorded interviews were transcribed verbatim and analyzed via thematic content analysis. Participants were highly educated and included survivors of breast, prostate, and blood-related cancers. Interviewees emphasized the importance of adequately preparing survivors to serve as advocates. Given the intellectual challenge of peer review, interviewees noted the need for intensive and ongoing training on how to review proposals, and they identified mock reviews and peer mentoring as effective strategies to complement didactic instruction. Participants also stressed the need to address social challenges inherent in advocate-scientist encounters. In addition to training for both advocates and scientists, participants reported that opportunities for informal social interaction were important for facilitating collaboration. Finally, participants recommended structuring advocates' role so as to give them a voice via equal voting privileges and protected opportunities to speak. Programs that seek to include cancer survivors in peer review can prepare advocates for the intellectual and social challenges of working with scientists through careful attention to training, networking, and programmatic design. Cancer survivors have been leaders in developing a role for patient advocates in the peer review of research. As the concept of patient-centered outcomes continues to gain currency, lessons learned from early programs for patient inclusion in peer review can help to inform future efforts aimed at giving patients a voice in shaping agendas for health-related research.

Abstract 3197: Functional microscale cell-based systems for studying hematologic cancers in complex microenvironments

Abstract Our ability to improve treatments for blood-related cancers such as multiple myeloma (MM) is currently hindered by limitations in lab procedures for studying cell signaling mechanisms in drug resistance. Conventional assays for studying signal transduction (gel shift assays) require large quantities of cell sample (&amp;gt; 100,000 cells per condition) that often cannot be acquired safely and reliably from primary bone marrow aspirations of different patients. Furthermore, in vitro assays often do not adequately represent key aspects of the complex bone marrow microenvironment, including spatial organization of stromal cell types. The objective of this study was to develop a new functional assay using microfluidics technology to examine signal transduction events, specifically in improved in vitro microenvironments, for non-adherent cells such as those associated with hematologic cancers, and for low cell number applications (∼1000 cells per condition) including patient samples. Successful development of this assay would provide an alternative to gel shift assays and streamline experiments. We developed microscale cell culture chambers that used a surface tension-based passive pumping method for fluidic delivery, obviating the need for external pumps and tubing commonly used in microfluidic systems, thus reducing dead volume and cell loss. To validate the platform, non-adherent RPMI8226 cells (human MM cell line) were cultured, treated with cytokines/drugs, fixed, and immunostained to determine cytoplasmic versus nuclear localization of NF-κB subunit RelA as a measure of canonical NF-κB activation. Fluorescent images of RelA were analyzed using custom image analysis for calculating ratio of nuclear to cytoplasmic signals (intensity ratio, IR) at single cell resolution. IR values of cells in a population were calculated to determine overall nuclear translocation and NF-κB activation. Results showed fluorescence immunostaining coupled with custom image analysis was able to detect dose-dependent TNF-α activation of NF-κB, and dose-dependent inhibition of NF-κB activity by bortezomib treatment. Ongoing work involves applying the platform to study effects of various drug treatments on NF-κB signaling in primary patient MM cells in monoculture and in coculture with bone marrow stromal cells. Our results demonstrate the platform is a functional, enabling tool for studying single-cell NF-κB signal transduction with low numbers of non-adherent cells. The platform is extensible to other hematologic cancers, applicable for other transcription factors (e.g., STAT3), amenable to coculture studies, and has potential to enable novel experiments with limited primary samples that may have significant impact in translational research. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 3197. doi:1538-7445.AM2012-3197

Cancer drug safety presents challenges

Cancer drug safety presents challenges

Pain in blood cancers

Patients with blood-related cancers (BRC) suffer from a substantial symptom burden, including several pain syndromes sustained by different causes and pathogenetic mechanisms. So, with regard to pain, a multifaceted clinical scenario may be observed in this setting. Indeed, pain may be correlated to disease itself, to disease-associated complications, to iatrogenic causes or may be due to unrelated clinical conditions. A close diagnostic procedure for the assessment of the underlying causes of the pain and of its pathogenetic mechanisms may direct the treatment approach which should be based on a multidisciplinary management and requires the integration of etiology-targeted interventions and painkilling drugs. The World Health Organization's three-step analgesic ladder for cancer pain relief can provide adequate pain control using oral drugs in most patients with BRC on pain, although more complex interventions may be necessary for many difficult-to-treat pain syndromes which are not infrequently encountered in this setting.

Cyclin D1 Pro241Pro (CCND1-G870A) Polymorphism Is Associated with Increased Cancer Risk in Human Populations: A Meta-Analysis

The G870A polymorphism in the CCND1 gene may influence cancer risk. However, data from published studies with individual low statistical power have been controversial. To evaluate whether combined evidence shows an association between this polymorphism and cancer, we considered all available studies in a meta-analysis. Sixty studies were combined representing data for 18,411 cases and 22,209 controls. In our meta-analysis, we investigated overall sample and two ethnic populations (Caucasians and Asians) as well as nine cancer subtypes. Individuals who are homozygous for A allele (AA) were found to be associated with significantly increased cancer risk in overall sample [odds ratio (OR), 1.23; 95% confidence interval (95% CI), 1.13-1.33; P <or= 0.0001], Caucasians (OR, 1.16; 95% CI, 1.07-1.26; P=0.0002), and Asians (OR, 1.26; 95% CI, 1.14-1.39; P <or= 0.001). Among the nine cancer subtypes investigated, modestly significant risk (ORs, 1.08 to 1.51; P=0.02 to 0.04) was detected in breast, colorectal, head and neck, and other cancers. Highly significant and increased risk was found to be associated with genitourinary (OR, 1.51; 95% CI, 1.20-1.89; P=0.0004) and blood-related cancers (OR, 1.62; 95% CI, 1.28-2.05; P <or= 0.0001). Individuals who are heterozygous for AG were found to be at increased risk in overall, ethnic groups, as well as breast and colorectal cancers. Significant dominant effects seem to prevail in the majority of the categories investigated, where some recessive effects were also detected. Overall, the risk effects associated with this polymorphism were small; however, due its common occurrence, it affects a large portion of the human population (AA, 25%; AG, 50%). Although the independent small risk associated with CCND1-A870G polymorphism is not clinically useful, its interaction with other genetic variants and environmental factors has been shown to be associated with further increase in cancer risk (OR, 1.6-7.1). In conclusion, our study strongly supports the increased cancer risk associated with CCND1-A870G polymorphism in the human population.

Saccharomyces cerevisiae ATM orthologue suppresses break-induced chromosome translocations

Chromosome translocations are frequently associated with many types of blood-related cancers and childhood sarcomas. Detection of chromosome translocations assists in diagnosis, treatment and prognosis of these diseases; however, despite their importance to such diseases, the molecular mechanisms leading to chromosome translocations are not well understood. The available evidence indicates a role for non-homologous end joining (NHEJ) of DNA double-strand breaks (DSBs) in their origin. Here we develop a yeast-based system that induces a reciprocal chromosome translocation by formation and ligation of breaks on two different chromosomes. We show that interchromosomal end joining is efficiently suppressed by the Tel1- and Mre11-Rad50-Xrs2-dependent pathway; this is distinct from the role of Tel1 in telomeric integrity and from Mec1- and Tel1-dependent checkpoint controls. Suppression of DSB-induced chromosome translocations depends on the kinase activity of Tel1 and Dun1, and the damage-induced phosphorylation of Sae2 and histone H2AX proteins. Tel1- and Sae2-dependent tethering and promotion of 5' to 3' degradation of broken chromosome ends discourage error-prone NHEJ and interchromosomal NHEJ, preserving chromosome integrity on DNA damage. Our results indicate that, like human ATM, Tel1 serves as a key regulator for chromosome integrity in the pathway that reduces the risk for DSB-induced chromosome translocations, and are probably pertinent to the oncogenic chromosome translocations in ATM-deficient cells.

Cancer incidence among pesticide applicators exposed to captan in the Agricultural Health Study

Captan is a widely used antifungal pesticide whose potential to cause cancer in humans is uncertain. We evaluated the incidence of cancer among pesticide applicators exposed to captan in the Agricultural Health Study. Detailed information on pesticide exposure and lifestyle factors was obtained from self-administered enrollment questionnaires completed between 1993 and 1997. Of the 48,986 applicators enrolled 4,383 (9%) had applied captan. Median follow-up time was 9.14 years. Poisson regression analysis was used to estimate relative risks (RR) for cancer subtypes by tertiles of captan exposure. We investigated risk for all cancers combined and sites of cancer for which at least 15 cases occurred among captan-exposed applicators. These sites included cancers of the prostate, lung, and colon, blood-related cancers, and colorectal cancers. During follow-up 2,912 incident primary cases of cancer were identified. No association between the highest tertile of captan exposure (>67.375 intensity-weighted days) and development of all cancers (RR = 0.89; 95% CI, 0.71-1.13) or cancer of any specific site was observed. Although our study is limited by low numbers of observed cancer cases and follow-up time of 9.14 years, it does not provide evidence of an increased risk for the development of cancer at the investigated sites.

Broken genes in solid tumours

Mutations that cause portions of two genes to fuse together and form a hybrid gene are frequent in blood-related cancers. New findings implicate one such fusion gene in the most common type of lung cancer.