dimanche 31 juillet 2011

Mutated genes in cancer (2) – EML4


In databases:

● Entrez (http://www.ncbi.nlm.nih.gov/sites/gquery): 27436 or EML4
● Ensembl (http://www.ensembl.org/index.html): ENSG00000143924
● UniProt (http://www.uniprot.org/): Q9HC35
● GeneCards (http://www.genecards.org/): EML4
● HGNC (http://www.genenames.org/): 1316 or EML4

Gene locus:


Protein name:

Echinoderm microtubule associated protein like 4

Protein Size:

981 amino acids; about 109 kDa


Strongly overexpressed during mitosis, EML4 is necessary for correct microtubule  formation.

Cancer-related alterations:

EML4 is involved in fusions with ALK (inv(2)(p21p23)) in non-small cell lung carcinoma (NSCLC). EML4-ALK fusion transcript is detectable in a low amount (frequency between 2,7% and 6,7%) of NSCLC-samples and NSCLC-cell-lines. EML4-ALK is a protein tyrosine kinase, which is constitutively dimerized and thus activated.


Alk-inhibitors impede proliferation in EML4-ALK-fusion positive lung cancer cell-lines. In experiments with transgenic mice, treatment with ALK-inhibitors resulted in reduced tumor mass. The EML4-ALK fusion gene was identified as a potentially targetable oncogenic driver in non-small cell lung cancer in 2007. A small molecule ALK inhibitor, crizotinib, may now be on the verge of approval by the FDA for the treatment of ALK-rearranged lung cancer (Gerber DE, Minna JD 2010).

References (free access):

ALK inhibition for non-small cell lung cancer: from discovery to therapy in record time. Gerber DE, Minna JD. Cancer Cell. 2010 Dec 14;18(6):548-51.

EML4-ALK mutations in lung cancer that confer resistance to ALK inhibitors. Choi YL, Soda M, Yamashita Y, Ueno T, Takashima J, Nakajima T, Yatabe Y, Takeuchi K, Hamada T, Haruta H, Ishikawa Y, Kimura H, Mitsudomi T, Tanio Y, Mano H; ALK Lung Cancer Study Group. N Engl J Med. 2010 Oct 28;363(18):1734-9.

The biology and treatment of EML4-ALK non-small cell lung cancer. Sasaki T, Rodig SJ, Chirieac LR, Jänne PA. Eur J Cancer. 2010 Jul;46(10):1773-80.

Mutated genes in cancer (1) – ABL1


In databases:

● Ensembl (http://www.ensembl.org/index.html): ENSG00000097007
● UniProt (http://www.uniprot.org/): P00519
● GeneCards (http://www.genecards.org/): ABL1
● HGNC (http://www.genenames.org/): 76 or ABL1
Enzyme Number (IUBMB): EC

Gene locus:


Protein name:

v-abl Abelson murine leukemia viral oncogene homolog 1

Protein Size:

1130-1143 amino acids (from alternative splicing); about 145 kDa


The proto-oncogene ABL1 encodes a protein tyrosine kinase involved in cell differentiation, cell division, cell adhesion, and stress response. It interacts with a large variety of cellular proteins including signalling adaptors, kinases, phosphatases, cell cycle regulators, transcription factors and cytoskeletal proteins. Activity of ABL1 protein is negatively regulated by its SH3 domain, and deletion of the SH3 domain turns ABL1 into an oncogene.

Cancer-related gene alterations:

A t(9;22)(q34;q11) (translocation) involving ABL1 and BCR is a cause of chronic myeloid leukemia (CML). In fact, all CML patients have a t(9;22), at least at the molecular level. A similar translocation is found also in acute myeloid leukemia (AML) and in acute lymphoblastic leukemia (ALL).
In ALL, another translocation, t(9;12)(q34;p12) (ETV6-ABL1), may occasionally be observed. It fuses ETV6 N-terminus to the tyrosine kinase domain from ABL1 C-terminus.
In T-ALL, t(9;9)(q34;q34) (NUP214-ABL1) and t(9;14)(q34;q32) (EML1-ABL1) are also observed. The NUP214-ABL1 gene is the second most prevalent fusion gene involving ABL1 in malignant hemopathies.
In B-ALL t(1;9)(q24;q34) (RCSD1-ABL1), t(1;9)(p34;q34) (SFPQ-ABL1) and t(9;10)(q34;q22.3) (ZMIZ1-ABL1) are also observed.

Somatic ABL1 mutations have been observed mainly in haematopoietic and lymphoid tissue cancers (up to 30% of cases). They are substitutions, exclusively, and most of them are found in a region (amino acids 232-499) corresponding to protein kinase activity.

Specific therapies:

Due to the development of novel drugs able to target the enhanced tyrosine kinase activity of BCR-ABL, treatments have changed radically over the last 10 years. The first of these drug is imatinib mesylate which has become the first line therapy for all patients with CML
Recent data suggest that pharmacological inhibition of endogenous ABL could lead to a genetic instability, potentially by inhibition of mismatch repair mechanisms. Long-term inhibition of ABL by tyrosine kinase inhibitor therapies could therefore be responsible of the occurrence of a mutator phenotypes.

References (free access):

ABL1 fusion genes in hematological malignancies: a review. De Braekeleer E, Douet-Guilbert N, Rowe D, Bown N, Morel F, Berthou C, Férec C, De Braekeleer M. Eur J Haematol. 2011 May;86(5):361-71.

Genomic amplification of BCR/ABL1 and a region downstream of ABL1 in chronic myeloid leukaemia: a FISH mapping study of CML patients and cell lines. Virgili A, Nacheva EP. Mol Cytogenet. 2010 Sep 1;3:15.

samedi 30 juillet 2011

Press review (July 30, 2011) – Revue de presse (30 juillet 2011)

Computer-aided mammography doesn't improve breast cancer detection
The widely used mammography software known as computer-aided detection (CAD) doesn't improve detection of invasive breast cancer, new research suggests.
By Kathleen Doheny. In USA Today

Screening has little impact on breast cancer deaths: study‎
Falling breast cancer death rates have little to do with breast screening but are down to better treatment and health systems, scientists said on Friday, in a study likely to fuel a long-running row over the merits of mammograms.
By Eric Gaillard, Elizabeth Fullerton. Reuters

Scant Evidence to Link 9/11 to Cancer, US Report Says
There is not enough evidence yet to say whether the dust and smoke cloud produced by the terrorist attack on the World Trade Center caused cancer, federal officials concluded in a report released on Tuesday.
By Anemona Hartocollis. In The New York Times

Convergence in head and neck cancer
In back-to-back papers published online July 28 in Science, researchers from the Broad Institute, Dana-Farber Cancer Institute, Johns Hopkins Kimmel Cancer Center, the University of Pittsburgh, and the University of Texas MD Anderson Cancer Center have confirmed genetic abnormalities previously suspected in head and neck cancer, including defects in the tumor suppressor gene known as p53. But the two teams also found mutations in the NOTCH family of genes, suggesting their role as regulators of an important stage in cell development may be impaired.
EurekAlert (press release)

Researchers Look to Dogs to Better Understand Intricacies of Bone Cancer
A new University of Minnesota discovery may help bone cancer patients fight their disease more effectively, according to new research published in the September issue of “Bone”.
In Science Daily

Are Cancers New Species?
Cancer is one of the scourges of modern society. An increasing number of people are fighting it, and a lot of research is being done in order to understand it better, hopefully leading to treatments or cures.
At present, the dominant theory is that cancer arises from a handful gene mutations. But recently, Peter Duesberg and his colleagues at UC Berkeley have launched the idea that cancer instead arises from chromosome disruptions, and that this, in fact, constitutes a form of speciation. So, according to this view, cancers are newly evolved species, as they have new chromosomal karyotypes. On top of this, cancers are autonomous and don’t need other cells for survival.
By Gunnar De Winter. In Science 2.0

Growing Up Near Livestock Tied to Blood Cancers
Children raised on livestock farms are at significantly greater risk of developing blood cancers -- such as leukemia, multiple myeloma and non-Hodgkin's lymphoma -- later in life, a new study contends.
In U.S. News & World Report

Cancer mystery solved
Same protein (maspin) can slow disease or put it on fast track.
By John Miner. In The London Free Press

Early-stage breast cancer: Microscopic tumor spread is no worry
Women with early-stage breast cancer have plenty of procedures and treatments to deal with. So it may come as welcome news that a large clinical trial has found no reason for doctors to perform two tests that were thought to help predict patient survival. Writing in the Journal of the American Medical Assn., the researchers say that the test results are meaningless.
By Karen Kaplan. Los Angeles Times

Researchers Find 3 Genes (MSR1, ASCC1, and CTHRC1) Linked to Esophagus Disorders
Mutations in three genes have been found to be more common among people with disorders of the esophagus, including esophageal cancer and Barrett esophagus (a complication of gastroesophageal reflux disease), a new study shows.
In U.S. News & World Report

Can the cat give you cancer? Parasite in their bellies linked with brain tumours
Scientists have found a link between brain tumours and a parasite that is found in both cats' stomachs and humans.
By Fiona Macrae. In The Daily Mail

Pas de lien entre le 11/09 et des cancers
Il n'existe pas de preuve que l'exposition aux poussières et aux décombres du World Trade Center après les attentats du 11 septembre 2001 à New York ait entraîné de nombreux cas de cancers, affirme un rapport du gouvernement américain.
Le Figaro

Plan cancer: à mi-parcours, Sarkozy exhorte à "ne pas relâcher l'effort"
Nicolas Sarkozy a souligné "la poursuite des avancées obtenues dans la lutte contre le cancer" et appelé "à ne pas relâcher l'effort, notamment en matière de prévention et de dépistage", en recevant lundi un nouveau rapport d'étape sur le plan cancer 2009-2013.
Voir aussi le site: www.plan-cancer.gouv.fr

Cancer de la prostate résistant : la testostérone est court-circuitée
Des chercheurs texans ont identifié un mécanisme de résistance à la castration hormonale dans les cancers de la prostate. La dihydrotestostérone (DHT), puissant androgène, continuerait à être synthétisée par une voie alternative indépendante de la testostérone.
Par Irène Drogou. Dans Le Quotidien du Médecin

vendredi 29 juillet 2011

Anticancer molecules (54) – Molécules anticancéreuses (54)


Name(s): tositumomab and I131 iodine tositumomab
Commercial name: Bexxar
Pharmacological class: B-lymphocyte-restricted differentiation antigen [CD20] inhibitor
Therapeutic class: antineoplastic
Action: tositumomab is a murine IgG2a lambda monoclonal antibody directed against the CD20 antigen, which is found on the surface of normal and malignant B lymphocytes. Iodine I131 tositumomab is a radio-iodinated derivative of tositumomab that has been covalently linked to Iodine-131. The tositumomab therapeutic regimen is administered in two discrete steps: the dosimetric and therapeutic steps. Each step consists of a sequential infusion of tositumomab followed by I131 tositumomab. The therapeutic step is administered 7-14 days after the dosimetric step.

In 2011, tositumomab and I131 tositumomab are approved:

            ● for the treatment of CD20 positive, follicular non-Hodgkin lymphoma, with or without transformation that is refractory to rituximab and has relapsed following chemotherapy.


Nom (s): tositumomab et iode 131 (I131)- tositumomab
Nom commercial: Bexxar
Classe pharmacologique: anticorps monoclonal (inhibiteur de l’antigène de différenciation CD20, restreint aux lymphocytes B)
Classe thérapeutique: antinéoplasiques
Action: le tositumomab est un anticorps monoclonal murin IgG2a lambda dirigé contre l'antigène CD20, qui se trouve sur la surface des lymphocytes B normaux et malins. L'iode 131 ( I131)-tositumomab est un dérivé radio-iodé du tositumomab qui a été lié de façon covalente à l'iode-131. Le schéma thérapeutique employant le  tositumomab consiste en deux étapes distinctes: les étapes dosimétrique et thérapeutique. Chaque étape consiste en une perfusion séquentielle de tositumomab suivie par l'iode 131 I tositumomab. L'étape thérapeutique est administrée 7-14 jours après l'étape dosimétrique.

 En 2011, les tositumomab et I131 tositumomab sont approuvés:

            ● pour le traitement du lymphome non hodgkinien folliculaire exprimant l’antigène CD20,  avec ou sans transformation, qui est réfractaire au rituximab et a réapparu après chimiothérapie.



Tumor types are classified according to the International Classification of Diseases for Oncology (ICD-O), 3rd Edition, World Health Organization, Geneva, 2000. The ICD-O-3 is a dual classification and coding system for both morphology and topography of a neoplasm.
The MORPHOLOGY code (Mxxxx/x) indicates the specific histologic term.
The TOPOGRAPHY code (C00-C80) is occasionally mentioned here.

Abbreviation: NOS, not otherwise specified


Les types de tumeurs sont classés en fonction de la « Classification Internationale des Maladies pour l'Oncologie (CIM-O), 3e édition, Organisation mondiale de la Santé, Genève, 2000. La CIM-O-3 est un système de classification et de codage pour la morphologie et la topographie d'une tumeur.
Le code de MORPHOLOGIE (Mxxxx/x) indique le terme spécifique histologique.
Le code de TOPOGRAPHIE (C00-C80) est occasionnellement mentionné ici.

Abréviation: SAI, sans autre indication


Brenner tumor, malignant
Tumeur de Brenner, maligne



Serous adenocarcinofibroma

Adénocarcinofibrome séreux

Mucinous adenocarcinofibroma

Adénocarcinofibrome mucineux


Phyllodes tumor, malignant
Tumeur phyllode, maligne


Synovial sarcoma, NOS

Synovialosarcome, SAI

Synovial sarcoma, spindle cell

Synovialosarcome à cellules fusiformes

Synovial sarcoma, epithelioid cell

Synovialosarcome à cellules épithélioïdes

Synovial sarcoma, biphasic

Synovialosarcome de type biphasique

Clear cell sarcoma, NOS (except of Kidney M-8964/3)

Sarcome à cellules claires, SAI (sauf le rein, voir M-89643)


Mesothelioma, malignant

Mésothéliome malin

Fibrous mesothelioma, malignant

Mésothéliome fibreux malin

Epithelioid mesothelioma, malignant

Mésothéliome épithélioïde malin

Mesothelioma, biphasic, malignant

Mésothéliome de type biphasique malin

(compilation : Marc Lacroix)