Focus: Quantitative in situ measurement of estrogen receptor mRNA predicts response to tamoxifen

PURPOSE:

Quantification of mRNA has historically been done by reverse transcription polymerase chain reaction (RT-PCR). Recently, a robust method of detection of mRNA utilizing in situ hybridization has been described that is linear and shows high specificity with low background. Here we describe the use of the AQUA method of quantitative immunofluorescence (QIF) for measuring mRNA in situ using ESR1 (the estrogen receptor alpha gene) in breast cancer to determine its predictive value compared to Estrogen Receptor α (ER) protein.

METHODS:

Messenger RNA for ER (ESR1) and Ubiquitin C (UbC) were visualized using RNAscope probes and levels were quantified by quantitative in situ hybridization (qISH) on two Yale breast cancer cohorts on tissue microarrays. ESR1 levels were compared to ER protein levels measured by QIF using the SP1 antibody.

RESULTS:

ESR1 mRNA is reproducibly and specifically measurable by qISH on tissue collected from 1993 or later. ESR1 levels were correlated to ER protein levels in a non-linear manner on two Yale cohorts. High levels of ESR1 were found to be predictive of response to tamoxifin.

CONCLUSION:

Quantification of mRNA using qISH may allow assessment of large cohorts with minimal formalin fixed, paraffin embedded tissue. Exploratory data using this method suggests that measurement of ESR1 mRNA levels may be predictive of response to endocrine therapy in a manner that is different from the predictive value of ER.

Source : Quantitative in situ measurement of estrogen receptor mRNA predicts response to tamoxifen. Bordeaux JM, Cheng H, Welsh AW, Haffty BG, Lannin DR, Wu X, Su N, Ma XJ, Luo Y, Rimm DL. PLoS One. 2012;7(5):e36559.

Free paper available at:

http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3350519/pdf/pone.0036559.pdf

Focus: Senescent Cells in Growing Tumors: Population Dynamics and Cancer Stem Cells

Tumors are defined by their intense proliferation, but sometimes cancer cells turn senescent and stop replicating. In the stochastic cancer model in which all cells are tumorigenic, senescence is seen as the result of random mutations, suggesting that it could represent a barrier to tumor growth. In the hierarchical cancer model a subset of the cells, the cancer stem cells, divide indefinitely while other cells eventually turn senescent. Here we formulate cancer growth in mathematical terms and obtain predictions for the evolution of senescence. We perform experiments in human melanoma cells which are compatible with the hierarchical model and show that senescence is a reversible process controlled by survivin. We conclude that enhancing senescence is unlikely to provide a useful therapeutic strategy to fight cancer, unless the cancer stem cells are specifically targeted.

Source: Senescent Cells in Growing Tumors: Population Dynamics and Cancer Stem Cells. La Porta CA, Zapperi S, Sethna JP. PLoS Comput Biol. 2012 Jan;8(1):e1002316

Article freely available at:

http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3261911/pdf/pcbi.1002316.pdf

Les tumeurs sont définies par leur prolifération intense, mais parfois les cellules cancéreuses deviennent sénescentes et cessent leur réplication. Dans le modèle stochastique du cancer dans lequel toutes les cellules sont tumorigènes, la sénescence est considérée comme le résultat de mutations aléatoires, ce qui suggère qu'il pourrait représenter un obstacle à la croissance de la tumeur. Dans le modèle hiérarchique du cancer un sous-ensemble des cellules, les cellules souches cancéreuses, se divisent indéfiniment, tandis que les autres cellules finissent par connaître la sénescence. Ici, nous formulons la croissance du cancer en termes mathématiques et nous obtenons des prédictions sur l'évolution de la sénescence. Nous effectuons des expériences dans les cellules de mélanome humain qui sont compatibles avec le modèle hiérarchique et montrent que la sénescence est un processus réversible contrôlée par la survivine. Nous concluons que favoriser la sénescence est peu susceptible de fournir une stratégie thérapeutique utile pour combattre le cancer, à moins que les cellules souches cancéreuses soient particulièrement ciblées.

Article (en anglais) librement disponible à l’adresse :

http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3261911/pdf/pcbi.1002316.pdf

Mutated genes in cancer (71) – NOTCH1

NOTCH1

In databases:

● Entrez (http://www.ncbi.nlm.nih.gov/sites/gquery): 4851 or NOTCH1

● Ensembl (http://www.ensembl.org/index.html): ENSG00000148400

● UniProt (http://www.uniprot.org/): P46531

● OMIM (http://www.ncbi.nlm.nih.gov/omim): 190198

● GeneCards (http://www.genecards.org/): NOTCH1

● HGNC (http://www.genenames.org/): 7881 or NOTCH1

● Enzyme Number (IUBMB): EC 2.1.2.11, EC 3.4.21.68

Gene locus:

9q34.3

Protein name:

Notch 1

Protein Size:

2555 amino acids; about 273 kDa

Function:

The protein encoded by NOTCH1 functions as a receptor for membrane-bound ligands of the Jagged and Delta-like families. It is involved in cell-fate determination, implementation of differentiation, proliferation and apoptotic programs.

Cancer-related alterations:

Notch1 mutations play a dual role in carcinogenesis as either a tumor suppressor or an oncogene. The role of NOTCH1 within and between cells depends on signal strength, timing, cell type, and context.

Altered NOTCH1 is a causative factor in the development of T-cell acute lymphoblastic leukemia and lymphoma (T-ALL). It is notably involved in T-ALL following translocation t(7;9)(q34;q34.3),  leading to the fusion gene NOTCH1-TRB@, in which the 3' portion of NOTCH1 is juxtaposed with the T cell receptor β (TRB@) locus. This leads to expression of truncated NOTCH1 transcripts and consequent production of dominant active, ligand-independent forms of the NOTCH1 receptor, causing T-ALL. Less than 1% of human T-ALLs exhibit the t(7;9) translocation, however, activating mutations in NOTCH1 independent of t(7;9) have been identified in more than 50% of human T-ALL.

Somatic point mutations have been found in tumors of haematopoietic and lymphoid tissue (up to 20%), oesophagus and upper aerodigestive tract, CNS, large intestine, lung, pancreas, breast. Most mutation events are substitution, with hot spots corresponding to amino acids 1575-1601.

References (open access):

The role of NOTCH1 signaling in T-ALL. Ferrando AA. Hematology Am Soc Hematol Educ Program. 2009:353-61.

http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2847371/pdf/nihms168983.pdf

Notch1 loss of heterozygosity causes vascular tumors and lethal hemorrhage in mice. Liu Z, Turkoz A, Jackson EN, Corbo JC, Engelbach JA, Garbow JR, Piwnica-Worms DR, Kopan R. J Clin Invest. 2011 Feb 1;121(2):800-8.

http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3026721/pdf/JCI43114.pdf

Characterization of Notch1 antibodies that inhibit signaling of both normal and mutated Notch1 receptors. Aste-Amézaga M, Zhang N, Lineberger JE, Arnold BA, Toner TJ, Gu M, Huang L, Vitelli S, Vo KT, Haytko P, Zhao JZ, Baleydier F, L'Heureux S, Wang H, Gordon WR, Thoryk E, Andrawes MB, Tiyanont K, Stegmaier K, Roti G, Ross KN, Franlin LL, Wang H, Wang F, Chastain M, Bett AJ, Audoly LP, Aster JC, Blacklow SC, Huber HE. PLoS One. 2010 Feb 8;5(2):e9094

http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2817004/pdf/pone.0009094.pdf

Inhibition of NOTCH signaling by gamma secretase inhibitor engages the RB pathway and elicits cell cycle exit in T-cell acute lymphoblastic leukemia cells. Rao SS, O'Neil J, Liberator CD, Hardwick JS, Dai X, Zhang T, Tyminski E, Yuan J, Kohl NE, Richon VM, Van der Ploeg LH, Carroll PM, Draetta GF, Look AT, Strack PR, Winter CG. Cancer Res. 2009 Apr 1;69(7):3060-8

http://cancerres.aacrjournals.org/content/69/7/3060.full.pdf+html

Tumor suppressor role of Notch-1 signaling in neuroendocrine tumors. Kunnimalaiyaan M, Chen H. Oncologist. 2007 May;12(5):535-42.

http://theoncologist.alphamedpress.org/content/12/5/535.full.pdf+html

Mutated genes in cancer (70) – FH

FH

In databases:

● Entrez (http://www.ncbi.nlm.nih.gov/sites/gquery): 2271 or FH

● Ensembl (http://www.ensembl.org/index.html): ENSG00000091483

● UniProt (http://www.uniprot.org/): P07954

● OMIM (http://www.ncbi.nlm.nih.gov/omim): 136850

● GeneCards (http://www.genecards.org/): FH

● HGNC (http://www.genenames.org/): 3700 or FH

● EC enzyme number : EC 4.2.1.2

Gene locus:

1q42.1

Protein name:

Fumarate hydratase (fumarase)

Protein Size:

510 amino acids; about 55 kDa

Function:

Fumarase is a homotetramer that plays a key enzymatic role in fundamental metabolic pathways. The mitochondrial isoenzyme catalyzes conversion of fumarate to malate in the Krebs, or tricarboxylic acid (TCA) cycle, in which acetyl-CoA produces CO2, reduced electron carriers (FADH2 and NADH) and ATP. The cytosolic isoenzyme is involved with amino acid metabolism.

Cancer-related alterations:

Germline mutations in FH are associated with two distinct conditions:

Homozygous and compound heterozygous mutations (e.g., missense and in-frame deletions) of the 3' end result in fumarate hydratase deficiency (FHD). FHD is characterized by progressive encephalopathy, developmental delay, hypotonia, cerebral atrophy and lactic and pyruvic acidemia. The most common allelic abnormality is a 3 base pair- AAA insertion.

Heterozygous 5' mutations (e.g., nonsense, missense and deletions ranging from one base pair to whole gene) predispose individuals to somatic mutations in the normal allele leading to Hereditary leiomyomatosis and renal cell carcinoma / multiple cutaneous and uterine leiomyomatosis (HLRCC/MCUL1).

Somatic mutations:    Loss-of-heterozygosity of the wild type allele results in functional nullizygosity for fumarate hydratase. Malignant uterine and kidney tumors characteristic of HLRCC can subsequently develop. Uterine leiomyomatosis has also been observed in patients with deletion of FH from structural rearrangements of 1q42.1. The probable mechanism is presumably haploinsufficiency

Références (open access):

Genetic and epigenetic alterations during renal carcinogenesis. Arai E, Kanai Y. Int J Clin Exp Pathol. 2010 Dec 13;4(1):58-73.

http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3016104/pdf/ijcep0004-0058.pdf

HIF and fumarate hydratase in renal cancer. Sudarshan S, Linehan WM, Neckers L. Br J Cancer. 2007 Feb 12;96(3):403-7.

http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2360036/pdf/6603547a.pdf

Genetic heterogeneity among uterine leiomyomata: insights into malignant progression. Hodge JC, Morton CC. Hum Mol Genet. 2007 Apr 15;16 Spec No 1:R7-13.

http://hmg.oxfordjournals.org/content/16/R1/R7.full.pdf+html

Structural basis of fumarate hydratase deficiency. Picaud S, Kavanagh KL, Yue WW, Lee WH, Muller-Knapp S, Gileadi O, Sacchettini J, Oppermann U. J Inherit Metab Dis. 2011 Jun;34(3):671-6.

http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3109261/pdf/10545_2011_Article_9294.pdf

Press Review (May 19, 2012) – Revue de presse (19 mai 2012)

Study unpicks gene changes behind breast cancer‎

Scientists have mapped the complete genetic codes of 21 breast cancers and created a catalogue of the mutations that accumulate in breast cells, raising hopes that the disease may be able to be spotted earlier and treated more effectively in future.

In Reuters

http://www.reuters.com/article/2012/05/17/us-cancer-breast-genetics-idUSBRE84G0XT20120517

Advanced Prostate Cancer Drug May Help at Earlier Stage

In study, one-third benefited from taking Zytiga plus hormone therapy for 6 months before surgery.

By Amanda Gardner. In U.S. News & World Report

http://health.usnews.com/health-news/news/articles/2012/05/17/advanced-prostate-cancer-drug-may--help-at-earlier-stage

Coffee Drinking Linked To Long Life

Your morning Starbucks stop is doing more than keeping you awake -- that coffee may be helping you live longer, according to a new study in the New England Journal of Medicine

In Huffington Post

http://www.huffingtonpost.com/2012/05/17/coffee-longer-life-new-research-finds_n_1524228.html

Scientific instruments maker Agilent to buy cancer diagnostics provider Dako for $2.2 billion‎‎

Agilent Technologies Inc. said Thursday that it is buying Dako, a Denmark-based cancer diagnostic company, for about $2.2 billion to help it develop a wider range of cancer-fighting products, expand Agilent’s life sciences division and boost revenue.

By Lindsay Tanner. In Washington Post.

http://www.washingtonpost.com/business/technology/agilent-technologies-and-swedish-private-equity-group-to-acquire-dako-for-about-22b/2012/05/17/gIQANwfkVU_story.html

More cutting-edge cancer research supported by industry‎

An analysis by Fox Chase suggests researchers need to be more aware of potential conflicts of interest than ever before.

In EurekAlert

http://www.eurekalert.org/pub_releases/2012-05/fccc-mcc051612.php

Hybrid vaccine demonstrates potential to prevent breast cancer recurrence‎

A breast cancer vaccine already shown to elicit a powerful immune response in women with varying levels of HER2 expression has the ability to improve recurrence rates and is well tolerated in an adjuvant setting, according to new research from a clinical trial led by researchers at The University of Texas MD Anderson Cancer Center.

In Medical XPress.

http://medicalxpress.com/news/2012-05-hybrid-vaccine-potential-breast-cancer.html

Video-assisted thoracic surgery valuable tool in lung cancer screening‎ ‎

CT screening of high-risk Danish population yields higher incidence of early stage lung cancer amenable to VATS resections.

In EurekAlert

http://www.eurekalert.org/pub_releases/2012-05/iaft-vat051512.php

Pfizer drug effective in rare children's cancers‎

Crizotinib eradicated cancer in 7 of 8 lymphoma patients

By Bill Berkrot. In Reuters

http://www.reuters.com/article/2012/05/16/cancer-pfizer-children-idUSL1E8GGN3820120516

Cancer mammaire : vaccin + létrozole à l'essai chez la souris‎‎‎‎

Selon une étude publiée par l’équipe de l’Américain Michael DeGregorio dans « Clinical Cancer Research », l’association d’un vaccin ciblant les cellules tumorales et de létrozole, un antiestrogène, accroît significativement la survie chez la souris.

Par Cyrille Vanlerberghe. Dans Le Quotidien du Médecin

http://www.lequotidiendumedecin.fr/information/cancer-mammaire-vaccin-letrozole-l-essai-chez-la-souris

Compléments alimentaires: attention au risque de cancer‎

Pris à des niveaux trop élevés, en « automédication », certains compléments alimentaires peuvent être dangereux. C’est le cas du bêta-carotène, du sélénium et de l'acide folique qui, à partir de 3 fois l’apport journalier recommandé, pourraient accroître le risque de développer plusieurs types de cancers. Alors qu’en France, dès 2009, les autorités ont appelé à la vigilance -d’autant que alors que les déficits en nutriments sont très rares en population générale- cette étude de l'Université du Colorado financée par les NIH et relayée dans le Journal of the National Cancer Institute met en garde contre la supplémentation abusive.

Dans Santé Log

http://www.santelog.com/modules/connaissances/actualite-sante-complements-alimentaires-attention-au-risque-de-cancer_8290_lirelasuite.htm

Boire trois tasses de café par jour diminuerait les risques de décès‎

Les adultes de 50 à 71 ans qui boivent au moins trois tasses de café par jour pourraient voir leur risque de décès diminuer de 10% par rapport à ceux qui n'en consomment pas, selon une étude de l'Institut national américain du cancer (NCI) publiée mercredi.

Dans L’Orient-Le Jour

http://www.lorientlejour.com/category/Dernières+Infos/article/759278/Boire_trois_tasses_de_cafe_par_jour_diminuerait_les_risques_de_deces.html

Areva condamné après la mort par cancer d'un ex-salarié d'une mine d'uranium‎‎

Le groupe Areva a été condamné vendredi après la mort d'un ex-salarié d'une mine d'uranium du groupe français du nucléaire au Niger, décédé en 2009 d'un cancer du poumon, un jugement qui pourrait ouvrir la voie à d'autres poursuites et condamnations.

Dans Libération

http://www.liberation.fr/depeches/2012/05/11/areva-condamne-apres-la-mort-par-cancer-d-un-ex-salarie-d-une-mine-d-uranium_818019

Cancer de la peau : polémique autour de la publicité H&M‎‎‎

Débordantes de glamour pour leurs créateurs, les affiches de publicité H&M provoquent la colère de scientifiques en France et d'associations en Europe, qui les jugent malsaines. Difficile de rater cette jeune femme brûlant sous un soleil de plomb, juste vêtue d'un bikini fuchsia.Trop brune, sa peau ? C'est ce que pensent des chercheurs suisses qui travaillent contre le cancer de la peau.

Dans Le Parisien

http://www.leparisien.fr/laparisienne/beaute/cancer-de-la-peau-polemique-autour-de-la-publicite-h-m-12-05-2012-1997187.php

Cancer de la prostate : un dépistage ciblé‎‎

De nouveaux marqueurs apparaissent pour distinguer les tumeurs nécessitant un traitement et les autres..

Par Anne Prigent. Dans Le Figaro

http://sante.lefigaro.fr/actualite/2012/05/10/18169-cancer-prostate-depistage-cible

Cancer : les cellules souches, bouclier contre la chimiothérapie‎

Des cellules souches génétiquement modifiées ont protégé trois patients atteints d’une tumeur au cerveau des effets secondaires graves d’une chimiothérapie et ont augmenté leurs chances de survie. L’un d’entre eux est toujours vivant trois ans après. Cette technique, novatrice, promet de belles perspectives si son efficacité se confirme à plus grande échelle.

Par Janlou Chaput. Dans Futura-Santé

http://www.futura-sciences.com/fr/news/t/medecine/d/cancer-les-cellules-souches-bouclier-contre-la-chimiotherapie_38658/

Anticancer molecules (86) – Molécules anticancéreuses (86) - PROCARBAZINE

PROCARBAZINE

Name: procarbazine hydrochloride

Commercial name: Matulane, Natulan, Natulanar

Pharmacological class: alkylating agent

Therapeutic class: antineoplastic

Action: the precise mode of cytotoxic action of procarbazine has not been clearly defined. There is evidence that the drug may act by inhibition of protein, RNA and DNA synthesis.

In 2011, procarbazine hydrochloride is approved:

            ● to be used with other drugs to treat advanced Hodgkin lymphoma.

***

Nom: chlorhydrate de procarbazine

Nom commercial: Matulane, Natulan, Natulanar

Classe pharmacologique: agent alkylant

Classe thérapeutique: antinéoplasiques

Action: le mode d’action cytotoxique précis de la procarbazine n'a pas été clairement défini. Il est cependant évident que le médicament peut agir par inhibition de la synthèse de protéines, d'ARN et d'ADN.

En 2011, le chlorhydrate de procarbazine est approuvé:

            ● pour une utilisation avec d'autres médicaments pour traiter un lymphome de Hodgkin.

Mutated genes in cancer (69) – PTCH1

PTCH1

In databases:

● Entrez (http://www.ncbi.nlm.nih.gov/sites/gquery): 5727 or PTCH1

● Ensembl (http://www.ensembl.org/index.html): ENSG00000185920

● UniProt (http://www.uniprot.org/): Q13635

● OMIM (http://www.ncbi.nlm.nih.gov/omim): 601309

● GeneCards (http://www.genecards.org/): PTCH1

● HGNC (http://www.genenames.org/): 9585 or PTCH1

Gene locus:

9q22.32

Protein name:

Patched 1

Protein Size:

1447 amino acids; about 161 kDa

Function:

The protein encoded by PTCH1 acts as a receptor for sonic hedgehog, a secreted molecule implicated in the formation of embryonic structures and in tumorigenesis, as well as indian hedgehog and desert hedgehog. Associates with the smoothened protein (SMO) to transduce the hedgehog's proteins signal. PTCH1 functions as a tumor suppressor. It is thought to have a repressive activity on cell proliferation and could play a role in DNA maintenance, repair and/or replication, since NBCSS syndrome is a chromosome instability syndrome.

Cancer-related alterations:

Germinal mutations lead to protein truncation in nevoid basal cell carcinoma syndrome (NBCCS) patients (see below); mutations types are variable: nucleotide substitutions (missense/nonsense), small deletions, or small insertions mainly, leading to protein truncation; these mutations have been observed in most exons; there is, so far, no mutation hot spot.

Somatic mutation and allele loss events have been observed in basal cell carcinoma, in NBCCS and in sporadic basal cell carcinoma. Mutation and allele loss have also been found in sporadic primitive neuroectodermal tumors (PNETs), sporadic medulloblastomas and in a few cases of esophageal squamous cell carcinoma and invasive transitional cell carcinoma of the bladder; mutations have also been reported in a low frequency of sporadic trichoepitheliomas (tumors often associated with basal cell carcinomas) and in sporadic odontogenic keratocysts

A large majority of these somatic mutations are substitutions. There are no mutation hot spots

Genetic alterations in PTCH1 are the cause of basal cell nevus syndrome (BCNS) also known as Gorlin syndrome or Gorlin-Goltz syndrome. BCNS is an autosomal dominant disease characterized by nevoid basal cell carcinomas (NBCCS) and developmental abnormalities such as rib and craniofacial alterations, polydactyly, syndactyly, and spina bifida. In addition, the patients suffer from a multitude of tumors like basal cell carcinomas (BCC), fibromas of the ovaries and heart, cysts of the skin, jaws and mesentery, as well as medulloblastomas and meningiomas. PTCH1 is also mutated in squamous cell carcinoma (SCC).

References (open access):

Nevoid basal cell carcinoma syndrome (Gorlin syndrome). Lo Muzio L. Orphanet J Rare Dis. 2008 Nov 25;3:32.

http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2607262/pdf/1750-1172-3-32.pdf

Gorlin syndrome or basal cell nevus syndrome (BCNS): A case report. Shivaswamy KN, Sumathy TK, Shyamprasad AL, Ranganathan C. Dermatol Online J. 2010 Sep 15;16(9):6.

http://dermatology.cdlib.org/1609/2_case_presentations/4_10-00114/shivaswamy.html

Mechanisms of inactivation of PTCH1 gene in nevoid basal cell carcinoma syndrome: modification of the two-hit hypothesis. Pan S, Dong Q, Sun LS, Li TJ. Clin Cancer Res. 2010 Jan 15;16(2):442-50.

http://clincancerres.aacrjournals.org/content/16/2/442.full.pdf+html

Patched1 functions as a gatekeeper by promoting cell cycle progression. Adolphe C, Hetherington R, Ellis T, Wainwright B. Cancer Res. 2006 Feb 15;66(4):2081-8.

http://cancerres.aacrjournals.org/content/66/4/2081.full.pdf+html