Redox regulation of vascular remodeling.

Cell Mol Life Sci. 2016 Jan;73(2):349-63

Authors: Karimi Galougahi K, Ashley EA, Ali ZA

Abstract
Vascular remodeling is a dynamic process of structural and functional changes in response to biochemical and biomechanical signals in a complex in vivo milieu. While inherently adaptive, dysregulation leads to maladaptive remodeling. Reactive oxygen species participate in homeostatic cell signaling in tightly regulated- and compartmentalized cellular circuits. It is well established that perturbations in oxidation-reduction (redox) homeostasis can lead to a state of oxidative-, and more recently, reductive stress. We provide an overview of the redox signaling in the vasculature and review the role of oxidative- and reductive stress in maladaptive vascular remodeling. Particular emphasis has been placed on essential processes that determine phenotype modulation, migration and fate of the main cell types in the vessel wall. Recent advances in systems biology and the translational opportunities they may provide to specifically target the redox pathways driving pathological vascular remodeling are discussed.

PMID: 26483132 [PubMed - indexed for MEDLINE]

Leveraging Social Media to Promote Public Health Knowledge: Example of Cancer Awareness via Twitter.

JMIR Public Health Surveill. 2016 Jan-Jun;2(1):e17

Authors: Xu S, Markson C, Costello KL, Xing CY, Demissie K, Llanos AA

Abstract
BACKGROUND: As social media becomes increasingly popular online venues for engaging in communication about public health issues, it is important to understand how users promote knowledge and awareness about specific topics.
OBJECTIVE: The aim of this study is to examine the frequency of discussion and differences by race and ethnicity of cancer-related topics among unique users via Twitter.
METHODS: Tweets were collected from April 1, 2014 through January 21, 2015 using the Twitter public streaming Application Programming Interface (API) to collect 1% of public tweets. Twitter users were classified into racial and ethnic groups using a new text mining approach applied to English-only tweets. Each ethnic group was then analyzed for frequency in cancer-related terms within user timelines, investigated for changes over time and across groups, and measured for statistical significance.
RESULTS: Observable usage patterns of the terms "cancer", "breast cancer", "prostate cancer", and "lung cancer" between Caucasian and African American groups were evident across the study period. We observed some variation in the frequency of term usage during months known to be labeled as cancer awareness months, particularly September, October, and November. Interestingly, we found that of the terms studied, "colorectal cancer" received the least Twitter attention.
CONCLUSIONS: The findings of the study provide evidence that social media can serve as a very powerful and important tool in implementing and disseminating critical prevention, screening, and treatment messages to the community in real-time. The study also introduced and tested a new methodology of identifying race and ethnicity among users of the social media. Study findings highlight the potential benefits of social media as a tool in reducing racial and ethnic disparities.

PMID: 27227152 [PubMed]

Bioinformatic Studies to Predict MicroRNAs with the Potential of Uncoupling RECK Expression from Epithelial-Mesenchymal Transition in Cancer Cells.

Cancer Inform. 2016;15:91-102

Authors: Wang Z, Murakami R, Yuki K, Yoshida Y, Noda M

Abstract
RECK is downregulated in many tumors, and forced RECK expression in tumor cells often results in suppression of malignant phenotypes. Recent findings suggest that RECK is upregulated after epithelial-mesenchymal transition (EMT) in normal epithelium-derived cells but not in cancer cells. Since several microRNAs (miRs) are known to target RECK mRNA, we hypothesized that certain miR(s) may be involved in this suppression of RECK upregulation after EMT in cancer cells. To test this hypothesis, we used three approaches: (1) text mining to find miRs relevant to EMT in cancer cells, (2) predicting miR targets using four algorithms, and (3) comparing miR-seq data and RECK mRNA data using a novel non-parametric method. These approaches identified the miR-183-96-182 cluster as a strong candidate. We also looked for transcription factors and signaling molecules that may promote cancer EMT, miR-183-96-182 upregulation, and RECK downregulation. Here we describe our methods, findings, and a testable hypothesis on how RECK expression could be regulated in cancer cells after EMT.

PMID: 27226706 [PubMed]

Antiviral activity of doxycycline against vesicular stomatitis virus in vitro.

FEMS Microbiol Lett. 2015 Nov;362(22)

Authors: Wu ZC, Wang X, Wei JC, Li BB, Shao DH, Li YM, Liu K, Shi YY, Zhou B, Qiu YF, Ma ZY

Abstract
Doxycycline (Dox) is a tetracycline derivative with broad-spectrum antimicrobial activities that is used as an effector substance in inducible gene-expression systems. We investigated the antiviral activity of Dox against vesicular stomatitis virus (VSV) infection in cultured H1299 cells. Dox at concentrations of 1.0-2.0 μg ml(-1) significantly inhibited VSV replication and the VSV-induced cytopathic effect in dose-dependent manners, suggesting that Dox may have broader activity in inhibiting viral replication, in addition to its well-defined bacteriostatic activity. Dox exerted its antiviral effect at the early-mid stage of VSV infection, suggesting that it did not interfere with VSV infectivity, adsorption, or entry into target cells. These results indicate that Dox can inhibit VSV infection and may therefore have potential applications for the treatment of viral infections.

PMID: 26459887 [PubMed - indexed for MEDLINE]

Metastatic malignant struma ovarii with coexistence of Hashimoto's thyroiditis.

Endocrinol Diabetes Metab Case Rep. 2016;:160030

Authors: Russo M, Marturano I, Masucci R, Caruso M, Fornito MC, Tumino D, Tavarelli M, Squatrito S, Pellegriti G

Abstract
Struma ovarii is a rare ovarian teratoma characterized by the presence of thyroid tissue as the major component. Malignant transformation of the thyroidal component (malignant struma ovarii) has been reported in approximately 5% of struma ovarii. The management and follow-up of this unusual disease remain controversial. We report the case of a woman with a history of autoimmune thyroiditis and a previous resection of a benign struma ovarii that underwent hystero-annexiectomy for malignant struma ovarii with multiple papillary thyroid cancer foci and peritoneal involvement. Total thyroidectomy and subsequent radioiodine treatment lead to complete disease remission after 104 months of follow-up. The diagnosis and natural progression of malignant struma ovarii are difficult to discern, and relapses can occur several years after diagnosis. A multidisciplinary approach is mandatory; after surgical excision of malignant struma, thyroidectomy in combination with (131)I therapy should be considered after risk stratification in accordance with a standard approach in differentiated thyroid cancer patients.
LEARNING POINTS: Malignant struma ovarii is a rare disease; diagnosis is difficult and management is not well defined.Predominant sites of metastasis are adjacent pelvic structures.Thyroidectomy and (131)I therapy should be considered after risk stratification in accordance with standard approaches in DTC patients.

PMID: 27224256 [PubMed - as supplied by publisher]

Radiologic and Clinicopathologic Findings of Inflammatory Myofibroblastic Tumor.

J Comput Assist Tomogr. 2016 May 25;

Authors: Tan H, Wang B, Xiao H, Lian Y, Gao J

Abstract
PURPOSE: The aim of the study was to describe the clinical, radiographic, and pathologic features of inflammatory myofibroblastic tumor (IMT) to enhance the recognition of this rare disease.
MATERIALS AND METHODS: The clinical, imaging, and pathologic findings were retrospectively reviewed in 54 patients with IMT lesions, which were conformed by biopsy or surgical pathology. Of 54 patients, 51 had preoperative computed tomography (CT) examination and 13 had preoperative magnetic resonance imaging records.
RESULTS: The clinical appearances of these 54 patients had some relationship with the locations of lesions. Of 54 IMT patients, 87.0% cases (47/54) had solitary lesion. The mean long diameter of the lesions located at the sites of chest, abdomen, and pelvic regions was bigger than that of other locations (F = 3.025, P = 0.038). On plain CT images, soft tissue mass was found in all IMT lesions, except for 3 lesions that arose in the intestine tract, appearing as focal or diffuse thickening in the bowel wall. After contrast administration, all lesions were persistently enhanced; 72.7% cases (24/33) demonstrated heterogeneous enhancement with various cystic regions. Comparing the CT features with different anatomic lesions, ill-defined margin on the plain CT images and calcification were seen more frequently in the lesions of the head and neck (P = 0.010 and 0.035); however, the other radiological findings had no significant differences (all P > 0.05). Twelve of 51 IMT patients showed invasion into adjacent structures. On magnetic resonance imaging, 92.3% lesions (12/13) showed soft tissue masses demonstrating isointense to hypointense contrast compared with skeletal muscle on T1-weighted images and heterogeneously high signals on T2-weighted images; 85.7%(6/7) of lesions were heterogeneously enhanced with cystic changes. Immunohistochemistry showed that the percentage of positive staining for SMA, vimentin, anaplastic lymphoma kinase, CD68, CD34, CD99, B-cell lymphoma/leukemia-2, cytokeratin, Desmin, and S-100 protein were 88.9%, 87.0%, 44.4%, 59.3%, 53.7%, 29.6%, 42.6%, 28.5%, 13.0%, and 24.1%, respectively.
CONCLUSIONS: Inflammatory myofibroblastic tumor can involve any part of the body, and the clinical and radiological appearances are various owing to different anatomic sites. An ill-defined soft tissue mass heterogeneous enhancement with or without invasion into adjacent structures on computed tomographic or magnetic resonance images and positive staining for SMA and vimentin on immunohistochemical examination could suggest the diagnosis.

PMID: 27224222 [PubMed - as supplied by publisher]

Don't Do Different Things - Do Things Differently! Drug Development in Rare Diseases The Patient's Perspective.

Clin Pharmacol Ther. 2016 May 25;

Authors: Speid L

Abstract
Introduction The pharmaceutical industry and regulatory authorities have traditionally made risk benefit decisions, without consulting patients. Today there is a movement to engage the patient in these decisions. This is particularly pertinent for the rare disease patient population, who have limited access to effective diagnostics and treatments. We argue that their involvement at the earliest point of drug development will lead to more appropriate decision making, and potentially reduce the attrition rate. This article is protected by copyright. All rights reserved.

PMID: 27223901 [PubMed - as supplied by publisher]

Identification of β-Dystrobrevin as a Direct Target of miR-143: Involvement in Early Stages of Neural Differentiation.

PLoS One. 2016;11(5):e0156325

Authors: Quaranta MT, Spinello I, Paolillo R, Macchia G, Boe A, Ceccarini M, Labbaye C, Macioce P

Abstract
Duchenne Muscular Dystrophy, a genetic disorder that results in a gradual breakdown of muscle, is associated to mild to severe cognitive impairment in about one-third of dystrophic patients. The brain dysfunction is independent of the muscular pathology, occurs early, and is most likely due to defects in the assembly of the Dystrophin-associated Protein Complex (DPC) during embryogenesis. We have recently described the interaction of the DPC component β-dystrobrevin with members of complexes that regulate chromatin dynamics, and suggested that β-dystrobrevin may play a role in the initiation of neuronal differentiation. Since oxygen concentrations and miRNAs appear as well to be involved in the cellular processes related to neuronal development, we have studied how these factors act on β-dystrobrevin and investigated the possibility of their functional interplay using the NTera-2 cell line, a well-established model for studying neurogenesis. We followed the pattern of expression and regulation of β-dystrobrevin during the early stages of neuronal differentiation induced by exposure to retinoic acid (RA) under hypoxia as compared with normoxia, and found that β-dystrobrevin expression is regulated during RA-induced differentiation of NTera-2 cells. We also found that β-dystrobrevin pattern is delayed under hypoxic conditions, together with a delay in the differentiation and an increase in the proliferation rate of cells. We identified miRNA-143 as a direct regulator of β-dystrobrevin expression, demonstrated that β-dystrobrevin is expressed in the nucleus and showed that, in line with our previous in vitro results, β-dystrobrevin is a repressor of synapsin I in live cells. Altogether the newly identified regulatory pathway miR-143/β-dystrobrevin/synapsin I provides novel insights into the functions of β-dystrobrevin and opens up new perspectives for elucidating the molecular mechanisms underlying the neuronal involvement in muscular dystrophy.

PMID: 27223470 [PubMed - as supplied by publisher]

The risk of re-identification versus the need to identify individuals in rare disease research.

Eur J Hum Genet. 2016 May 25;

Authors: Hansson MG, Hanns L, Olaf R, Franz S, Michael O, Yaffa R, Caron M, Dawkins H, Domenica T, Manuel P, Simon W

Abstract
There is a growing concern in the ethics literature and among policy makers that de-identification or coding of personal data and biospecimens is not sufficient for protecting research subjects from privacy invasions and possible breaches of confidentiality due to the possibility of unauthorized re-identification. At the same time, there is a need in medical science to be able to identify individual patients. In particular for rare disease research there is a special and well-documented need for research collaboration so that data and biosamples from multiple independent studies can be shared across borders. In this article, we identify the needs and arguments related to de-identification and re-identification of patients and research subjects and suggest how the different needs may be balanced within a framework of using unique encrypted identifiers.European Journal of Human Genetics advance online publication, 25 May 2016; doi:10.1038/ejhg.2016.52.

PMID: 27222291 [PubMed - as supplied by publisher]

Eosinophilic cholecystitis with common bile duct stricture: a rare disease.

BMJ Case Rep. 2016;2016

Authors: Mehanna D, Naseem Z, Mustaev M

Abstract
Although the most common cause of cholecystitis is gallstones, other conditions may present as acute cholecystitis. We describe a case of eosinophilic cholecystitis with common bile duct stricture. A 36-year-old woman initially had generalised abdominal pain and peripheral eosinophilia. Diagnostic laparoscopy showed eosinophilic ascites and necrotic nodules on the posterior abdominal wall. She was treated with anthelminthics on presumption of toxacara infection based on borderline positivity of serological tests. She later presented with acute cholecystitis and had a cholecystectomy and choledocotomy. Day 9 T-tube cholangiogram showed irregular narrowing of the distal common bile duct. The patient's symptoms were improved with steroids and the T-tube was subsequently removed.

PMID: 27222280 [PubMed - in process]

Systemic and organ involvement in monogenic autoinflammatory disorders: a global review filtered through internists' lens.

Intern Emerg Med. 2016 May 25;

Authors: Cattalini M, Soliani M, Lopalco G, Rigante D, Cantarini L

Abstract
Monogenic autoinflammatory disorders (AIDs) are rare diseases driven by cytokine-mediated extraordinary sterile inflammation that results from the activation of innate immune pathways. The clinical hallmark of these diseases is the recurrence of stereotyped episodes of systemic- and organ-specific inflammation; the most common systems involved being the skin, musculoskeletal system, gastrointestinal tract, and central nervous system. The autoinflammatory disorders may have a profound impact on the quality of life of the affected patients, and a delayed diagnosis may lead to severe complications, the most dreadful of which is AA-Amyloidosis. This review gives an overview on the four main AIDs, namely familial Mediterranean fever, tumor necrosis factor receptor-associated periodic syndrome, cryopyrinopathies, and mevalonate kinase deficiency, focusing on their clinical phenotype in adults and differential diagnosis, suggesting a diagnostic algorithm, and reviewing the available treatments.

PMID: 27221072 [PubMed - as supplied by publisher]

Involvement of herbal medicine as a cause of mesenteric phlebosclerosis: results from a large-scale nationwide survey.

J Gastroenterol. 2016 May 24;

Authors: Shimizu S, Kobayashi T, Tomioka H, Ohtsu K, Matsui T, Hibi T

Abstract
BACKGROUND: Mesenteric phlebosclerosis (MP) is a rare disease characterized by venous calcification extending from the colonic wall to the mesentery, with chronic ischemic changes from venous return impairment in the intestine. It is an idiopathic disease, but increasing attention has been paid to the potential involvement of herbal medicine, or Kampo, in its etiology. Until now, there were scattered case reports, but no large-scale studies have been conducted to unravel the clinical characteristics and etiology of the disease.
METHODS: A nationwide survey was conducted using questionnaires to assess possible etiology (particularly the involvement of herbal medicine), clinical manifestations, disease course, and treatment of MP.
RESULTS: Data from 222 patients were collected. Among the 169 patients (76.1 %), whose history of herbal medicine was obtained, 147 (87.0 %) used herbal medicines. The use of herbal medicines containing sanshishi (gardenia fruit, Gardenia jasminoides Ellis) was reported in 119 out of 147 patients (81.0 %). Therefore, the use of herbal medicine containing sanshishi was confirmed in 70.4 % of 169 patients whose history of herbal medicine was obtained. The duration of sanshishi use ranged from 3 to 51 years (mean 13.6 years). Patients who discontinued sanshishi showed a better outcome compared with those who continued it.
CONCLUSIONS: The use of herbal medicine containing sanshishi is associated with the etiology of MP. Although it may not be the causative factor, it is necessary for gastroenterologists to be aware of the potential risk of herbal medicine containing sanshishi for the development of MP.

PMID: 27220772 [PubMed - as supplied by publisher]

Focus on the diagnostic problems of primary adenocarcinoma of the third and fourth portion of the duodenum. Case report.

G Chir. 2015 Jul-Aug;36(4):183-6

Authors: Bandi M, Scagliarini L, Anania G, Pedriali M, Resta G

Abstract
Although the small intestine constitutes over 75% of the length and 90% of the mucosal surface of the gastrointestinal tract, small intestine cancer is rare and accounts for only 1% of gastrointestinal malignancies. Adenocarcinoma together with carcinoid tumours are the most common histological types of primary malignant tumours of the small bowel but others, including lymphoma and leiomyosarcoma, may less frequently be encountered. Adenocarcinomas are predominantly located in the duodenum. Primary adenocarcinoma of the duodenum is a rare malignant tumor, accounting for 0.3-0.5% of all gastroenteral malignancies. The diagnosis of primary adenocarcinoma of duodenum is often delayed because its symptoms and signs are nonspecific. In this work we want to focus on the diagnostic and therapeutic problems of duodenal adenocarcinoma, reporting a case report.

PMID: 26712074 [PubMed - indexed for MEDLINE]

A rare localization of cerebral venous sinus thrombosis. Case report.

G Chir. 2015 Mar-Apr;36(2):79-83

Authors: Carangelo B, Lavalle L, Tiezzi G, Branco D, Lippa L, Mileo E, Costantino G, Mariottini A, Muscas G, Maturo A

Abstract
In this work the Authors report their experience on the treatment of a case of cavernous venous sinus thrombosis. The diagnosis is clinical and neuroradiological, CT, MRN, cerebral angiography and orbital venography have aided in establishing the diagnosis during life. Very interesting is the therapeutic approach.

PMID: 26017108 [PubMed - indexed for MEDLINE]

A study of mucosal melanoma of the oral cavity in India: a rare tumor.

Ear Nose Throat J. 2014 Aug;93(8):E4-7

Authors: Chaturvedi P, Lerra S, Gupta P, Pai PS, Chaukar DA, Agarwal JP, D'Cruz AK

Abstract
Malignant melanomas involving the mucosa are rare and aggressive lesions. Their rarity has made the formulation of staging and treatment protocols very difficult, as most of the available information comes from case reports and small case series. We conducted a retrospective study to analyze the behavior of melanomas of the oral mucosa in patients who were treated at Tata Memorial Hospital in Mumbai, a tertiary care referral center for malignancies and one of the largest cancer centers on the Indian subcontinent. During the 22-year period from January 1986 through December 2007, we found only 13 such cases, which had occurred in 8 men and 5 women, aged 26 to 70 years (mean: 37.5). All patients had been offered surgery with curative intent. Mucosal melanomas have exhibited a greater tendency for distant recurrence than for local treatment failure, which is why adjuvant radiation therapy has not been shown to confer any consistent benefit. In our study, only 3 of the 13 patients (23.1%) remained alive 2 years after diagnosis, despite aggressive treatment. Tumor staging, optimal treatment, and prognostic factors for oral mucosal melanoma are far from clear, and further research is needed. Despite the small number of patients in this study, it still represents one of the largest series of oral mucosal melanoma patients in India.

PMID: 25181674 [PubMed - indexed for MEDLINE]

Cytotoxicity of Salvia miltiorrhiza Against Multidrug-Resistant Cancer Cells.

Am J Chin Med. 2016 May 24;:1-24

Authors: Wu CF, Bohnert S, Thines E, Efferth T

Abstract
Salvia miltiorrhiza Bunge (Lamiaceae) is a well-known Chinese herb that possesses numerous therapeutic activities, including anticancer effects. In this study, the cytotoxicity and the biological mechanisms of S. miltiorrhiza (SM) root extract on diverse resistant and sensitive cancer cell lines were investigated. CEM/ADR5000 cells were 1.68-fold resistant to CCRF-CEM cells, while HCT116 (p53[Formula: see text] and U87.MG[Formula: see text]EGFR cells were hypersensitive (collateral sensitive) compared to their parental cells. SM root extract stimulated ROS generation, cell cycle S phase arrest and apoptosis. The induction of the intrinsic apoptotic pathway was validated by increased cleavage of caspase 3, 7, 9 and poly ADP-ribose polymerase (PARP). MAP kinases including JNK, ERK1/2 and p38 were obviously phosphorylated and nuclear P65 was downregulated upon SM treatment. Transcriptome-wide COMPARE analysis revealed that the expression of encoding genes with diverse functions were associated with the cellular response to cryptotanshinone, one of the main constituents of SM root extract. In conclusion, SM root extract exerted profound cytotoxicity towards various sensitive and resistant cancer cells and induced the intrinsic apoptotic pathway.

PMID: 27222067 [PubMed - as supplied by publisher]

Systems Metabolic Engineering of Escherichia coli.

EcoSal Plus. 2016 May;7(1)

Authors: Choi KR, Shin JH, Cho JS, Yang D, Lee SY

Abstract
Systems metabolic engineering, which recently emerged as metabolic engineering integrated with systems biology, synthetic biology, and evolutionary engineering, allows engineering of microorganisms on a systemic level for the production of valuable chemicals far beyond its native capabilities. Here, we review the strategies for systems metabolic engineering and particularly its applications in Escherichia coli. First, we cover the various tools developed for genetic manipulation in E. coli to increase the production titers of desired chemicals. Next, we detail the strategies for systems metabolic engineering in E. coli, covering the engineering of the native metabolism, the expansion of metabolism with synthetic pathways, and the process engineering aspects undertaken to achieve higher production titers of desired chemicals. Finally, we examine a couple of notable products as case studies produced in E. coli strains developed by systems metabolic engineering. The large portfolio of chemical products successfully produced by engineered E. coli listed here demonstrates the sheer capacity of what can be envisioned and achieved with respect to microbial production of chemicals. Systems metabolic engineering is no longer in its infancy; it is now widely employed and is also positioned to further embrace next-generation interdisciplinary principles and innovation for its upgrade. Systems metabolic engineering will play increasingly important roles in developing industrial strains including E. coli that are capable of efficiently producing natural and nonnatural chemicals and materials from renewable nonfood biomass.

PMID: 27223822 [PubMed - as supplied by publisher]

Cox process representation and inference for stochastic reaction-diffusion processes.

Nat Commun. 2016;7:11729

Authors: Schnoerr D, Grima R, Sanguinetti G

Abstract
Complex behaviour in many systems arises from the stochastic interactions of spatially distributed particles or agents. Stochastic reaction-diffusion processes are widely used to model such behaviour in disciplines ranging from biology to the social sciences, yet they are notoriously difficult to simulate and calibrate to observational data. Here we use ideas from statistical physics and machine learning to provide a solution to the inverse problem of learning a stochastic reaction-diffusion process from data. Our solution relies on a non-trivial connection between stochastic reaction-diffusion processes and spatio-temporal Cox processes, a well-studied class of models from computational statistics. This connection leads to an efficient and flexible algorithm for parameter inference and model selection. Our approach shows excellent accuracy on numeric and real data examples from systems biology and epidemiology. Our work provides both insights into spatio-temporal stochastic systems, and a practical solution to a long-standing problem in computational modelling.

PMID: 27222432 [PubMed - in process]

Data Mining for Identification of Molecular Targets in Ovarian Cancer.

Asian Pac J Cancer Prev. 2016;17(4):1691-9

Authors: Villegas-Ruiz V, Juarez-Mendez S

Abstract
Ovarian cancer is possibly the sixth most common malignancy worldwide, in Mexico representing the fourth leading cause of gynecological cancer death more than 70% being diagnosed at an advanced stage and the survival being very poor. Ovarian tumors are classified according to histological characteristics, epithelial ovarian cancer as the most common (~80%). We here used high-density microarrays and a systems biology approach to identify tissue-associated deregulated genes. Non-malignant ovarian tumors showed a gene expression profile associated with immune mediated inflammatory responses (28 genes), whereas malignant tumors had a gene expression profile related to cell cycle regulation (1,329 genes) and ovarian cell lines to cell cycling and metabolism (1,664 genes).

PMID: 27221839 [PubMed - in process]

Genomic Landscape of Colorectal Mucosa and Adenomas.

Cancer Prev Res (Phila). 2016 May 24;

Authors: Borras E, San Lucas FA, Chang K, Zhou R, Masand G, Fowler J, Mork ME, You YN, Taggart MW, McAllister F, Jones DA, Davies GE, Edelmann W, Ehli EA, Lynch PM, Hawk ET, Capella G, Scheet P, Vilar E

Abstract
The molecular basis of the adenoma-to-carcinoma transition has been deduced using comparative analysis of genetic alterations observed through the sequential steps of intestinal carcinogenesis. However, comprehensive genomic analyses of adenomas and at-risk mucosa are still lacking. Therefore, our aim was to characterize the genomic landscape of colonic at-risk mucosa and adenomas. We analyzed the mutation profile and copy number changes of 25 adenomas and adjacent mucosa from 12 familial adenomatous polyposis patients using whole-exome sequencing and validated allelic imbalances (AI) in 37 adenomas using SNP arrays. We assessed for evidence of clonality and performed estimations on the proportions of driver and passenger mutations using a systems biology approach. Adenomas had lower mutational rates than did colorectal cancers and showed recurrent alterations in known cancer driver genes (APC, KRAS, FBXW7, TCF7L2) and AIs in chromosomes 5, 7, and 13. Moreover, 80% of adenomas had somatic alterations in WNT pathway genes. Adenomas displayed evidence of multiclonality similar to stage I carcinomas. Strong correlations between mutational rate and patient age were observed in at-risk mucosa and adenomas. Our data indicate that at least 23% of somatic mutations are present in at-risk mucosa prior to adenoma initiation. The genomic profiles of at-risk mucosa and adenomas illustrate the evolution from normal tissue to carcinoma via greater resolution of molecular changes at the inflection point of premalignant lesions. Furthermore, substantial genomic variation exists in at-risk mucosa before adenoma formation, and deregulation of the WNT pathway is required to foster carcinogenesis. Cancer Prev Res; 9(6); 1-11. ©2016 AACR.

PMID: 27221540 [PubMed - as supplied by publisher]