lundi 30 juillet 2012

Focus : A remarkably simple genome underlies highly malignant pediatric rhabdoid cancers

Cancer is principally considered a genetic disease, and numerous mutations are thought essential to drive its growth. However, the existence of genomically stable cancers and the emergence of mutations in genes that encode chromatin remodelers raise the possibility that perturbation of chromatin structure and epigenetic regulation are capable of driving cancer formation. Here we sequenced the exomes of 35 rhabdoid tumors, highly aggressive cancers of early childhood characterized by biallelic loss of SMARCB1, a subunit of the SWI/SNF chromatin remodeling complex. We identified an extremely low rate of mutation, with loss of SMARCB1 being essentially the sole recurrent event. Indeed, in 2 of the cancers there were no other identified mutations. Our results demonstrate that high mutation rates are dispensable for the genesis of cancers driven by mutation of a chromatin remodeling complex. Consequently, cancer can be a remarkably genetically simple disease.

Source: A remarkably simple genome underlies highly malignant pediatric rhabdoid cancers. Lee RS, Stewart C, Carter SL, Ambrogio L, Cibulskis K, Sougnez C, Lawrence MS, Auclair D, Mora J, Golub TR, Biegel JA (, Getz G (, Roberts CW ( J Clin Invest. 2012 Jul 16.
Free paper available at:

Focus : Comprehensive molecular characterization of human colon and rectal cancer

To characterize somatic alterations in colorectal carcinoma, we conducted a genome-scale analysis of 276 samples, analysing exome sequence, DNA copy number, promoter methylation and messenger RNA and microRNA expression. A subset of these samples (97) underwent low-depth-of-coverage whole-genome sequencing. In total, 16% of colorectal carcinomas were found to be hypermutated: three-quarters of these had the expected high microsatellite instability, usually with hypermethylation and MLH1 silencing, and one-quarter had somatic mismatch-repair gene and polymerase ε (POLE) mutations. Excluding the hypermutated cancers, colon and rectum cancers were found to have considerably similar patterns of genomic alteration. Twenty-four genes were significantly mutated, and in addition to the expected APC, TP53, SMAD4, PIK3CA and KRAS mutations, we found frequent mutations in ARID1A, SOX9 and FAM123B. Recurrent copy-number alterations include potentially drug-targetable amplifications of ERBB2 and newly discovered amplification of IGF2. Recurrent chromosomal translocations include the fusion of NAV2 and WNT pathway member TCF7L1. Integrative analyses suggest new markers for aggressive colorectal carcinoma and an important role for MYC-directed transcriptional activation and repression.

Source: Comprehensive molecular characterization of human colon and rectal cancer. Cancer Genome Atlas Network: Muzny DM, Bainbridge MN, Chang K, Dinh HH, Drummond JA, Fowler G, Kovar CL, Lewis LR, Morgan MB, Newsham IF, Reid JG, Santibanez J, Shinbrot E, Trevino LR, Wu YQ, Wang M, Gunaratne P, Donehower LA, Creighton CJ, Wheeler DA, Gibbs RA, Lawrence MS, Voet D, Jing R, Cibulskis K, Sivachenko A, Stojanov P, McKenna A, Lander ES, Gabriel S, Getz G, Ding L, Fulton RS, Koboldt DC, Wylie T, Walker J, Dooling DJ, Fulton L, Delehaunty KD, Fronick CC, Demeter R, Mardis ER, Wilson RK, Chu A, Chun HJ, Mungall AJ, Pleasance E, Robertson A, Stoll D, Balasundaram M, Birol I, Butterfield YS, Chuah E, Coope RJ, Dhalla N, Guin R, Hirst C, Hirst M, Holt RA, Lee D, Li HI, Mayo M, Moore RA, Schein JE, Slobodan JR, Tam A, Thiessen N, Varhol R, Zeng T, Zhao Y, Jones SJ, Marra MA, Bass AJ, Ramos AH, Saksena G, Cherniack AD, Schumacher SE, Tabak B, Carter SL, Pho NH, Nguyen H, Onofrio RC, Crenshaw A, Ardlie K, Beroukhim R, Winckler W, Getz G, Meyerson M, Protopopov A, Zhang J, Hadjipanayis A, Lee E, Xi R, Yang L, Ren X, Zhang H, Sathiamoorthy N, Shukla S, Chen PC, Haseley P, Xiao Y, Lee S, Seidman J, Chin L, Park PJ, Kucherlapati R, Auman JT, Hoadley KA, Du Y, Wilkerson MD, Shi Y, Liquori C, Meng S, Li L, Turman YJ, Topal MD, Tan D, Waring S, Buda E, Walsh J, Jones CD, Mieczkowski PA, Singh D, Wu J, Gulabani A, Dolina P, Bodenheimer T, Hoyle AP, Simons JV, Soloway M, Mose LE, Jefferys SR, Balu S, O'Connor BD, Prins JF, Chiang DY, Hayes D, Perou CM, Hinoue T, Weisenberger DJ, Maglinte DT, Pan F, Berman BP, Van Den Berg DJ, Shen H, Triche T Jr, Baylin SB, Laird PW, Getz G, Noble M, Voet D, Saksena G, Gehlenborg N, DiCara D, Zhang J, Zhang H, Wu CJ, Liu SY, Shukla S, Lawrence MS, Zhou L, Sivachenko A, Lin P, Stojanov P, Jing R, Park RW, Nazaire MD, Robinson J, Thorvaldsdottir H, Mesirov J, Park PJ, Chin L, Thorsson V, Reynolds SM, Bernard B, Kreisberg R, Lin J, Iype L, Bressler R, Erkkilä T, Gundapuneni M, Liu Y, Norberg A, Robinson T, Yang D, Zhang W, Shmulevich I, de Ronde JJ, Schultz N, Cerami E, Ciriello G, Goldberg AP, Gross B, Jacobsen A, Gao J, Kaczkowski B, Sinha R, Aksoy B, Antipin Y, Reva B, Shen R, Taylor BS, Chan TA, Ladanyi M, Sander C, Akbani R, Zhang N, Broom BM, Casasent T, Unruh A, Wakefield C, Hamilton SR, Cason R, Baggerly KA, Weinstein JN, Haussler D, Benz CC, Stuart JM, Benz SC, Sanborn J, Vaske CJ, Zhu J, Szeto C, Scott GK, Yau C, Ng S, Goldstein T, Ellrott K, Collisson E, Cozen AE, Zerbino D, Wilks C, Craft B, Spellman P, Penny R, Shelton T, Hatfield M, Morris S, Yena P, Shelton C, Sherman M, Paulauskis J, Gastier-Foster JM, Bowen J, Ramirez NC, Black A, Pyatt R, Wise L, White P, Bertagnolli M, Brown J, Chan TA, Chu GC, Czerwinski C, Denstman F, Dhir R, Dörner A, Fuchs CS, Guillem JG, Iacocca M, Juhl H, Kaufman A, Kohl B 3rd, Van Le X, Mariano MC, Medina EN, Meyers M, Nash GM, Paty PB, Petrelli N, Rabeno B, Richards WG, Solit D, Swanson P, Temple L, Tepper JE, Thorp R, Vakiani E, Weiser MR, Willis JE, Witkin G, Zeng Z, Zinner MJ, Zornig C, Jensen MA, Sfeir R, Kahn AB, Chu AL, Kothiyal P, Wang Z, Snyder EE, Pontius J, Pihl TD, Ayala B, Backus M, Walton J, Whitmore J, Baboud J, Berton DL, Nicholls MC, Srinivasan D, Raman R, Girshik S, Kigonya PA, Alonso S, Sanbhadti RN, Barletta SP, Greene JM, Pot DA, Shaw KR, Dillon LA, Buetow K, Davidsen T, Demchok JA, Eley G, Ferguson M, Fielding P, Schaefer C, Sheth M, Yang L, Guyer MS, Ozenberger BA, Palchik JD, Peterson J, Sofia HJ, Thomson E. Nature. 2012 Jul 18;487(7407):330-7.
Free paper available at:

vendredi 27 juillet 2012

Press Review (July 28, 2012) – Revue de presse (28 juillet 2012)

Cancer Drug May Flush Out 'Hidden' HIV: Study‎‎
Strategy could help battle 'reservoir' of germs, but research is in early stages.
By Randy Dotinga. In U.S. News & World Report

Brittany Wenger, 17, Wins Google Science Fair Grand Prize For Breast Cancer Diagnosis App‎‎‎
Have you ever helped the hard-of-hearing listen to music? Or built a computer program to diagnose breast cancer? These kids have.
By Dino Grandoni. In Huffington Post

Pregnancy post 30 lowers cancer risk‎‎
Women who last give birth at age 40 or older have a 44 per cent decreased risk of endometrial cancer when compared to women who have their last birth under the age of 25, a new study has revealed.
In Times of India

Antioxidants Might Help Cut Pancreatic Cancer Risk, Study Suggests‎ ‎‎
But the research cannot prove cause and effect, and better trials are needed, experts say.
In U.S. News & World Report

New York State passes legislation to help improve breast cancer detection‎
The National Cancer Institute estimates in 2012 there will be 226,870 new cases of breast cancer in women with 39,510 deaths. In response to a need to improve breast cancer detection and prevention Governor Andrew M. Cuomo signed legislation on July 23, 2012 that requires mammography services to inform patients if dense breast tissue is found during an exam.
By Harold Mandel. In The Examiner

Should cancer be kept secret?‎‎
Some hide life-threatening illnesses from friends and family, but suffer guilt.
By Leanne Italie. In Salon

FDA Approves Everolimus (Afinitor) for Metastatic Breast Cancer‎
The US Food and Drug Administration (FDA) approved the mTOR inhibitor everolimus (Afinitor) last week for use in postmenopausal women with HER2-negative, hormone-receptor–positive advanced breast cancer patients. Afinitor was approved in combination with exemestane(Drug information on exemestane) (Aromasin) in those patients whose cancer progressed following treatment with letrozole or anastrozole.
By Anna Azvolinsky. In Cancer Network

New biomarker for common lung cancer predicts responses to chemotherapy‎‎‎‎
Patients with the most common type of lung cancer are notoriously insensitive to chemotherapy drugs, including cisplatin. New findings related to the cellular pathways that regulate responses to cisplatin have now been published by Cell Press on July 26th in the journal Cell Reports. The findings reveal a potential biomarker that can be used to predict how these patients will respond to chemotherapy, as well as the patients' overall prognosis, paving the way for personalized treatment strategies
In EurekAlert (press release)

Limiter le sel pour diminuer le risque de cancer de l'estomac‎‎ ‎‎
Un organisme anglais de prévention du cancer alerte sur l'impact d'une alimentation trop salée, qui favorise le risque de tumeur à l'estomac.
Par Romy Raffin. Dans Le Figaro

Cancer du pancréas : découverte d'un processus qui bloquerait les métastases‎
Des scientifiques du centre de recherche en cancérologie de Marseille (CRCM) ont annoncé avoir identifié un processus cellulaire au sein des tumeurs pancréatiques qui permettrait de bloquer la formation de métastases. Une découverte porteuse d'espoir pour ce cancer trop souvent mortel.
Dans MaxiSciences

Un médicament contre le cancer pour débusquer le VIH‎
Une catégorie de médicaments couramment employés dans le traitement du cancer permettrait de débusquer le VIH-sida lorsqu'il se cache sous forme latente dans le sang des malades, affirment des chercheurs américains.

Le bronzage en spray pourrait causer des cancers et de l'infertilité‎
Bronzer est définitivement une activité risquée. Après les cabines de bronzage, soupçonnées d'augmenter les risques de cancer, c'est au tour des autobronzants d'être pointés du doigt par la recherche, rapporte The Telegraph.

jeudi 26 juillet 2012

Focus: Complexities of TGF-β Targeted Cancer Therapy

            Many advanced tumors produce excessive amounts of Transforming Growth Factor-β (TGF-β) which, in normal epithelial cells, is a potent growth inhibitor. However, in oncogenically activated cells, the homeostatic action of TGF-β is often diverted along alternative pathways. Hence, TGF-β signaling elicits protective or tumor suppressive effects during the early growth-sensitive stages of tumorigenesis. However, later in tumor development when carcinoma cells become refractory to TGF-β-mediated growth inhibition, the tumor cell responds by stimulating pathways with tumor progressing effects. At late stages of malignancy, tumor progression is driven by TGF-β overload. The tumor microenvironment is a target of TGF-β action that stimulates tumor progression via pro-tumorigenic effects on vascular, immune, and fibroblastic cells. Bone is one of the richest sources of TGF-β in the body and a common site for dissemination of breast cancer metastases. Osteoclastic degradation of bone matrix, which accompanies establishment and growth of metastases, triggers further release of bone-derived TGF-β. This leads to a vicious positive feedback of tumor progression, driven by ever increasing levels of TGF-β released from both the tumor and bone matrix. It is for this reason, that pharmaceutical companies have developed therapeutic agents that block TGF-β signaling. Nonetheless, the choice of drug design and dosing strategy can affect the efficacy of TGF-β therapeutics. This review will describe pre-clinical and clinical data of four major classes of TGF-β inhibitor, namely i) ligand traps, ii) antisense oligonucleotides, iii) receptor kinase inhibitors and iv) peptide aptamers. Long term dosing strategies with TGF-β inhibitors may be ill-advised, since this class of drug has potentially highly pleiotropic activity, and development of drug resistance might potentiate tumor progression. Current paradigms for the use of TGF-β inhibitors in oncology have therefore moved towards the use of combinatorial therapies and short term dosing, with considerable promise for the clinic.

Source: Complexities of TGF-β Targeted Cancer Therapy. Connolly EC, Freimuth J, Akhurst RJ ( Int J Biol Sci. 2012;8(7):964-78.
Free paper available at:

mercredi 25 juillet 2012

FDA approves Afinitor for advanced breast cancer

            The U.S. Food and Drug Administration recently approved Afinitor (everolimus) for use in combination with Aromasin (exemestane) to treat certain postmenopausal women with advanced hormone-receptor positive, HER2-negative breast cancer.

            The drug combination is intended for use in women with recurrence or progression of their cancer after treatment with Femara (letrozole) or Arimidex (anastrozole).

             “This is the first approval from the class of drugs known as mTOR inhibitors for the treatment of postmenopausal women with advanced hormone-receptor positive breast cancer,” said Richard Pazdur, M.D., director of the Office of Hematology and Oncology Products in the FDA’s Center for Drug Evaluation and Research. “Afinitor is another example of the value of continuing to study drugs in additional types of cancer after their initial approval.”

            The FDA has previously approved Afinitor to treat patients with advanced renal cell carcinoma that has progressed after treatment with other cancer therapies, in adult patients with progressive advanced neuroendocrine tumors of pancreatic origin, for patients with renal angiomyolipoma and tuberous sclerosis complex (TSC) not requiring immediate surgery, and for adults and children with subependymal giant cell astrocytoma associated with TSC who require treatment but are not candidates for curative surgery.
See also :

mardi 24 juillet 2012

FDA approves Kyprolis for some patients with multiple myeloma

            The U.S. Food and Drug Administration recently approved Kyprolis (carfilzomib) to treat patients with multiple myeloma who have received at least two prior therapies, including treatment with Velcade (bortezomib) and an immunomodulatory therapy.

            A form of blood cancer that arises from plasma cells, multiple myeloma usually grows in bone marrow, the soft, spongy tissue found inside most bones. The bone marrow is where normal blood cells are produced.

lundi 23 juillet 2012

Anticancer molecules (93) – Molécules anticancéreuses (93) - SIPULEUCEL-T


Name: sipuleucel-T
Commercial name: Provenge
Pharmacological class: autologous cellular immunotherapy
Therapeutic class: antineoplastic (cancer vaccine)
Action: Sipuleucel-T is a cellular immunotherapy consisting of autologous peripheral blood mononuclear cells (PBMCs), obtained by leukapheresis and activated with a recombinant human protein (PAP-GM-CSF) consisting of prostatic acid phosphatase linked to granulocyte-macrophage colony-stimulating factor.

In 2011, sipuleucel-T is approved:

● for the treatment of asymptomatic or minimally symptomatic metastatic castrate-resistant (hormone refractory) prostate cancer.


Nom: sipuleucel-T
Nom commercial: Provenge
Classe pharmacologique: immunothérapie cellulaire autologue
Classe thérapeutique: antinéoplasique (vaccin contre le cancer)
Action: le sipuleucel-T est une immunothérapie cellulaire constituée de cellules autologues mononuclées de sang périphérique, obtenues par leucaphérèse et activées avec une protéine recombinante humaine (PAP-GM-CSF), composé de la phosphatase acide prostatique liée au « granulocyte-macrophage colony-stimulating factor ».

En 2011, le sipuleucel-T est approuvé:

● pour le traitement des métastases asymptomatiques ou peu symptomatiques du cancer de la prostate hormono-résistant

samedi 21 juillet 2012

Press Review (July 21, 2012) – Revue de presse (21 juillet 2012)

Questioning Surgery for Early Prostate Cancer‎‎‎
A new study shows that prostate cancer surgery, which often leaves men impotent or incontinent, does not appear to save the lives of men with early-stage disease, who account for most cases, and many of these men would do just as well to choose no treatment at all.
By Tara Parker-Pope. In The New York Times (blog)

Genetic Aberrations Seen as Path to Stop Colon Cancer‎
More than 200 researchers investigating colon cancer tumors have found genetic vulnerabilities that could lead to powerful new treatments. The hope is that drugs designed to strike these weak spots will eventually stop a cancer that is now almost inevitably fatal once it has spread.
By Gina Kolata. In The New York Times

Serious side effects more likely in new cancer drugs‎‎
Many new cancer drugs may come at a price - including a higher risk of diarrhea, skin problems and high blood pressure, according to an analysis of studies used to get those medications approved.
By Genevra Pittman. In Reuters

Fukushima increases risk of cancer – but not by much‎
Radiation from Japan's Fukushima Daiichi nuclear power plant will lead to deaths from cancer – but so few that proving a link with the nuclear accident could be impossible.
By Sara Reardon. In New Scientist

Why Having a Large Baby May Raise Your Risk of Breast Cancer‎‎‎‎
New research shows that women who have larger babies have more than twice the risk of breast cancer, compared with mothers who give birth to smaller infants. What's the connection?
By Alice Park. In TIME

Cervical Cancer Spotted Later in Women Without Health Insurance‎‎
Study found lack of coverage predicted more advanced disease.
In U.S. News & World Report

Breast cancer metastasis to bone driven by stress, researchers report‎
Stress can promote breast cancer cell colonization of bone, Vanderbilt Center for Bone Biology investigators have discovered.
By Anne Seccombe. In The Examiner

Cancer and Injuries More Likely in People With Serious Mental Illness‎‎
People with serious mental illness -- schizophrenia, bipolar disorder and disabling depression -- are 2.6 times more likely to develop cancer than the general population, new Johns Hopkins research suggests.
In Science Daily

Deadly Liver Cancer May Be Triggered by Cells Changing Identity‎‎‎
A rare type of cancer thought to derive from cells in the bile ducts of the liver may actually develop when one type of liver cell morphs into a totally different type, a process scientists used to consider all but impossible. UCSF researchers triggered this kind of cellular transformation -- and caused tumors to form in mice -- by activating just two genes.
In Science Daily

Cancers et essais nucléaires : un rapport établit un lien vraisemblable‎
Selon le spécialiste Florent de Vathaire, les retombées radioactives des essais nucléaires français au Sahara et en Polynésie sont possiblement à l’origine de certains cas de cancer chez des militaires et des professionnels du nucléaire. Le lien ne pourra pourtant jamais être établi avec certitude.
Par Janlou Chaput. Dans Futura-Sciences

Cancer du col : se faire vacciner protège les autres‎‎ ‎‎
La vaccination contre le papillomavirus humain protège dans une même population les femmes immunisées mais aussi celles qui ne le sont pas.
Par Vincent Delfau. Dans Le Figaro

Des nanoparticules d'or contre le cancer de la prostate‎
Testé en laboratoire, ce traitement aurait moins d'inconvénients que la chimiothérapie.
Par Jean-Luc Nothias. Dans Le Figaro

L'Avastin n'améliore pas la survie globale dans le cancer du sein avancé
Selon une revue systématique de la Cochrane Library, l'antiangiogénique, anticorps monoclonal anti-VEFG, bévacizumab (Avastin®, Roche) offre un bénéfice modeste en termes de survie sans progression et aucun bénéfice en termes de survie globale chez les patientes atteints d'un cancer du sein métastatique qui le reçoivent en association avec une chimiothérapie classique.
Par Aude Lecrubier. Dans Medscape France

jeudi 19 juillet 2012

Focus : VEGF Inhibits Tumor Cell Invasion and Mesenchymal Transition through a MET/VEGFR2 Complex

Inhibition of VEGF signaling leads to a proinvasive phenotype in mouse models of glioblastoma multiforme (GBM) and in a subset of GBM patients treated with bevacizumab. Here, we demonstrate that vascular endothelial growth factor (VEGF) directly and negatively regulates tumor cell invasion through enhanced recruitment of the protein tyrosine phosphatase 1B (PTP1B) to a MET/VEGFR2 heterocomplex, thereby suppressing HGF-dependent MET phosphorylation and tumor cell migration. Consequently, VEGF blockade restores and increases MET activity in GBM cells in a hypoxia-independent manner, while inducing a program reminiscent of epithelial-to-mesenchymal transition highlighted by a T-cadherin to N-cadherin switch and enhanced mesenchymal features. Inhibition of MET in GBM mouse models blocks mesenchymal transition and invasion provoked by VEGF ablation, resulting in substantial survival benefit.

Source: VEGF Inhibits Tumor Cell Invasion and Mesenchymal Transition through a MET/VEGFR2 Complex. Lu KV, Chang JP, Parachoniak CA, Pandika MM, Aghi MK, Meyronet D, Isachenko N, Fouse SD, Phillips JJ, Cheresh DA, Park M, Bergers G ( Cancer Cell. 2012 Jul 10;22(1):21-35.
Free paper available at:

L'inhibition de la signalisation du VEGF («vascular endothelial growth factor » ou facteur de croissance endothelial vasculaire) conduit à un phénotype pro-invasif dans des modèles murins de glioblastome multiforme (GBM) et dans un sous-ensemble de patients atteints de GBM traités avec le bevacizumab. Ici, nous démontrons que le VEGF régule directement et négativement l'invasion des cellules tumorales grâce à un meilleur recrutement de la protéine tyrosine phosphatase 1B (PTP1B) sur l’hétérocomplexe MET/VEGFR2, supprimant ainsi la phosphorylation HGF-dépendante de MET et la migration des cellules tumorales. Par conséquent, le blocage du VEGF restaure et augmente l’activité de MET dans les cellules de GBM d'une manière indépendante de l'hypoxie, tout en induisant un programme qui rappelle la transition épithéliale-mésenchymateuse. L'inhibition de la MET dans les modèles de souris à GBM bloque la transition épithéliale-mésenchymateuse et l'invasion provoquée par la suppression du VEGF, ce dont il résulte une survie nettement accrue.

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

mercredi 18 juillet 2012

Focus: A public resource facilitating clinical use of genomes

Rapid advances in DNA sequencing promise to enable new diagnostics and individualized therapies. Achieving personalized medicine, however, will require extensive research on highly reidentiable, integrated datasets of genomic and health information. To assist with this, participants in the Personal Genome Project choose to forgo privacy via our institutional review boardapproved “open consent” process. The contribution of public data and samples facilitates both scientic discovery and standardization of methods. We present our ndings after enrollment of more than 1,800 participants, including whole-genome sequencing of 10 pilot participant genomes (the PGP-10). We introduce the GenomeEnvironment-Trait Evidence (GET-Evidence) system. This tool automatically processes genomes and prioritizes both published and novel variants for interpretation. In the process of reviewing the presumed healthy PGP-10 genomes, we nd numerous literature references implying serious disease. Although it is sometimes impossible to rule out a late-onset effect, stringent evidence requirements can address the high rate of incidental ndings. To that end we develop a peer production system for recording and organizing variant evaluations according to standard evidence guidelines, creating a public forum for reaching consensus on interpretation of clinically relevant variants. Genome analysis becomes a two-step process: using a prioritized list to record variant evaluations, then automatically sorting reviewed variants using these annotations. Genome data, health and trait information, participant samples, and variant interpretations are all shared in the public domain—we invite others to review our results using our participant samples and contribute to our interpretations. We offer our public resource and methods to further personalized medical research.

Source: A public resource facilitating clinical use of genomes. Ball MP, Thakuria JV, Zaranek AW, Clegg T, Rosenbaum AM, Wu X, Angrist M, Bhak J, Bobe J, Callow MJ, Cano C, Chou MF, Chung WK, Douglas SM, Estep PW, Gore A, Hulick P, Labarga A, Lee JH, Lunshof JE, Kim BC, Kim JI, Li Z, Murray MF, Nilsen GB, Peters BA, Raman AM, Rienhoff HY, Robasky K, Wheeler MT, Vandewege W, Vorhaus DB, Yang JL, Yang L, Aach J, Ashley EA, Drmanac R, Kim SJ, Li JB, Peshkin L, Seidman CE, Seo JS, Zhang K, Rehm HL, Church GM. Proc Natl Acad Sci U S A. 2012 Jul 13. [Epub ahead of print]
Free paper available at:

Focus: p53, a target of estrogen receptor (ER) alpha, modulates DNA damage-induced growth suppression in ER-positive breast cancer cells

            In response to genotoxic stress, the p53 tumor suppressor induces target genes for cell cycle arrest, apoptosis and DNA repair. Although p53 is the most commonly mutated gene in all human cancers, it is only mutated in about 20% of breast cancers. 70% of all breast cancer cases are estrogen receptor positive (ER-positive) and express estrogen receptor alpha (ERα). ER-positive breast cancer generally indicates good patient prognosis and treatment responsiveness with anti-estrogens such as tamoxifen. However, ER-positive breast cancer patients can experience loss or a reduction in ERα, which is associated with aggressive tumor growth, increased invasiveness, poor prognosis, and loss of p53 function. Consistent with this, we found that p53 is a target gene of ERα. Specifically, we found that knockdown of ERα decreases expression of p53 and its downstream target genes, MDM2 and p21. In addition, we found that ERα activates p53 transcription via binding to ERE half-sites within the p53 promoter. Moreover, we found that loss of ERα desensitizes, whereas ectopic expression of ERα sensitizes, breast cancer cells to DNA damage-induced growth suppression in a p53-dependent manner. Together, this study provides an insight into a feedback loop between ERα and p53 and a biological role of p53 in the DNA damage response in ER-positive breast cancers.

Source: p53, a target of estrogen receptor (ER) alpha, modulates DNA damage-induced growth suppression in ER-positive breast cancer cells. Berger CE, Qian Y, Liu G, Chen H (, J Biol Chem. 2012 Jul 11.
Free paper available at:

mardi 17 juillet 2012

Mutated genes in cancer (76) – PDGFRA


In databases:

● Entrez ( 5156 or PDGFRA
● Ensembl ( ENSG00000134853
● UniProt ( P16234
● GeneCards ( PDGFRA
● HGNC ( 8803 or PDGFRA
● Enzyme Number (IUBMB): EC 2.7.10.-, EC

Gene locus:


Protein name:

Platelet-derived growth factor receptor, alpha polypeptide

Protein Size:

1089 amino acids; about 123 kDa

Function :

PDGFRA encodes a cell surface tyrosine kinase receptor for members of the platelet-derived growth factor family. These growth factors are mitogens for cells of mesenchymal origin. The identity of the growth factor bound to a receptor monomer determines whether the functional receptor is a homodimer or a heterodimer, composed of both platelet-derived growth factor receptor alpha and beta polypeptides. Activation of PDGFRA kinase activity initiates intracellular signaling through the MAPK, PI 3-K and PKCγ pathways.

Cancer-related alterations:

Somatic PDGFRA mutations have been found in tumors of small intestine (about 50% of cases), stomach and soft tissue. Two-thirds of these mutations are “substitution missense”, for which a mutation hot spot exists, corresponding to amino acid 842.

Gastrointestinal stromal tumors (GISTs) are rare neoplasms of mesenchymal origin arising in the gastrointestinal tract. These tumors are characterized by activating mutations of either receptor tyrosine kinase KIT or PDGFRA, which are found in 85% of cases.

Fusion genes involving PDGFRA and various other genes (FIP1L1, CDK5RAP2, STRN, KIF5B, ETV6, BCR is the cause of diseases accompanied by eosinophilia (see below):

del(4)(q12q12)                       FIP1L1-PDGFRA                 ● CEL
ins(9;4)(q33;q12q25) CDK5RAP2-PDGFRA         ● CEL
t(2;4)(p22;q12)                       STRN-PDGFRA                   ● MPD with eosinophilia
t(4;10)(q12;p11)                     KIF5B-PDGFRA                  ● MPS  with hypereosinophilia
t(4;12)(q12;p13)                     ETV6-PDGFRA                    ● MPD with hypereosinophilia
t(4;22)(q12;q11.2)                  BCR-PDGFRA                     ● MPD and atypical CML

CEL: chronic eosinophilic leukemia ; MPD : myeloproliferative disorder ; MPS : myeloproliferative syndrome ; CML : chronic myeloid leukemia

The most investigated of these fusion genes is FIP1L1-PDGFRA (see, among others, Fukushima et al. 2009).


The introduction of imatinib mesylate, which targets the kinases presenting with PDGFRA or KIT alterations, has dramatically changed the management of GISTs, which were resistant to conventional cytotoxic chemotherapy, both in advanced and localized phases. However, although the majority of GISTs show an initial clinical response to imatinib, the development of resistance to this tyrosine kinase inhibitor as well as to the alternative kinase inhibitor sunitinib is problematic (Downs-Kelly & Rubin, 2011).
Rare cases of mutant FIP1L1-PDGFRA that are resistant to imatinib mesylate (eg, T674I, D842V) have been reported. In vitro, the T674I, but not the D842V, mutant was shown to be sensitive to other kinase inhibitors, including nilotinib, sorafenib, and PKC412 . Also, there are reported instances of interferon alfa–induced complete clinical remissions in FIP1L1-PDGFRA–positive clonal eosinophilia (Tefferi et al. 2010)

References (open access):

Gastrointestinal stromal tumors: molecular mechanisms and targeted therapies. Downs-Kelly E, Rubin BP. Patholog Res Int. 2011 Apr 14;2011:708596.

Hypereosinophilic syndrome and clonal eosinophilia: point-of-care diagnostic algorithm and treatment update. Tefferi A, Gotlib J, Pardanani A. Mayo Clin Proc. 2010 Feb;85(2):158-64.

FIP1L1-PDGFRalpha imposes eosinophil lineage commitment on hematopoietic stem/progenitor cells. Fukushima K, Matsumura I, Ezoe S, Tokunaga M, Yasumi M, Satoh Y, Shibayama H, Tanaka H, Iwama A, Kanakura Y. J Biol Chem. 2009 Mar 20;284(12):7719-32.

lundi 16 juillet 2012

Focus : Cancer Epigenetics: From Mechanism to Therapy

The epigenetic regulation of DNA-templated processes has been intensely studied over the last 15 years. DNA methylation, histone modication, nucleosome remodeling, and RNA-mediated targeting regulate many biological processes that are fundamental to the genesis of cancer. Here, we present the basic principles behind these epigenetic pathways and highlight the evidence suggesting that their misregulation can culminate in cancer. This information, along with the promising clinical and preclinical results seen with epigenetic drugs against chromatin regulators, signies that it is time to embrace the central role of epigenetics in cancer.

Source: Cancer Epigenetics: From Mechanism to Therapy. Mark A. Dawson, Tony Kouzarides ( Cell, Volume 150, Issue 1, 12-27, 6 July 2012.
Free paper available at:

La régulation épigénétique a été intensément étudiée au cours des 15 dernières années. La méthylation de l'ADN, la modification des histones, le remodelage des nucléosomes, et le ciblage médié par l'ARN régulent de nombreux processus biologiques qui sont essentiels à la genèse du cancer. Ici, nous présentons les principes de base de ces voies épigénétiques et nous soulignons les éléments de preuve suggérant que le dérèglement de ces voies peut aboutir à un cancer. Cette information, ainsi que les résultats cliniques et précliniques prometteurs observés avec des « médicaments épigénétiques » contre les régulateurs de la chromatine, signifient qu'il est temps d’accorder la plus grande considération au rôle central de l'épigénétique dans le cancer.

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

samedi 14 juillet 2012

Press Review (July 14, 2012) – Revue de presse (14 juillet 2012)

A Life-Death Predictor Adds to a Cancer's Strain‎‎
Doctors try to give survival odds based on a tumor’s appearance and size, but often that is just an educated guess.
By Gina Kolata. In The New York Times

Continued Progression in Cancer Diagnostics and Discussion
“As our population ages, cancer will increase in incidence and in prevalence,” says Dr. Richard Schilsky. As I continue my interview with Dr. Schilsky, however, he appears to be promoting a more positive outlook on cancer. Now there is a new view on cancer, as it is coming to be seen more as a chronic illness rather than a life-ending prognosis. However, it is important to understand that cancer is not one disease..
By Jawad Arshad. In Triple Helix Online

Metastatic breast cancer: Bevacizumab slows progression, but has no impact on survival‎
The cancer drug bevacizumab (Avastin®) offers only a modest benefit in delaying disease progression in patients with advanced stage breast cancer, according to a systematic review by Cochrane researchers. The researchers assessed the efficacy of bevacizumab in combination with chemotherapy, an established cancer treatment in this indication, and found no overall survival benefit when adding bevacizumab to chemotherapy.
In Science Codex

Waiting for a Cancer Diagnosis‎‎‎‎
The period of time when you are waiting for a diagnosis is brutal. There's really no other way to describe it. As a nurse-turned-patient, I really had no idea just how difficult this waiting period really is. Waiting for my diagnosis of FBC (f-bomb breast cancer) was simultaneously heart-wrenching, nerve-wracking, confusing and downright scar‎.
By Hollye Harrington Jacobs. In Huffington Post

GSK pulls US bid to use Tykerb with Herceptin‎
British group GlaxoSmithKline has pulled a U.S. application seeking approval to use its breast cancer drug Tykerb in combination with Roche's rival product Herception for certain patients with advanced disease.
In Reuters

Heavy people more likely to have colon polyps‎
Obese and overweight people are more likely to develop colon polyps, a possible precursor to cancer, than are slimmer individuals, according to a new review of past research.
In Reuters

Cervical Cancer: The Silent Killer of Women in the Developing World‎
Like millions of mothers around the world, Adjaratou Kinda worries about her children's future. How will they fare in school? What career path will they choose? Will they be healthy and happy? But tragically, she must now also worry about how her five children will survive without their mother. Mrs. Kinda is one of more than 470,000 women diagnosed each year with cervical cancer, a prognosis that, in her West African home of Burkina Faso, is tantamount to a death sentence.
By Liz Lange. In Huffington Post

Vivre avec le cancer comme une maladie chronique‎ ‎‎
Le cancer n'est plus nécessairement synonyme de mort, selon la Fondation québécoise du cancer. Certaines personnes vivent avec plusieurs cancers sans jamais en décéder.
Dans Canoë

Cancer du sein : les femmes à grosse poitrine sont-elles plus à risques ?
Existerait-il un lien entre la taille de la poitrine et le risque de développer un cancer du sein ? C’est ce que suggère une étude parue fin juin montrant que trois gènes impliqués dans les tumeurs mammaires sont retrouvés chez les femmes aux plus fortes poitrines. Des résultats à prendre avec des pincettes…
Par Janlou Chaput. Dans Futura-Sciences

Obésité, diabète, cancer : une partie de la solution dans nos assiettes ?‎
Bien manger pour se maintenir en bonne santé, mais pas seulement. Notre alimentation modifierait également l’expression des gènes et permettrait donc à nos enfants de bénéficier d'un meilleur "capital santé". Explications de  Maximilien Rouer, président de BeCitizen, une société de conseil stratégique en développement durable.
Par Maximilien Rouer. Dans Le Nouvel Observatuer

Une mutation génétique rendrait certains traitements pour le cancer moins efficace
Une équipe de 55 chercheurs, dirigée par le Dr. Sin Tiong ONG de l'Ecole de Médecine Duke-NUS (National University of Singapore) [1], a découvert une mutation génétique rendant les traitements de certains cancers moins efficaces. Ils ont également identifié une solution pour pallier à ce problème. Les conclusions de l'équipe ont été publiées dans la revue Nature Medicine.

Des Zurichois découvrent le point d’accès des métastases aux organes
Des chercheurs de l’Université de Zurich ont découvert pour la première fois comment les métastases de cellules cancéreuses passent du sang dans les organes.
Dans La Tribune de Genève