RSS PAP

Risk and Protective Factors for the Occurrence of Sporadic Pancreatic Endocrine Neoplasms

2017-05-31T15:42:18-07:00

Pancreatic neuroendocrine neoplasms (PNENs) represent 10% of all pancreatic tumors by prevalence. Their incidence has reportedly increased over recent decades in parallel with that of pancreatic adenocarcinoma. PNENs are relatively rare and of the few institutions that have published potential risk factors, findings have been heterogenous.

AIM: To investigate the association between potential risk and protective factors for the occurrence of sporadic PNENs across a European population from several institutions. METHODS: A multinational European case-control study was conducted to examine the association of selected environmental, family and medical exposure factors using a standardized questionnaire in face-to-face interviews. A ratio of 1:3 cases to controls were sex and age matched at each study site. Adjusted univariate and multivariate logistic regression analysis were performed for statistically significant factors. RESULTS: In 201 cases and 603 controls non-recent onset diabetes (OR 2.09, CI 1.27-3.46) was associated with an increased occurrence of PNENs. The prevalence of non-recent onset diabetes was higher both in cases with metastatic disease (TNM stage III-IV) or advanced grade (G3) at the time of diagnosis. The use of metformin in combination with insulin was also associated with a more aggressive phenotype. Drinking coffee was more frequent in cases with localized disease at diagnosis. CONCLUSIONS: Non-recent onset diabetes was associated with an increased occurrence of PNENs and the combination of metformin and insulin was consistent with a more aggressive PNEN phenotype. In contrast to previous studies, smoking, alcohol and first-degree family history of cancer were not associated with PNEN occurrence.

SDHB mutation carriers with malignant pheochromocytoma respond better to CVD

2017-05-31T15:42:18-07:00

Pheochromocytomas and paragangliomas (PCC/PGL) are tumors in the adrenal medulla and extra adrenal sites, respectively. About a quarter are metastatic, often with a long latency period. Some PCC/PGL are defined as clinically aggressive given extensive local invasion into adjacent normal tissue. These tumors, like metastatic PCC/PGL, cannot be surgically cured and patients can have continued secretion of excessive catecholamines with all related sequelae. For patients with metastatic or aggressive tumors, treatment options are limited. External beam radiation can provide local control (Fishbein et al., 2012; Vogel et al., 2014). Systemic therapy includes radionucleotide treatment with 131I-MIBG or chemotherapy with cyclophosphamide, vincristine and dacarbazine (CVD), both of which have a limited progression-free survival (PFS) and complete or partial regression rates based on meta-analyses (Niemeijer et al., 2014; van Hulsteijn et al., 2014). Because 131I-MIBG is not uniformly available, CVD is the mainstay of systemic treatment, although predictors of response remain limited. Our objective was to describe the clinical characteristics of a cohort of patients with malignant PCC/PGL and to determine CVD-specific PFS in order to make recommendations regarding clinical management.

Rationale for the development of alternative forms of androgen deprivation therapy

Kumari, S., Senapati, D., Heemers, H. — 2017-05-31T15:42:18-07:00

With few exceptions, the almost 30,000 prostate cancer deaths annually in the United States are due to failure of androgen deprivation therapy. Androgen deprivation therapy prevents ligand-activation of the androgen receptor. Despite initial remission after androgen deprivation therapy, prostate cancer almost invariably progresses while continuing to rely on androgen receptor action. Androgen receptor's transcriptional output, which ultimately controls prostate cancer behavior, is an alternative therapeutic target, but its molecular regulation is poorly understood. Recent insights in the molecular mechanisms by which the androgen receptor controls transcription of its target genes are uncovering gene-specificity as well as context-dependency. Heterogeneity in the androgen receptor's transcriptional output is reflected both in its recruitment to diverse cognate DNA binding motifs and in its preferential interaction with associated pioneering factors, other secondary transcription factors and coregulators at those sites. This variability suggests that multiple, distinct modes of androgen receptor action that regulate diverse aspects of prostate cancer biology and contribute differentially to prostate cancer's clinical progression are active simultaneously in prostate cancer cells. Recent progress in the development of peptidomimetics and small molecules, and application of Chem-Seq approaches indicate the feasibility for selective disruption of critical protein-protein and protein-DNA interactions in transcriptional complexes. Here, we review the recent literature on the different molecular mechanisms by which the androgen receptor transcriptionally controls prostate cancer progression, and we explore the potential to translate these insights into novel, more selective forms of therapies that may bypass prostate cancer's resistance to conventional androgen deprivation therapy.

Loss-of-function mutations in the CABLES1 gene are a novel cause of Cushing's disease

2017-05-22T03:56:44-07:00

The CABLES1 cell cycle regulator participates in the adrenal-pituitary negative feedback, and its expression is reduced in corticotropinomas, pituitary tumors with a largely unexplained genetic basis. We investigated the presence of CABLES1 mutations/copy number variations (CNVs) and their associated clinical, histopathological and molecular features in patients with Cushing's disease (CD). Samples from 146 pediatric (118 germline DNA only/28 germline and tumor DNA) and 35 adult (tumor DNA) CD patients were screened for CABLES1 mutations. CNVs were assessed in 145 pediatric CD patients (87 germline DNA only/29 germline and tumor DNA). Four potentially pathogenic missense variants in CABLES1 were identified, two in young adults (c.532G>A, p.E178K and c.718C>T, p.L240F) and two in children (c.935G>A, p.G312D and c.1388A>G, and p.D463G) with CD; no CNVs were found. The four variants affected residues within or close to the predicted cyclin-dependent kinase-3 (CDK3)-binding region of the CABLES1 protein, and impaired its ability to block cell growth in a mouse corticotropinoma cell line (AtT20/D16v-F2). The four patients had macroadenomas. We provide evidence for a role of CABLES1 as a novel pituitary tumor-predisposing gene. Its function might link two of the main molecular mechanisms altered in corticotropinomas: the cyclin-dependent kinase/cyclin group of cell cycle regulators and the epidermal growth factor receptor signaling pathway. Further studies are needed to assess the prevalence of CABLES1 mutations among patients with other types of pituitary adenomas, and to elucidate the pituitary-specific functions of this gene.

Centrosome amplification: a suspect in breast cancer and racial disparities

Ogden, A., Rida, P. C. G., Aneja, R. — 2017-05-17T08:04:03-07:00

The multifaceted involvement of centrosome amplification (CA) in tumorigenesis is coming into focus following years of meticulous experimentation, which have elucidated the powerful abilities of CA to promote cellular invasion, disrupt stem cell division, drive chromosomal instability (CIN), and perturb tissue architecture, activities that can accelerate tumor progression. Integration of the extant in vitro, in vivo, and clinical data suggests that in some tissues CA may be a tumor-initiating event, in others a consequential "hit" in multistep tumorigenesis, and in still others non-tumorigenic. However, in vivo data are limited, do not specifically include breast models, and primarily focus on PLK4 (which has CA-independent mechanisms by which it promotes aggressive cellular phenotypes). In vitro breast cancer models suggest that CA can promote tumorigenesis in breast cancer cells in the setting of p53 loss or mutation, which can both trigger CA and promote cellular tolerance to its tendency to slow proliferation and induce aneuploidy. It is thus our perspective that CA is likely an early hit in multistep breast tumorigenesis that may sometimes be lost to preserve aggressive karyotypes acquired through centrosome clustering-mediated CIN, both numerical and structural. We also envision that the robust link between p53 and CA may underlie, to a considerable degree, racial health disparity in breast cancer outcomes. This question is clinically significant because, if it is true, then analysis of centrosomal profiles and administration of centrosome declustering drugs could prove highly efficacious in risk stratifying breast cancers and treating African American (AA) women with breast cancer.

KIF1B and NF1 are the most frequently mutated genes in paraganglioma tumors

2017-05-17T08:04:03-07:00

Dear Editor,

Pheochromocytomas and paragangliomas (PPGL) are rare neuroendocrine tumors arising from the adrenal medulla and extra-adrenal paraganglia, respectively. Forty percent are explained by germline mutations in known susceptibility genes. Furthermore, somatic mutations were identified in an additional 30% of PPGL, mostly in NF1, RET, VHL, MAX, and HRAS. However, screening is limited to a few studies mainly using Sanger sequencing (Burnichon, et al. 2012; Burnichon, et al. 2011; Crona, et al. 2013; Luchetti, et al. 2015; Stenman, et al. 2016; Weber, et al. 2012; Welander, et al. 2012). Our aim was to look for the prevalence and nature of somatic mutations using a targeted deep-sequencing approach in patients from a Belgian multicentric PPGL cohort. Targeted Next Generation Sequencing was performed in 74 tumors using a panel including 17 susceptibility genes. Variants considered as damaging by at least 5 prediction programs, or present in COSMIC and considered as damaging by at least 3 prediction programs, were considered to be disease-associated mutations. Somatic mutations were identified in 54% of patients. The most frequently mutated genes were NF1 (20.8%) and KIF1B (20.4%). While the high prevalence of somatic mutations in NF1 is in agreement with previous studies, the similarly elevated prevalence of mutations in KIF1B is novel.

SDHA mutated paragangliomas may be at high risk of metastasis

2017-05-12T07:05:53-07:00

We report the clinical outcomes of eleven patients with succinate dehydrogenase subunit A (SDHA) germline mutations from three UK tertiary referral centres to highlight a more diverse and expanding clinical spectrum of associated phenotypes. We suggest that SDHA paraganglioma related disease is not a low risk condition as first described. Of our six index cases, two developed metastatic disease and a further one had local vascular invasion. One patient developed multiple metachronous disease. Therefore, we believe these patients, like those with SDHB & SDHD mutations, should be part of a surveillance programme.

Gestational high-fat diet and bisphenol A exposure heightens mammary cancer risk

2017-05-09T06:20:47-07:00

In utero exposure to bisphenol A (BPA) increases mammary cancer susceptibility in offspring. High fat diet is widely believed to be a risk factor of breast cancer. The objective of this study was to determine whether maternal exposure to BPA in addition to high-butterfat (HBF) intake during pregnancy further impacts carcinogen-induced mammary cancer risk in offspring, and its dose-response curve. In this study, we found that gestational HBF intake in addition to a low-dose BPA (25 µg/kg BW/day) exposure increased mammary tumor incidence in a 50-day-of-age chemical carcinogen administration model and altered mammary gland morphology in offspring in a non-monotonic manner, while shortening tumor-free survival time compared with the HBF-alone group. In utero HBF and BPA exposure elicited differential effects at the gene level in PND21 mammary glands through DNA methylation, compared with HBF intake in the absence of BPA. Top HBF+BPA-dysregulated genes (ALDH1B1, ASTL, CA7, CPLX4, KCNV2, MAGEE2, and TUBA3E) are associated with poor overall survival in The Cancer Genomic Atlas (TCGA) human breast cancer cohort (n=1,082). Furthermore, the prognostic power of the identified genes was further enhanced in the survival analysis of Caucasian patients with estrogen receptor-positive tumors. In conclusion, concurrent HBF dietary and a low-dose BPA exposure during pregnancy increases mammary tumor incidence in offspring, accompanied by alterations in mammary gland development and gene expression, and possibly through epigenetic reprogramming.

Effect of hormone secretory syndromes on neuroendocrine tumor prognosis

2017-05-08T09:07:36-07:00

The treatment of hormone hypersecretory syndromes caused by neuroendocrine tumors (NETs) can be a major challenge. NETs originating from the small intestine often secrete serotonin causing flushing, diarrhea and valve fibrosis, leading to dehydration or heart failure in severe cases. NETs from the pancreas can secrete a wider variety of hormones, like insulin, glucagon and gastrin leading to distinct clinical syndromes. Historically mortality in patients with functioning NETs was high due to the complications caused by the hypersecretion of hormones. This has been reduced with several drugs: proton-pump inhibitors decrease acid secretion caused by gastrinomas. Somatostatin analogs can inhibit the secretion of multiple hormones and these are now the cornerstone for treating patients with a gastroenteropancreatic NET. However, peptide receptor radionuclide therapy (PRRT) with radiolabeled somatostatin analogues and everolimus can also decrease symptoms of hypersecretion and increase progression-free survival. Several factors affect the survival in patients with a functioning NET. Complications of hypersecretion negatively impact survival, however secretion of hormones is also often a sign of a well-differentiated NET and due to the symptoms, functioning NETs can be detected in an earlier stage suggesting a positive effect on prognosis. The effect on survival is also dependent of the type of hormone being secreted. This review aims to study the effect of hormone secretion on the prognosis of NETs with the contemporary treatments options available today.

Obesity and menopause modify the epigenomic profile of breast cancer

2017-04-25T10:14:48-07:00

Obesity is a high risk factor for breast cancer. This relationship could be marked by a specific methylome. The current work was aimed to explore the impact of obesity and menopausal status on variation in breast cancer methylomes. Data from Infinium 450K array-based methylomes of 64 breast tumor were coupled with information on BMI and menopausal status. Additionally, DNA methylation results were validated in 18 non-tumor and 81 tumor breast samples. Breast tumors arising in either pre- or postmenopausal women stratified by BMI or menopausal status alone were not associated with a specific DNA methylation pattern. Intriguingly, the DNA methylation pattern identified in association with the high-risk group (postmenopausal women with high BMI (>25) and premenopausal women with normal or low BMI<25) exclusively characterized by hypermethylation of 1,287 CpG sites as compared with the low risk group. These CpG sites included the promoter region of fourteen protein-coding genes of which CpG methylation over the ZNF577 promoter region represents the top scoring associated event. In an independent cohort, the ZNF577 promoter methylation remained statistically significant in association with the high-risk group. Additionally, the impact of ZNF577 promoter methylation on mRNA expression levels was demonstrated in breast cancer cell lines after treatment with a demethylating agent (5-azacytidine). In conclusion, the epigenome of breast tumors is affected by a complex interaction between BMI and menopausal status. The ZNF577 methylation quantification is clearly relevant for the development of novel biomarkers of precision therapy in breast cancer.

Impact of 27-hydroxylase (CYP27A1) and 27-hydroxycholesterol in breast cancer

2017-04-25T10:14:48-07:00

The impact of systemic 27-hydroxycholesterol (27HC) and intra-tumoral CYP27A1 expression on pathobiology and clinical response to statins in breast cancer needs clarification. 27HC is an oxysterol produced from cholesterol by the monooxygenase CYP27A1, which regulates intracellular cholesterol homeostasis. 27HC also acts as an endogenous selective estrogen receptor (ER) modulator capable of increasing breast cancer growth and metastasis. 27HC levels can be modulated by statins or direct inhibition of CYP27A1, thereby attenuating its pro-tumorigenic activities. Herein, the effect of statins on serum 27HC and tumor-specific CYP27A1 expression was evaluated in 42 breast cancer patients treated with atorvastatin within a phase II clinical trial. Further, the associations between CYP27A1 expression with other primary tumor pathological features and clinical outcomes were studied in two additional independent cohorts. Statin treatment effectively decreased serum 27HC and deregulated CYP27A1 expression in tumors. However, these changes were not associated with anti-proliferative responses to statin treatment. CYP27A1 was heterogeneously expressed among primary tumors, with high expression significantly associated with high tumor grade, ER negativity and basal-like subtype. High CYP27A1 expression was independently prognostic for longer recurrence-free and overall survival. Importantly, the beneficial effect of high CYP27A1 in ER positive breast cancer seemed limited to women ≤50 years. These results establish a link between CYP27A1 and breast cancer pathobiology and prognosis and propose that the efficacy of statins in reducing serum lipids does not directly translate to anti-proliferative effects in tumors. Changes in other undetermined serum or tumor factors suggestively mediate the anti-proliferative effects of statins in breast cancer.

Incidence and prevalence of multiple endocrine neoplasia 2B in Denmark:a nationwide study

2017-04-24T08:14:00-07:00

Extract: Multiple endocrine neoplasia 2B (MEN2B) is an autosomal dominant inherited cancer syndrome associating medullary thyroid carcinoma (MTC), pheochromocytoma (PHEO), ganglioneuromatosis of the aerodigestive tract and facial, ophthalmologic and skeletal abnormalities. MEN2B is caused by the M918T and A883F mutation of the REarranged during Transfection (RET) proto-oncogene in approximately 95% and <5% of cases, respectively. Only very few other mutations have been reported to cause MEN2B. In approximately 75% of MEN2B patients, mutations occur as de novo (Wells, et al. 2015) ...

Cell death response to anti-mitotic drug treatment in cell culture, mouse tumor model and the clinic

Shi, J., Mitchison, T. J. — 2017-03-01T07:10:42-08:00

Anti-mitotic cancer drugs include classic microtubule-targeting drugs, such as taxanes and vinca alkaloids, and the newer spindle-targeting drugs, such as inhibitors of the motor protein, Kinesin-5 (aka KSP, Eg5, KIF11), and Aurora-A, Aurora-B and Polo-like kinases. Microtubule-targeting drugs are among the first line of chemotherapies for a wide spectrum of cancers, but patient responses vary greatly. We still lack understanding of how these drugs achieve a favorable therapeutic index, and why individual patient responses vary. Spindle-targeting drugs have so far shown disappointing results in the clinic, but it is possible that certain patients could benefit if we understand their mechanism of action better. Pre-clinical data from both cell culture and mouse tumor models showed that the cell death response is the most variable point of the drug action. Hence, in this review we focus on current mechanistic understanding of the cell death response to anti-mitotics. We first draw on extensive results from cell culture studies, and then cross-examine them with the more limited data from animal tumor models and the clinic. We end by discussing how cell-type variation in cell death response might be harnessed to improve anti-mitotic chemotherapy by better patient stratification, new drug combinations and identification of novel targets for drug development.