ACCS

Gene Summary

Gene:ACCS; 1-aminocyclopropane-1-carboxylate synthase homolog (inactive)
Aliases: ACS, PHACS
Location:11p11.2
Summary:-
Databases:VEGA, OMIM, HGNC, Ensembl, GeneCard, Gene
Protein:1-aminocyclopropane-1-carboxylate synthase-like protein 1
Source:NCBIAccessed: 09 March, 2017

Ontology:

What does this gene/protein do?
Show (4)

Cancer Overview

Research Indicators

Publications Per Year (1992-2017)
Graph generated 10 March 2017 using data from PubMed using criteria.

Literature Analysis

Mouse over the terms for more detail; many indicate links which you can click for dedicated pages about the topic.

  • DNA Methylation
  • Genetic Predisposition
  • Immunohistochemistry
  • Adolescents
  • TP53
  • Pancreatic Cancer
  • DNA Copy Number Variations
  • Carcinoma, Acinar Cell
  • p53 Protein
  • Signal Transduction
  • Angiogenesis
  • Messenger RNA
  • Toll-Like Receptor 4
  • Adrenocortical Adenoma
  • MicroRNAs
  • Cohort Studies
  • Genes, myb
  • Proto-Oncogene Proteins c-kit
  • RT-PCR
  • Biomarkers, Tumor
  • Chromosome 11
  • Adrenal Cortex
  • Adenoma
  • FISH
  • Adrenocortical Cancer
  • Adenoid Cystic Carcinoma
  • Staging
  • Gene Expression Profiling
  • Adrenocortical Carcinoma
  • Cancer Gene Expression Regulation
  • Translocation
  • Oncogene Fusion Proteins
  • Salivary Glands
  • DNA Mutational Analysis
  • Childhood Cancer
  • Sequence Deletion
  • Oligonucleotide Array Sequence Analysis
  • Up-Regulation
  • Loss of Heterozygosity
  • Cancer DNA
  • Mutation
Tag cloud generated 09 March, 2017 using data from PubMed, MeSH and CancerIndex

Specific Cancers (4)

Data table showing topics related to specific cancers and associated disorders. Scope includes mutations and abnormal protein expression.

Note: list is not exhaustive. Number of papers are based on searches of PubMed (click on topic title for arbitrary criteria used).

Latest Publications: ACCS (cancer-related)

Nishimura R, Okamoto N, Satou M, et al.
Bright-field HER2 dual in situ hybridization (DISH) assay on breast cancer cell blocks: a comparative study with histological sections.
Breast Cancer. 2016; 23(6):917-921 [PubMed] Free Access to Full Article Related Publications
BACKGROUND: HER2 testing for samples from recurrent or metastatic disease is recommended by the 2013 update of the American Society of Clinical Oncology/College of American Pathologists (ASCO/CAP) guidelines and cytological analysis can be applied to several types of metastatic lesions. However, the practical method to assess the HER2 testing of breast cancer cytology specimens has yet to be resolved. Therefore, we conducted the bright-field HER2 dual in situ hybridization (DISH) assay on cell blocks (CBs) prepared from breast cancer cell samples as a validation study before clinical use.
METHODS: CBs were prepared from tumor cell samples collected from 54 surgically excised breast tumors. The cells were fixed in 10 % buffered formalin for 16-28 h, and embedded in paraffin. The INFORM HER2/neu Dual ISH DNA Probe Cocktail was used for the DISH assay on the Ventana BenchMark ULTRA (Roche Diagnostics).
RESULTS: Successful results were obtained in 51 of 54 CB specimens, and the results from the CB specimens were in agreement with those from the histological sections in 48 of the 51 cases (concordance rate, 94 %; kappa, 0.846). The intraclass correlation coefficient (ICC) between the CB and histological specimens in the continuous HER2/CEP17 signal count ratio was 0.89 (95 % CI 0.81-0.93), and the Pearson's CC was 0.91 (95 % CI 0.85-0.94).
CONCLUSION: The HER2 DISH assay, utilizing 10 % buffered formalin-fixed CB, would be a reliable and ideal method to assess the HER2 gene status of breast cancer cytological specimens.

Moon A, Cohen C, Siddiqui MT
MYB expression: Potential role in separating adenoid cystic carcinoma (ACC) from pleomorphic adenoma (PA).
Diagn Cytopathol. 2016; 44(10):799-804 [PubMed] Related Publications
BACKGROUND: Basaloid tumors of the salivary gland both benign and malignant comprise ACC, cellular PA, basal cell adenoma (BCA), and basal cell adenocarcinoma. Rendering a diagnosis given a limited biopsy or fine needle aspiration (FNA) sample proves challenging. Activation of MYB by gene fusion has been found in salivary gland ACCs; therefore we investigated the utility of MYB immunohistochemistry (IHC) as a tool for distinguishing ACCs from other basaloid neoplasms.
METHODS: We selected 48 cases of ACC (11 FNA blocks [CB]), 37 histologic resections [HR]), 74 PA (36 CB, 38 HR), and 18 BCA (7 CB, 11 HR). FNA CB showed 82% of ACCs (N = 9 of 11) as positive for MYB nuclear staining whereas 68% of ACCs (N = 25 of 37) were positive in HR.
RESULTS: All PA were negative for MYB nuclear staining in both CB (N = 0 of 36) and HR (N = 0 of 38). CB showed 29% of BCA (N = 2 of 7) as positive for MYB nuclear staining and 55% (N = 6 of 11) positive in HR. Both ACC and BCA showed significantly higher mean staining intensity than PA in both CB and HR (P < 0.0001). When comparing ACC and BCA, significantly higher mean staining intensity was observed in CB (P = 0.02382) but not in HR (P = 0.42952).
CONCLUSION: MYB nuclear staining may prove useful in separating ACC from PA and BCA, especially in limited cellular samples. Diagn. Cytopathol. 2016;44:799-804. © 2016 Wiley Periodicals, Inc.

Rubin B, Regazzo D, Redaelli M, et al.
Investigation of N-cadherin/β-catenin expression in adrenocortical tumors.
Tumour Biol. 2016; 37(10):13545-13555 [PubMed] Related Publications
β-catenin is a multifunctional protein; it is a key component of the Wnt signaling, and it plays a central role in cadherin-based adhesions. Cadherin loss promotes tumorigenesis by releasing membrane-bound β-catenin, hence stimulating Wnt signaling. Cadherins seem to be involved in tumor development, but these findings are limited in adrenocortical tumors (ACTs). The objective of this study was to evaluate alterations in key components of cadherin/catenin adhesion system and of Wnt pathway. This study included eight normal adrenal samples (NA) and 95 ACT: 24 adrenocortical carcinomas (ACCs) and 71 adrenocortical adenomas (ACAs). β-catenin mutations were evaluated by sequencing, and β-catenin and cadherin (E-cadherin and N-cadherin) expression was analyzed by quantitative reverse transcription PCR (qRT-PCR) and by immunohistochemistry (IHC). We identified 18 genetic alterations in β-catenin gene. qRT-PCR showed overexpression of β-catenin in 50 % of ACC (12/24) and in 48 % of ACA (21/44). IHC data were in accordance with qRT-PCR results: 47 % of ACC (7/15) and 33 % of ACA (11/33) showed increased cytoplasmic or nuclear β-catenin accumulation. N-cadherin downregulation has been found in 83 % of ACC (20/24) and in 59 % of ACA (26/44). Similar results were obtained by IHC: N-cadherin downregulation was observed in 100 % (15/15) of ACC and in 55 % (18/33) of ACA. β-catenin overexpression together with the aberrant expression of N-cadherin may play important role in ACT tumorigenesis. The study of differentially expressed genes (such as N-cadherin and β-catenin) may enhance our understanding of the biology of ACT and may contribute to the discovery of new diagnostic and prognostic tools.

Byun JM, Kim YJ, Yoon HJ, et al.
Cytogenetic profiles of 2806 patients with acute myeloid leukemia-a retrospective multicenter nationwide study.
Ann Hematol. 2016; 95(8):1223-32 [PubMed] Related Publications
The cytogenetic and molecular data is recognized as the most valuable prognostic factor in acute myeloid leukemia (AML). Our aim was to systemically analyze the cytogenetics of Korean AML patients and to compare the cytogenetic profiles of various races to identify possible geographic heterogeneity. We retrospectively reviewed medical records of 2806 AML patients diagnosed at 11 tertiary teaching hospitals in Korea between January 2007 and December 2011. The most common recurrent chromosomal abnormality was t(8;21) (8.8 %, 238/2717), but t(15;17) showed an almost same number (8.6 %,235/2717). Among de novo AML, the most frequent aberrations were t(15;17), observed in 229 (10.7 %). The most common French-American-British (FAB) classification type was M2 (32.2 %), and recurrent cytogenetic abnormalities correlated with the FAB subtypes. Among 283 secondary AML cases, myelodysplastic syndrome was the most common predisposing factor. About 67.1 % of the secondary AML cases were associated with chromosomal aberrations, and chromosome 7 abnormalities (n = 45, 15.9 %) were most common. The incidence of FLT3 internal tandem duplication mutation was relatively low at 15 %. Our study reports certain similarities and differences in comparison to previous reports. Such discrepancies call for extensive epidemiological studies to clarify the role of genetic as well as geographic heterogeneity in the pathogenesis of AML.

Mancuso G, Bovio E, Rena O, et al.
Prognostic impact of a 3-MicroRNA signature in cytological samples of small cell lung cancer.
Cancer Cytopathol. 2016; 124(9):621-9 [PubMed] Related Publications
BACKGROUND: Small cell lung cancer (SCLC) is a highly aggressive neoplasm that accounts for approximately 10% to 15% of lung cancers. In most cases, the diagnosis relies on cytology and needs to be confirmed by immunohistochemistry. Although several genetic and molecular abnormalities have been recorded, molecular markers able to predict the prognosis are still lacking. MicroRNA (miRNA) signatures have been recently proposed as useful biomarkers in lung cancer because of their high stability during standard sample processing.
METHODS: Cytological samples for 50 patients with SCLC were collected from primary tumors (n = 25) and metastases (n = 25) by means of fine-needle aspiration (FNA) or bronchial washing (BW); they were fixed in ethanol (FNA) or Duboscq-Brazil fluid (BW). The 3-miRNA panel expression (miR-192, miR-200c, and miR-205) was quantified with a TaqMan polymerase chain reaction miRNA assay and was compared with overall survival (OS) and clinicopathological data.
RESULTS: All samples had sufficient RNA for the miRNA expression analysis to be performed, regardless of the sample source or the fixative medium. Patients with a low expression level of the 3-miRNA panel were associated with better OS in univariate (P = .032) and multivariate analyses (P = .022). Moreover, in the group of patients older than the mean age of our cohort (65.8 years), a significant OS advantage (P = .013) was seen for patients with a low expression level of the 3-miRNA panel.
CONCLUSIONS: A specific 3-miRNA signature is potentially useful for predicting survival for patients with SCLC, and it may be feasible with cytological samples taken during standard diagnostic procedures. Cancer Cytopathol 2016;124:621-9. © 2016 American Cancer Society.

Al Hamal Z, Jordan M, Hachem RY, et al.
Mycobacterium arupense in Cancer Patients: An Emerging Infection or a Commensal Organism.
Medicine (Baltimore). 2016; 95(14):e2691 [PubMed] Free Access to Full Article Related Publications
Mycobacterium arupense is a slow-growing, nonchromogenic, acid-fast bacillus. Its clinical spectrum, epidemiology, and frequency of colonization versus true infection remain unknown. We evaluated the clinical significance of M arupense and positive cultures from cancer patients.We retrospectively reviewed records of all cancer patients treated at our institution between 2007 and 2014 to identify those who had positive cultures for M arupense. Mycobacterium arupense was identified by sequencing the 16S rRNA and hsp65 genes. A total of 53 patients had positive cultures, 100% of which were isolated from respiratory specimens. Of these, 7 patients met the American Thoracic Society/Infectious Diseases Society of America criteria for a definitive diagnosis of M arupense infection, 14 cases were considered to be probable infections, and 29 cases were considered to be possible infections. Of the included patients, 13 received therapy for M arupense infection and 40 did not.The outcomes of treated and untreated patients did not differ significantly. No relapses of M arupense infection. In addition, there were no M arupense-related deaths in either group.In cancer patients, M arupense appears to be mostly a commensal organism rather than a pathogen. Patients who did or did not receive treatment had similar outcomes. Validation of these findings in a larger prospective trial is warranted.

Ordóñez-Mena JM, Schöttker B, Mons U, et al.
Quantification of the smoking-associated cancer risk with rate advancement periods: meta-analysis of individual participant data from cohorts of the CHANCES consortium.
BMC Med. 2016; 14:62 [PubMed] Free Access to Full Article Related Publications
BACKGROUND: Smoking is the most important individual risk factor for many cancer sites but its association with breast and prostate cancer is not entirely clear. Rate advancement periods (RAPs) may enhance communication of smoking related risk to the general population. Thus, we estimated RAPs for the association of smoking exposure (smoking status, time since smoking cessation, smoking intensity, and duration) with total and site-specific (lung, breast, colorectal, prostate, gastric, head and neck, and pancreatic) cancer incidence and mortality.
METHODS: This is a meta-analysis of 19 population-based prospective cohort studies with individual participant data for 897,021 European and American adults. For each cohort we calculated hazard ratios (HRs) for the association of smoking exposure with cancer outcomes using Cox regression adjusted for a common set of the most important potential confounding variables. RAPs (in years) were calculated as the ratio of the logarithms of the HRs for a given smoking exposure variable and age. Meta-analyses were employed to summarize cohort-specific HRs and RAPs.
RESULTS: Overall, 140,205 subjects had a first incident cancer, and 53,164 died from cancer, during an average follow-up of 12 years. Current smoking advanced the overall risk of developing and dying from cancer by eight and ten years, respectively, compared with never smokers. The greatest advancements in cancer risk and mortality were seen for lung cancer and the least for breast cancer. Smoking cessation was statistically significantly associated with delays in the risk of cancer development and mortality compared with continued smoking.
CONCLUSIONS: This investigation shows that smoking, even among older adults, considerably advances, and cessation delays, the risk of developing and dying from cancer. These findings may be helpful in more effectively communicating the harmful effects of smoking and the beneficial effect of smoking cessation.

Wang M, Aldubayan S, Connor AA, et al.
Genetic testing for Lynch syndrome in the province of Ontario.
Cancer. 2016; 122(11):1672-9 [PubMed] Related Publications
BACKGROUND: In November 2001, genetic testing for Lynch syndrome (LS) was introduced by the Ministry of Health and Long-Term Care (MOH) in Ontario for individuals at high risk for LS cancers according to either tumor immunohistochemistry staining or their family history. This article describes the outcomes of the program and makes recommendations for improving it and informing other public health care programs.
METHODS: Subjects were referred for molecular testing of the mismatch repair (MMR) genes MutL homolog 1, MutS homolog 2, and MutS homolog 6 if they met 1 of 7 MOH criteria. Testing was conducted from January 2001 to March 2015 at the Molecular Diagnostic Laboratory of Mount Sinai Hospital in Toronto.
RESULTS: A total of 1452 subjects were tested. Of the 662 subjects referred for testing because their tumor was immunodeficient for 1 or more of the MMR genes, 251 (37.9%) carried a germline mutation. In addition, 597 subjects were tested for a known family mutation, and 298 (49.9%) were positive; 189 of these 298 subjects (63.4%) were affected with cancer at the time of testing. An additional 193 subjects were referred because of a family history of LS, and 34 of these (17.6%) had a mutation identified.
CONCLUSIONS: These results indicate that the provincial criteria are useful in identifying LS carriers after an MMR-deficient tumor is identified. Placing greater emphasis on testing unaffected relatives in families with a known mutation may identify more unaffected carriers and facilitate primary prevention in those individuals. Cancer 2016;122:1672-9. © 2016 American Cancer Society.

Wang F, Zhang B, Zhou L, et al.
Imaging Dendrimer-Grafted Graphene Oxide Mediated Anti-miR-21 Delivery With an Activatable Luciferase Reporter.
ACS Appl Mater Interfaces. 2016; 8(14):9014-21 [PubMed] Related Publications
MicroRNAs (miRNAs) are a class of post-transcriptional gene regulators involved in various physiological processes including carcinogenesis, and they have emerged as potential targets for tumor theranostics. However, the employment of antisense oligonucleotides, termed anti-miRs, for antagonizing miRNA functions in vivo has largely been impeded by a lack of effective delivery carriers. Here, we describe the development of polyamidoamine (PAMAM) dendrimer and polyethylene glycol (PEG)-functionalized nanographene oxide (NGO) conjugate (NGO-PEG-dendrimer) for the efficient delivery of anti-miR-21 into non-small-cell lung cancer cells. To monitor the delivery of anti-miR-21 into cells and tumors, we also constructed an activatable luciferase reporter (Fluc-3xPS) containing three perfectly complementary sequences against miR-21 in the 3' untranslated region (UTR) of the reporter. Compared with bare dendrimer and Lipofectamine 2000 (Lipo2000), NGO-PEG-dendrimer showed considerably lower cytotoxicity and higher transfection efficiency. As demonstrated by in vitro bioluminescence imaging and Western blotting assays, NGO-PEG-dendrimer effectively delivered anti-miR-21 into the cytoplasm and resulted in the upregulation of luciferase intensity and PTEN target protein expression in a dose-dependent manner. Moreover, transfection with anti-miR-21 by NGO-PEG-dendrimer led to stronger inhibition of cell migration and invasion than did bare dendrimer or Lipo2000 transfection. The intravenous delivery of anti-miR-21 via NGO-PEG-dendrimer induced a significant increase in the bioluminescence signal within the Fluc-3xPS reporter-transplanted tumor areas. These results suggest that NGO-PEG-dendrimer could be an efficient and a potential nanocarrier for delivering RNA oligonucleotides. In addition, the strategy of combining NGO-PEG-dendrimer with an activatable luciferase reporter allows the image-guided monitoring of the delivery process, which can provide insights into the RNA-based cancer treatments.

Behray M, Webster CA, Pereira S, et al.
Synthesis of Diagnostic Silicon Nanoparticles for Targeted Delivery of Thiourea to Epidermal Growth Factor Receptor-Expressing Cancer Cells.
ACS Appl Mater Interfaces. 2016; 8(14):8908-17 [PubMed] Related Publications
The novel thiourea-functionalized silicon nanoparticles (SiNPs) have been successfully synthesized using allylamine and sulforaphane, an important anticancer drug, followed by a hydrosilylation reaction on the surface of hydrogen terminated SiNPs. Their physiochemical properties have been investigated by photoluminescence emission, Fourier transform infrared spectroscopy (FTIR) and elemental analysis. The MTT [3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide] assay has been employed to evaluate in vitro toxicity in human colorectal adenocarcinoma (Caco-2) cells and human normal colon epithelial (CCD) cells. The results show significant toxicity of thiourea SiNPs after 72 h of incubation in the cancer cell line, and the toxicity is concentration dependent and saturated for concentrations above 100 μg/mL. Confocal microscopy images have demonstrated the internalization of thiourea-functionalized SiNPs inside the cells. Flow cytometry data has confirmed receptor-mediated targeting in cancer cells. This nanocomposite takes advantage of the epidermal growth factor receptor (EGFR) active targeting of the ligand in addition to the photoluminescence properties of SiNPs for bioimaging purposes. The results suggest that this novel nanosystem can be extrapolated for active targeting of the receptors that are overexpressed in cancer cells such as EGFR using the targeting characteristics of thiourea-functionalized SiNPs and therefore encourage further investigation and development of anticancer agents specifically exploiting the EGFR inhibitory activity of such nanoparticles.

Ji M, Li P, Sheng N, et al.
Sialic Acid-Targeted Nanovectors with Phenylboronic Acid-Grafted Polyethylenimine Robustly Enhance siRNA-Based Cancer Therapy.
ACS Appl Mater Interfaces. 2016; 8(15):9565-76 [PubMed] Related Publications
Small interference RNA (siRNA)-based therapy holds great potential for cancer treatment. However, its clinical application remains unsatisfied due to the lack of a safe and effective RNA delivery system. Aberrantly elevated sialyation on cell membrane has been reported as an attractive target for cancer diagnosis and therapy. In this study, phenylboronic acid (PBA) was conjugated onto low molecular weight polyethylenimine (PEI1.8k) to generate amphiphilic PBA-grafted PEI1.8k (PEI-PBA) nanovector, which was designed to facilitate cancer-targeted RNA delivery through the recognition of sialic structures on a cancer cell membrane. PEI-PBA simultaneously encapsulated siRNA to form PEI-PBA/siRNA nanocomplexes with great biocompatibility, serum stability and RNase resistance. The cell culture study showed that PEI-PBA/siRNA dramatically increased siRNA uptake up to 70-90% in several cancer cell lines, which relied on the interaction between PBA and sialic acid on cell membrane. Moreover, the PEI-PBA nanovector effectively promoted the lysosome escape of siRNA, decreasing the expression of target gene Polo-like kinase 1 (PLK-1) in cancer cells. The systemic administration of PEI-PBA/PLK-1 siRNA (PEI-PBA/siPLK1) nanocomplexes not only facilitated tumor-targeted siRNA delivery but also significantly decreased PLK-1 expression in tumors, thereby robustly inducing tumor apoptosis and cell cycle arrest. Additionally, the administration of PEI-PBA/siPLK1 did not cause significant systemic toxicity or immunotoxicity. Hence, sialic acid-targeted PEI-PBA could be a highly efficient and safe nanovector to improve the efficacy of cancer siRNA therapy.

Allison DB, Lilo MT, Geddes S, et al.
Detection of PIK3CA mutations, including a novel mutation of V344G in exon 4, in metastatic lung adenocarcinomas: A retrospective study of 115 FNA cases.
Cancer Cytopathol. 2016; 124(7):485-92 [PubMed] Related Publications
BACKGROUND: Phosphatidylinositol-4,5-bisphosphate 3-kinase catalytic subunit alpha (PIK3CA) mutations and amplification are detected in 1% of primary lung adenocarcinomas (ADCs) and in 38% of primary lung squamous cell carcinomas. Alterations of PIK3CA in metastatic non-small cell lung carcinoma (NSCLC), however, are still not fully understood. This study investigated PIK3CA alterations in metastatic ADCs and correlated the findings with those for other commonly tested molecular abnormalities via fine-needle aspiration (FNA) and small-core biopsy materials.
METHODS: This study identified 115 FNA cases of metastatic lung ADC with standard lung cancer panel analysis by targeted next-generation sequencing and fluorescence in situ hybridization at the Johns Hopkins Medical Institute over a 12-month period. The panel included mutational analysis of PIK3CA, AKT, BRAF, EGFR, ERBB2, KRAS, and NRAS genes and tests of rearrangements for ALK and ROS1 genes.
RESULTS: A PIK3CA mutation was detected in 7 of 115 cases of metastatic ADC (6.1%). The majority of the mutations were located in exon 9 or exon 20; however, a mutation in exon 1 was seen in 1 case. Furthermore, p.V344G in exon 4 was detected in 2 cases. Among cases with PIK3CA mutations, 4 had coexisting EGFR mutations, whereas 2 had a coexisting BRAF or KRAS mutation.
CONCLUSIONS: Several common mutations as well as a novel mutation in the PIK3CA gene were observed in metastatic NSCLC (particularly ADC). The unique role, however, of PIK3CA mutations in metastatic NSCLC and the clinical implications need to be further investigated. Cancer Cytopathol 2016;124:485-92. © 2016 American Cancer Society.

Yuan W, Zhang Z, Dai B, et al.
Whole-exome sequencing of duodenal adenocarcinoma identifies recurrent Wnt/β-catenin signaling pathway mutations.
Cancer. 2016; 122(11):1689-96 [PubMed] Related Publications
BACKGROUND: Genomic alterations of small bowel cancers remain poorly understood due to the rarity of these diseases. In the current study, the authors report the identification of somatic mutations from patients with duodenal adenocarcinoma by whole-exome sequencing.
METHODS: Whole-exome sequencing and follow-up analysis were conducted in 12 matched tumor-normal tissue duodenal adenocarcinoma tissue pairs to examine the genetic characteristics of this disease. Somatic mutations (single-nucleotide variants and short insertion/deletions) were obtained and filtered and then searched for recurrently mutated genes and pathways.
RESULTS: An excess of C-to-T transitions at the CpG dinucleotide was observed in the substitution of bases. The authors identified recurrent mutations in tumor protein p53 (TP53), KRAS, catenin (cadherin-associated protein) β-1 (CTNNB1), AT-rich interactive domain 2 (ARID2), adenomatous polyposis coli (APC), erb-b2 receptor tyrosine kinase 2 (ERBB2), ARID1A, cadherin-related family member 1 (CDHR1), NRAS, Bcl-2-related ovarian killer (BOK), radial spoke head 14 homolog (chlamydomonas) (RTDR1), cell division cycle 27 (CDC27), catalytic subunit of phosphoinositide-3-kinase (PIK3CA), and SMAD family member 4 (SMAD4). Pathway scan indicated that the Wnt signaling pathway, regulation of the actin cytoskeleton pathway, ErbB signaling pathway, and the pathway of focal adhesion were the most extensively affected pathways.
CONCLUSIONS: This genomic characterization of duodenal adenocarcinoma provides researchers with insight into its somatic landscape and highlights the vital role of the Wnt/β-catenin signaling pathway. The study data also indicate that duodenal adenocarcinomas have a genetic resemblance to gastric and colorectal cancers. These discoveries may benefit the future development of molecular diagnosis and personalized therapies. Cancer 2016;122:1689-96. © 2016 American Cancer Society.

Kwon MJ, Kim JW, Jung JP, et al.
Low incidence of KRAS, BRAF, and PIK3CA mutations in adenocarcinomas of the ampulla of Vater and their prognostic value.
Hum Pathol. 2016; 50:90-100 [PubMed] Related Publications
Ampullary adenocarcinomas (A-ACs) are rare malignancies with considerable importance because of their high curable resection rate and improved survival rate among periampullary cancers. The RAS-RAF-MAPK pathway is involved in the development of A-ACs and is a potential therapeutic target. However, molecular profiles of A-ACs and their prognostic impact are poorly understood. Peptide nucleic acid-mediated polymerase chain reaction clamping and Mutyper were used to detect KRAS, BRAF, and PIK3CA mutations in 62 paraffinized samples of A-ACs. Of 62 A-ACs, 30.6% had KRAS mutations, but no BRAF mutations and low frequency (1.6%) of PIK3CA mutation were detected. KRAS mutation was correlated with poor tumor differentiation and was a predictor of shorter recurrence-free survival period in overall A-ACs, whereas the prognosis according to the histologic subtypes was not affected by KRAS mutation. Lymph node metastasis was an independent prognostic factor of poor overall survival. Intestinal- and pancreatobiliary-type A-ACs had similar prognosis. Intestinal- and pancreatobiliary-type A-ACs had different prognostic factors; tumor differentiation and lymph node metastasis strongly predicted overall survival and recurrence-free survival in pancreatobiliary-type tumors, respectively, whereas no independent prognostic factors were demonstrated for intestinal-type tumors. Low incidence of KRAS mutations and their strong prognostic value in A-ACs may suggest the potential of survival benefit depending on the epidermal growth factor receptor-targeted therapy. Much lower frequencies of BRAF and PIK3CA mutations may suggest that they do not play a major role in the tumorigenesis of A-ACs. Different therapeutic protocols should be considered for treating pancreatobiliary- and intestinal-type A-ACs.

Acs B, Szekely N, Szasz AM, et al.
Reliability of immunocytochemistry and fluorescence in situ hybridization on fine-needle aspiration cytology samples of breast cancers: A comparative study.
Diagn Cytopathol. 2016; 44(6):466-71 [PubMed] Related Publications
INTRODUCTION: To characterize breast tumors and metastases, fine-needle aspiration cytology (FNAB) can be a favorable first choice. However, the diagnostic accuracy of ancillary tests applied to FNAB samples is yet to be validated.
PATIENTS AND METHODS: We examined 110 breast cancer patients' paired cytological and surgical resection specimens evaluated between 2005 and 2014. Comparison of ER and Her2 immunocytochemical (ICC) and immunohistochemical (IHC) staining and HER2 fluorescence in situ hybridization (FISH) was performed.
RESULTS: Significant difference (p < 0.001) and moderate correlation (κ = 0.446) were noted between results of 97 paired ICC an IHC reactions for ER expression. ICC for ER status had a sensitivity of 75%, specificity of 100%, positive predictive value (PPV) of 100%, and negative predictive value (NPV) of 38.2%. Significant difference (p = 0.012) and moderate correlation (κ = 0.541) were found between results of 77 paired ICC an IHC reactions for Her2 expression. The Her2 ICC had a sensitivity of 54%, specificity of 95.4%, PPV of 66.7%, and NPV of 92.6%. The results of FISH carried out on 23 paired samples of FNAB and surgical specimens indicated perfect correlation (κ = 1.000) and no significant difference (p = 1.000). FISH performed on FNAB has sensitivity, specificity, PPV, and NPV of 100%.
CONCLUSION: The correlation of ICC and IHC is moderate regarding ER and Her2 expression of the same tumor. FISH performed on FNAB samples is suitable to categorize primary and metastatic breast cancer in regard of HER2 gene amplification status and can be used as a predictive test in respect of therapies targeting HER2. Diagn. Cytopathol. 2016;44:466-471. © 2016 Wiley Periodicals, Inc.

Song YS, Lim JA, Choi H, et al.
Prognostic effects of TERT promoter mutations are enhanced by coexistence with BRAF or RAS mutations and strengthen the risk prediction by the ATA or TNM staging system in differentiated thyroid cancer patients.
Cancer. 2016; 122(9):1370-9 [PubMed] Related Publications
BACKGROUND: Recent reports suggest that mutations in the promoter of the gene encoding telomerase reverse transcriptase (TERT) affect thyroid cancer outcomes.
METHODS: In all, 551 patients with differentiated thyroid cancer (DTC) enrolled in this study. The median follow-up duration was 4.8 years (interquartile range, 3.4-10.6 years).
RESULTS: TERT promoter mutations were detected in 25 DTCs (4.5%): 2.8% in neither BRAF-mutated nor RAS-mutated tumors, 4.8% in BRAF-mutated tumors, and 11.3% in RAS-mutated tumors. Moreover, they were frequently observed in American Thyroid Association (ATA) high-risk and TNM stage III/IV groups (9.1% and 12.9%, respectively). The coexistence of BRAF or RAS with TERT promoter mutations increased aggressive clinicopathologic features, recurrence (hazard ratio [HR] for BRAF, 4.64; 95% confidence interval [CI], 1.42-15.18; HR for RAS, 5.36; 95% CI, 1.20-24.02), and mortality (HR for BRAF, 15.13; 95% CI, 1.55-148.23; HR for RAS, 14.75; 95% CI, 1.30-167.00), even after adjustments for the age at diagnosis and sex, although the significance was lost after additional adjustments for pathologic characteristics. Furthermore, TERT promoter mutations significantly increased the risk of both recurrence and mortality in the ATA high-risk (HR for recurrence, 5.79; 95% CI, 2.07-16.18; HR for mortality, 16.16; 95% CI, 2.10-124.15) and TNM stage III/IV groups (HR for recurrence, 3.60; 95% CI, 1.19-10.85; HR for mortality, 9.06; 95% CI, 2.09-39.26).
CONCLUSIONS: The coexistence of BRAF or RAS mutations enhanced the prognostic effects of TERT promoter mutations. Furthermore, TERT promoter mutations strengthened the predictions of mortality and recurrence by the ATA and TNM staging systems, particularly for high-risk patients with DTC. Cancer 2016;122:1370-1379. © 2016 American Cancer Society.

Bell D, Bell AH, Bondaruk J, et al.
In-depth characterization of the salivary adenoid cystic carcinoma transcriptome with emphasis on dominant cell type.
Cancer. 2016; 122(10):1513-22 [PubMed] Related Publications
BACKGROUND: Adenoid cystic carcinoma (ACC), 1 of the most common salivary gland malignancies, arises from the intercalated ducts, which are composed of inner ductal epithelial cells and outer myoepithelial cells. The objective of this study was to determine the genomic subtypes of ACC with emphasis on dominant cell type to identify potential specific biomarkers for each subtype and to improve the understanding of this disease.
METHODS: A whole-genome expression study was performed based on 42 primary salivary ACCs and 5 normal salivary glands. RNA from these specimens was subjected to expression profiling with RNA sequencing, and results were analyzed to identify transcripts in epithelial-dominant ACC (E-ACC), myoepithelial-dominant ACC (M-ACC), and all ACC that were expressed differentially compared with the transcripts in normal salivary tissue.
RESULTS: In total, the authors identified 430 differentially expressed transcripts that were unique to E-ACC, 392 that were unique to M-ACC, and 424 that were common to both M-ACC and E-ACC. The sets of E-ACC-specific and M-ACC-specific transcripts were sufficiently large to define and differentiate E-ACC from M-ACC. Ingenuity pathway analysis identified known cancer-related genes for 60% of the E-ACC transcripts, 69% of the M-ACC transcripts, and 68% of the transcripts that were common in both E-ACC and M-ACC. Three sets of highly expressed candidate genes-distal-less homeobox 6 (DLX6) for E-ACC; protein keratin 16 (KRT16), SRY box 11 (SOX11), and v-myb avian myeloblastosis viral oncogene homolog (MYB) for M-ACC; and engrailed 1 (EN1) and statherin (STATH), which are common to both E-ACC and M-ACC)-were further validated at the protein level.
CONCLUSIONS: The current results enabled the authors to identify novel potential therapeutic targets and biomarkers in E-ACC and M-ACC individually, with the implication that EN1, DLX6, and OTX1 (orthodenticle homeobox 1) are potential drivers of these cancers. Cancer 2016;122:1513-22. © 2016 American Cancer Society.

Fujisawa Y, Sakaguchi K, Ono H, et al.
Combined steroidogenic characters of fetal adrenal and Leydig cells in childhood adrenocortical carcinoma.
J Steroid Biochem Mol Biol. 2016; 159:86-93 [PubMed] Related Publications
Although childhood adrenocortical carcinomas (c-ACCs) with a TP53 mutation are known to produce androgens, detailed steroidogenic characters have not been clarified. Here, we examined steroid metabolite profiles and expression patterns of steroidogenic genes in a c-ACC removed from the left adrenal position of a 2-year-old Brazilian boy with precocious puberty, using an atrophic left adrenal gland removed at the time of tumorectomy as a control. The c-ACC produced not only abundant dehydroepiandrosterone-sulfate but also a large amount of testosterone via the Δ5 pathway with Δ5-androstenediol rather than Δ4-androstenedione as the primary intermediate metabolite. Furthermore, the c-ACC was associated with elevated expressions of CYP11A1, CYP17A1, POR, HSD17B3, and SULT2A1, a low but similar expression of CYB5A, and reduced expressions of AKR1C3 (HSD17B5) and HSD3B2. Notably, a Leydig cell marker INSL3 was expressed at a low but detectable level in the c-ACC. Furthermore, molecular studies revealed a maternally inherited heterozygous germline TP53 mutation, and several post-zygotic genetic aberrations in the c-ACC including loss of paternally derived chromosome 17 with a wildtype TP53 and loss of maternally inherited chromosome 11 and resultant marked hyperexpression of paternally expressed growth promoting gene IGF2 and drastic hypoexpression of maternally expressed growth suppressing gene CDKN1C. These results imply the presence of combined steroidogenic properties of fetal adrenal and Leydig cells in this patient's c-ACC with a germline TP53 mutation and several postzygotic carcinogenic events.

Yin LX, Ha PK
Genetic alterations in salivary gland cancers.
Cancer. 2016; 122(12):1822-31 [PubMed] Related Publications
Salivary gland cancers are an incredibly heterogeneous group of tumors that include 24 histologically distinct tumor types. The use of new genetic methods has paved the way for promising advancements in our understanding of the molecular biology underlying each type of tumor. The objective of this review was to highlight common oncogenes, tumor suppressor genes, and cytogenetic and epigenetic changes associated with the most common tumor types: mucoepidermoid carcinoma, adenoid cystic carcinoma, salivary duct carcinoma, mammary analogue secretory carcinoma, hyalinizing clear cell carcinoma, carcinoma ex pleomorphic adenoma, and acinic cell carcinoma. Recent insights into the pathogenesis of each cancer subtype have helped better define and classify these tumors. Further research in salivary gland cancers should focus on determining the key genes involved in the tumorigenesis of each distinct malignancy and identifying individualized chemotherapies directed at these targets. Cancer 2016;122:1822-31. © 2016 American Cancer Society.

Vo DD, Tran TP, Staedel C, et al.
Oncogenic MicroRNAs Biogenesis as a Drug Target: Structure-Activity Relationship Studies on New Aminoglycoside Conjugates.
Chemistry. 2016; 22(15):5350-62 [PubMed] Related Publications
MicroRNAs (miRNAs) are a recently discovered category of small RNA molecules that regulate gene expression at the post-transcriptional level. Accumulating evidence indicates that miRNAs are aberrantly expressed in a variety of human cancers and that the inhibition of these oncogenic miRNAs could find application in the therapy of different types of cancer. Herein, we describe the synthesis and biological evaluation of new small-molecule drugs that target oncogenic miRNAs production. In particular, we chose to target two miRNAs (i.e., miRNA-372 and -373) implicated in various types of cancer, such as gastric cancer. Their precursors (pre-miRNAs) are overexpressed in cancer cells and lead to mature miRNAs after cleavage of their stem-loop structure by the enzyme Dicer in the cytoplasm. Some of the newly synthesized conjugates can inhibit Dicer processing of the targeted pre-miRNAs in vitro with increased efficacy relative to our previous results (D.D. Vo et al., ACS Chem. Biol. 2014, 9, 711-721) and, more importantly, to inhibit proliferations of adenocarcinoma gastric cancer (AGS) cells overexpressing these miRNAs, thus representing promising leads for future drug development.

Lim TH, Lim AS, Thike AA, et al.
Implications of the Updated 2013 American Society of Clinical Oncology/College of American Pathologists Guideline Recommendations on Human Epidermal Growth Factor Receptor 2 Gene Testing Using Immunohistochemistry and Fluorescence In Situ Hybridization for Breast Cancer.
Arch Pathol Lab Med. 2016; 140(2):140-7 [PubMed] Related Publications
CONTEXT: Human epidermal growth factor receptor 2 (HER2/neu) amplification is used as a predictive marker for trastuzumab treatment in breast cancer. Both immunohistochemistry (IHC) and fluorescence in situ hybridization (FISH) testing algorithms have been based on the 2007 American Society of Clinical Oncology/College of American Pathologists (ASCO/CAP) guidelines. In late 2013, the guidelines were updated with new scoring criteria.
OBJECTIVE: To assess the impact of the revised ASCO/CAP recommendations on both IHC and FISH results by using the dual-color HER2/neu and centromeric FISH probes.
DESIGN: Retrospective analysis of 590 invasive carcinomas with concurrent IHC and dual-color HER2/neu and centromeric 17 (CEP17) FISH results, based on 2007 ASCO/CAP guidelines, was conducted from July 2011 to June 2013. With the revised guidelines, patients were recategorized and concordance rates between the 2 assays were recalculated.
RESULTS: Overall concordance rates for FISH and IHC decreased from 94.9% to 93.8% with reclassification. Negative FISH cases decreased from 79.1% to 69.3%. However, equivocal FISH cases were significantly increased from 0.7% to 9.5%, leading to more retesting. Both positive IHC and FISH cases were also noted to be increased, leading to more patients being eligible for trastuzumab treatment, especially those patients with concurrent HER2/neu and CEP17 polysomy. Approximately 1% of patients with initial FISH negative results were reclassified as having positive results when both the ratios and average copy number of HER2/neu were considered under the revised guidelines.
CONCLUSIONS: The revised 2013 ASCO/CAP guidelines can potentially lead to more patients being eligible for trastuzumab therapy but additional retesting is to be expected owing to an increased number of equivocal FISH cases.

López JE, Sullivan ED, Fierke CA
Metal-dependent Deacetylases: Cancer and Epigenetic Regulators.
ACS Chem Biol. 2016; 11(3):706-16 [PubMed] Related Publications
Epigenetic regulation is a key factor in cellular homeostasis. Post-translational modifications (PTMs) are a central focus of this regulation as they function as signaling markers within the cell. Lysine acetylation is a dynamic, reversible PTM that has garnered recent attention due to alterations in various types of cancer. Acetylation levels are regulated by two opposing enzyme families: lysine acetyltransferases (KATs) and histone deacetylases (HDACs). HDACs are key players in epigenetic regulation and have a role in the silencing of tumor suppressor genes. The dynamic equilibrium of acetylation makes HDACs attractive targets for drug therapy. However, substrate selectivity and biological function of HDAC isozymes is poorly understood. This review outlines the current understanding of the roles and specific epigenetic interactions of the metal-dependent HDACs in addition to their roles in cancer.

Zhang P, Wang C, Zhao J, et al.
Near Infrared-Guided Smart Nanocarriers for MicroRNA-Controlled Release of Doxorubicin/siRNA with Intracellular ATP as Fuel.
ACS Nano. 2016; 10(3):3637-47 [PubMed] Related Publications
In chemotherapy, it is a great challenge to recruit endogenous stimuli instead of external intervention for targeted delivery and controlled release; microRNAs are the most promising candidates due to their vital role during tumorigenesis and significant expression difference. Herein, to amplify the low abundant microRNAs in live cells, we designed a stimuli-responsive DNA Y-motif for codelivery of siRNA and Dox, in which the cargo release was achieved via enzyme-free cascade amplification with endogenous microRNA as trigger and ATP (or H(+)) as fuel through toehold-mediated strand displacement. Furthermore, to realize controlled release in tumor cells, smart nanocarriers were constructed with stimuli-responsive Y-motifs, gold nanorods, and temperature-sensitive polymers, whose surfaces could be reversibly switched between PEG and RGD states via photothermal conversion. The PEG corona kept the nanocarriers stealth during blood circulation to protect the Y-motifs against nuclease digestion and enhance passive accumulation, whereas the exposed RGD shell under near-infrared (NIR) irradiation at tumor sites facilitated the specific receptor-mediated endocytosis by tumor cells. Through modulating NIR laser, microRNA, or ATP expressions, the therapy efficacies to five different cell lines were finely controlled, presenting NIR-guided accumulation, massive release, efficient gene silence, and severe apoptosis in HeLa cells; in vivo study showed that a low dosage of nanocarriers synergistically inhibited the tumor growth by silencing gene expression and inducing cell apoptosis under mild NIR irradiation, though they only brought minimum damage to normal organs. The combination of nanomaterials, polymers, and DNA nanomachines provided a promising tool for designing smart nanodevices for disease therapy.

Huang T, Li J, Zhang C, et al.
Distinguishing Lung Adenocarcinoma from Lung Squamous Cell Carcinoma by Two Hypomethylated and Three Hypermethylated Genes: A Meta-Analysis.
PLoS One. 2016; 11(2):e0149088 [PubMed] Free Access to Full Article Related Publications
Significant differences in the aberrant methylation of genes exist among various histological types of non-small cell lung cancer (NSCLC), which includes adenocarcinoma (AC) and squamous cell carcinoma (SCC). Different chemotherapeutic regimens should be administered to the two NSCLC subtypes due to their unique genetic and epigenetic profiles. The purpose of this meta-analysis was to generate a list of differentially methylated genes between AC and SCC. Our meta-analysis encompassed 151 studies on 108 genes among 12946 AC and 10243 SCC patients. Our results showed two hypomethylated genes (CDKN2A and MGMT) and three hypermethylated genes (CDH13, RUNX3 and APC) in ACs compared with SCCs. In addition, our results showed that the pooled specificity and sensitivity values of CDH13 and APC were higher than those of CDKN2A, MGMT and RUNX3. Our findings might provide an alternative method to distinguish between the two NSCLC subtypes.

Pandharipande PV, Jeon A, Heberle CR, et al.
Screening for Pancreatic Adenocarcinoma in BRCA2 Mutation Carriers: Results of a Disease Simulation Model.
EBioMedicine. 2015; 2(12):1980-6 [PubMed] Free Access to Full Article Related Publications
BACKGROUND: BRCA2 mutation carriers are at increased risk for multiple cancers including pancreatic adenocarcinoma (PAC). Our goal was to compare the effectiveness of different PAC screening strategies in BRCA2 mutation carriers, from the standpoint of life expectancy.
METHODS: A previously published Markov model of PAC was updated and extended to incorporate key aspects of BRCA2 mutation carrier status, including competing risks of breast- and ovarian-cancer specific mortality. BRCA2 mutation carriers were modeled and analyzed as the primary cohort for the analysis. Additional higher risk BRCA2 cohorts that were stratified according to the number of first-degree relatives (FDRs) with PAC were also analyzed. For each cohort, one-time screening and annual screening were evaluated, with screening starting at age 50 in both strategies. The primary outcome was net gain in life expectancy (LE) compared to no screening. Sensitivity analysis was performed on key model parameters, including surgical mortality and MRI test performance.
FINDINGS: One-time screening at age 50 resulted in a LE gain of 3.9 days for the primary BRCA2 cohort, and a gain of 5.8 days for those with BRCA2 and one FDR. Annual screening resulted in LE loss of 12.9 days for the primary cohort and 1.3 days for BRCA2 carriers with 1 FDR, but resulted in 20.6 days gained for carriers with 2 FDRs and 260 days gained for those with 3 FDRs. For patients with ≥ 3 FDRs, annual screening starting at an earlier age (i.e. 35-40) was optimal.
INTERPRETATION: Among BRCA2 mutation carriers, aggressive screening regimens may be ineffective unless additional indicators of elevated risk (e.g., 2 or more FDRs) are present. More clinical studies are needed to confirm these findings.
FUNDING: American Cancer Society - New England Division - Ellison Foundation Research Scholar Grant (RSG-15-129-01-CPHPS).

Tiram G, Segal E, Krivitsky A, et al.
Identification of Dormancy-Associated MicroRNAs for the Design of Osteosarcoma-Targeted Dendritic Polyglycerol Nanopolyplexes.
ACS Nano. 2016; 10(2):2028-45 [PubMed] Related Publications
The presence of dormant, microscopic cancerous lesions poses a major obstacle for the treatment of metastatic and recurrent cancers. While it is well-established that microRNAs play a major role in tumorigenesis, their involvement in tumor dormancy has yet to be fully elucidated. We established and comprehensively characterized pairs of dormant and fast-growing human osteosarcoma models. Using these pairs of mouse tumor models, we identified three novel regulators of osteosarcoma dormancy: miR-34a, miR-93, and miR-200c. This report shows that loss of these microRNAs occurs during the switch from dormant avascular into fast-growing angiogenic phenotype. We validated their downregulation in patients' tumor samples compared to normal bone, making them attractive candidates for osteosarcoma therapy. Successful delivery of miRNAs is a challenge; hence, we synthesized an aminated polyglycerol dendritic nanocarrier, dPG-NH2, and designed dPG-NH2-microRNA polyplexes to target cancer. Reconstitution of these microRNAs using dPG-NH2 polyplexes into Saos-2 and MG-63 cells, which generate fast-growing osteosarcomas, reduced the levels of their target genes, MET proto-oncogene, hypoxia-inducible factor 1α, and moesin, critical to cancer angiogenesis and cancer cells' migration. We further demonstrate that these microRNAs attenuate the angiogenic capabilities of fast-growing osteosarcomas in vitro and in vivo. Treatment with each of these microRNAs using dPG-NH2 significantly prolonged the dormancy period of fast-growing osteosarcomas in vivo. Taken together, these findings suggest that nanocarrier-mediated delivery of microRNAs involved in osteosarcoma tumor-host interactions can induce a dormant-like state.

Nishimura R, Okamoto N, Satou M, et al.
HER 2 immunohistochemistry for breast cancer cell blocks can be used in the same way as that used for histological specimens.
Diagn Cytopathol. 2016; 44(4):274-9 [PubMed] Free Access to Full Article Related Publications
BACKGROUND: Human epidermal growth factor receptor 2 (HER2) testing of samples from recurrent or metastatic breast cancer is recommended by the 2013 update of the American Society of Clinical Oncology/College of American Pathologists guidelines. Although cytological analysis can be applied to several types of metastatic lesions, the practical method for HER2 testing of cytological specimens is yet to be resolved. We conducted immunohistochemical (IHC) staining for HER2 in breast cancer cell blocks (CBs) and compared the results with those from the corresponding histological specimens. In cases of discrepancy between the two types of specimen, the bright-field HER2 dual in situ hybridization (DISH) assay was performed.
METHODS: CBs were prepared from 54 surgically excised breast cancers. The cells were fixed in 10% buffered formalin and embedded in paraffin. A Ventana BenchMark ULTRA (Roche Diagnostics) with anti-HER-2/neu (4B5) rabbit monoclonal primary antibody and INFORM HER2/neu Dual ISH DNA Probe Cocktail was used for the assays.
RESULTS: Successful results were obtained in 52 of 54 CBs. Forty cases showed agreement between CBs and the histological specimens. No discrepancy was observed between the two types of specimens in cases where HER2 expression was positive. IHC results of CB in 12 discrepant cases were HER2 intermediate or negative. The DISH results of 11 of these cases were negative.
CONCLUSION: IHC staining of HER2 for breast cancer CBs can be used in the same way as that used for histological specimens, although the number of equivocal cases in CBs is greater than that in histological specimens. Diagn. Cytopathol. 2016;44:274-279. © 2016 The Authors Diagnostic Cytopathology Published by Wiley Periodicals, Inc.

Chebib I, Jo VY
Round cell sarcoma with CIC-DUX4 gene fusion: Discussion of the distinctive cytomorphologic, immunohistochemical, and molecular features in the differential diagnosis of round cell tumors.
Cancer Cytopathol. 2016; 124(5):350-61 [PubMed] Related Publications
BACKGROUND: Undifferentiated round cell sarcomas are a heterogeneous group, and include tumors that resemble the Ewing sarcoma family. Although a subset defined by recurrent CIC-DUX4 gene fusion has been recently characterized, data regarding the cytomorphologic features are currently limited. Two recent fine-needle aspiration (FNA) cases prompted review of the spectrum of round cell tumors in the differential diagnosis to determine distinctive diagnostic features.
METHODS: Two genetically confirmed FNA cases were identified. Cytomorphologic features were evaluated on FNA smears and hematoxylin and eosin-stained cell block and concurrent needle biopsy sections, and immunohistochemical studies performed on cell block and biopsy sections were reviewed.
RESULTS: The 2 patients were a 24-year-old man with a posterior mediastinal mass and a 69-year-old woman with a gluteal mass. FNA smears were cellular with tumor cells present in large groups and singly dispersed. Tumor cells had large, round-to-ovoid, hyperchromatic nuclei with irregular membranes, frequent large nucleoli, and a moderate amount of vacuolated cytoplasm. Both cases demonstrated necrosis, and one case had prominent myxoid stroma. Immunohistochemistry demonstrated focal-to-multifocal CD99 positivity and diffuse nuclear staining for WT1; staining for cytokeratin, desmin, S-100, CD34, CD45, and TdT were negative. Fluorescence in situ hybridization demonstrated CIC-DUX4 fusion in both cases.
CONCLUSIONS: CIC-DUX4 round cell sarcoma differs from Ewing sarcoma in that it has more atypical cytologic features and lacks the diffuse membranous CD99 staining pattern characteristic of Ewing sarcoma. The differential diagnosis is broad, and requires the judicious use of ancillary studies. Focal-to-multifocal CD99 immunoreactivity and diffuse nuclear WT1 positivity is characteristic of CIC-DUX4 sarcoma, and should prompt molecular testing. Cancer Cytopathol 2016;124:350-61. © 2016 American Cancer Society.

Garcia-Albeniz X, Rudolph A, Hutter C, et al.
CYP24A1 variant modifies the association between use of oestrogen plus progestogen therapy and colorectal cancer risk.
Br J Cancer. 2016; 114(2):221-9 [PubMed] Free Access to Full Article Related Publications
BACKGROUND: Menopausal hormone therapy (MHT) use has been consistently associated with a decreased risk of colorectal cancer (CRC) in women. Our aim was to use a genome-wide gene-environment interaction analysis to identify genetic modifiers of CRC risk associated with use of MHT.
METHODS: We included 10 835 postmenopausal women (5419 cases and 5416 controls) from 10 studies. We evaluated use of any MHT, oestrogen-only (E-only) and combined oestrogen-progestogen (E+P) hormone preparations. To test for multiplicative interactions, we applied the empirical Bayes (EB) test as well as the Wald test in conventional case-control logistic regression as primary tests. The Cocktail test was used as secondary test.
RESULTS: The EB test identified a significant interaction between rs964293 at 20q13.2/CYP24A1 and E+P (interaction OR (95% CIs)=0.61 (0.52-0.72), P=4.8 × 10(-9)). The secondary analysis also identified this interaction (Cocktail test OR=0.64 (0.52-0.78), P=1.2 × 10(-5) (alpha threshold=3.1 × 10(-4)). The ORs for association between E+P and CRC risk by rs964293 genotype were as follows: C/C, 0.96 (0.61-1.50); A/C, 0.61 (0.39-0.95) and A/A, 0.40 (0.22-0.73), respectively.
CONCLUSIONS: Our results indicate that rs964293 modifies the association between E+P and CRC risk. The variant is located near CYP24A1, which encodes an enzyme involved in vitamin D metabolism. This novel finding offers additional insight into downstream pathways of CRC etiopathogenesis.

Borrelli N, Ugolini C, Giannini R, et al.
Role of gene expression profiling in defining indeterminate thyroid nodules in addition to BRAF analysis.
Cancer Cytopathol. 2016; 124(5):340-9 [PubMed] Related Publications
Fine-needle aspiration (FNA) is routinely used in the preoperative evaluation of thyroid nodules. However, 15% to 30% of aspirations yield indeterminate cytologic findings. Because the assessment of BRAF mutations seems to improve the diagnostic accuracy, this study evaluated BRAF mutations with Sanger sequencing and real-time methods in 650 consecutive thyroid aspirates. In addition, the expression of a large number of genes involved in basement membrane remodeling, extracellular matrix proteolysis, and cell adhesion was studied in both benign and malignant nodules to identify new diagnostic tools. In this prospective series, despite the use of a very sensitive BRAF mutational testing method, the frequency of a BRAF alteration being identified in indeterminate FNA samples was 3 of 68. Expression analysis revealed several genes that were differentially expressed between benign and malignant nodules (transforming growth factor, cadherin 1, collagen α1, catenin α1, integrin α3, and fibronectin 1 [FN1]), between follicular adenomas and follicular variant of papillary thyroid carcinoma (FN1, laminin γ1, integrin β2, connective tissue growth factor, catenin δ1, and integrin αV), and between BRAF-wild-type and BRAF-mutated papillary thyroid carcinomas (TIMP metallopeptidase inhibitor 1; catenin α1; secreted phosphoprotein 1; FN1; ADAM metallopeptidase with thrombospondin type 1 motif, 1; and selectin L). These data were partially confirmed with real-time polymerase chain reaction analysis and immunohistochemistry. When the cost/benefit ratio of the procedures was taken into account, BRAF mutational testing failed to increase diagnostic accuracy in cytologically indeterminate nodules. However, the additional analysis of the expression of specific molecular markers could have possible utility as a diagnostic tool, although further evidence based on a large series of samples is needed before definitive conclusions can be drawn. Cancer Cytopathol 2016;124:340-9. © 2015 American Cancer Society.

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