Toward a NOTCH1/FBXW7/RAS/PTEN–Based Oncogenetic Risk Classification of Adult T-Cell Acute Lymphoblastic Leukemia: A Group for Research in Adult Acute Lymphoblastic Leukemia Study

The Group for Research in Adult Acute Lymphoblastic Leukemia (GRAALL) recently reported a significantly better outcome in T-cell acute lymphoblastic leukemia (T-ALL) harboring NOTCH1 and/or FBXW7 (N/F) mutations compared with unmutated T-ALL. Despite this, one third of patients with N/F-mutated T-AL...

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Published in:	Journal of clinical oncology Vol. 31; no. 34; pp. 4333 - 4342
Main Authors:	TRINQUAND, Amélie, TANGUY-SCHMIDT, Aline, LHERITIER, Véronique, BOND, Jonathan, HUGUET, Françoise, BUZYN, Agnès, LEGUAY, Thibaud, CAHN, Jean-Yves, THOMAS, Xavier, CHALANDON, Yves, DELANNOY, André, BONMATI, Caroline, BEN ABDELALI, Raouf, MAURY, Sebastien, NADEL, Bertrand, MACINTYRE, Elizabeth, IFRAH, Norbert, DOMBRET, Hervé, ASNAFI, Vahid, LAMBERT, Jérôme, BELDJORD, Kheira, LENGLINE, Etienne, DE GUNZBURG, Noémie, PAYET-BORNET, Dominique, LHERMITTE, Ludovic, MOSSAFA, Hossein
Format:	Journal Article
Language:	English
Published:	Alexandria, VA American Society of Clinical Oncology 01-12-2013
Subjects:	Adult Biological and medical sciences Cell Cycle Proteins Cell Cycle Proteins - genetics Disease-Free Survival DNA Mutational Analysis F-Box Proteins F-Box Proteins - genetics F-Box-WD Repeat-Containing Protein 7 Female Gene Deletion Genetic Predisposition to Disease GTP Phosphohydrolases GTP Phosphohydrolases - genetics Hematologic and hematopoietic diseases Humans Immunology Innate immunity Kaplan-Meier Estimate Leukemias. Malignant lymphomas. Malignant reticulosis. Myelofibrosis Life Sciences Male Medical sciences Membrane Proteins Membrane Proteins - genetics Multivariate Analysis Mutation Phenotype Precursor T-Cell Lymphoblastic Leukemia-Lymphoma Precursor T-Cell Lymphoblastic Leukemia-Lymphoma - classification Precursor T-Cell Lymphoblastic Leukemia-Lymphoma - genetics Precursor T-Cell Lymphoblastic Leukemia-Lymphoma - mortality Precursor T-Cell Lymphoblastic Leukemia-Lymphoma - therapy Predictive Value of Tests Proportional Hazards Models Proto-Oncogene Proteins Proto-Oncogene Proteins - genetics Proto-Oncogene Proteins p21(ras) PTEN Phosphohydrolase PTEN Phosphohydrolase - genetics ras Proteins ras Proteins - genetics Receptor, Notch1 Receptor, Notch1 - genetics Risk Factors Time Factors Tumors Ubiquitin-Protein Ligases Ubiquitin-Protein Ligases - genetics Young Adult Adult T cell leukemia Risk Research Cancerology Lymphoproliferative syndrome Classification Adult PTEN Gene Acute lymphocytic leukemia Protooncogene Tumor suppressor gene Human Deltaretrovirus Retroviridae Malignant hemopathy Infection Virus Viral disease C-Onc gene Risk factor Oncogenetics Ras gene HTLV-I virus Cancer T cell acute lymphoblastic leukemia
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Summary:	The Group for Research in Adult Acute Lymphoblastic Leukemia (GRAALL) recently reported a significantly better outcome in T-cell acute lymphoblastic leukemia (T-ALL) harboring NOTCH1 and/or FBXW7 (N/F) mutations compared with unmutated T-ALL. Despite this, one third of patients with N/F-mutated T-ALL experienced relapse. In a series of 212 adult T-ALLs included in the multicenter randomized GRAALL-2003 and -2005 trials, we searched for additional N/K-RAS mutations and PTEN defects (mutations and gene deletion). N/F mutations were identified in 143 (67%) of 212 patients, and lack of N/F mutation was confirmed to be associated with a poor prognosis. K-RAS, N-RAS, and PTEN mutations/deletions were identified in three (1.6%) of 191, 17 (8.9%) of 191, and 21 (12%) of 175 patients, respectively. The favorable prognostic significance of N/F mutations was restricted to patients without RAS/PTEN abnormalities. These observations led us to propose a new T-ALL oncogenetic classifier defining low-risk patients as those with N/F mutation but no RAS/PTEN mutation (97 of 189 patients; 51%) and all other patients (49%; including 13% with N/F and RAS/PTEN mutations) as high-risk patients. In multivariable analysis, this oncogenetic classifier remained the only significant prognostic covariate (event-free survival: hazard ratio [HR], 3.2; 95% CI, 1.9 to 5.15; P < .001; and overall survival: HR, 3.2; 95% CI, 1.9 to 5.6; P < .001). These data demonstrate that the presence of N/F mutations in the absence of RAS or PTEN abnormalities predicts good outcome in almost 50% of adult T-ALL. Conversely, the absence of N/F or presence of RAS/PTEN alterations identifies the remaining cohort of patients with poor prognosis.
Bibliography:	ObjectType-Article-2 SourceType-Scholarly Journals-1 ObjectType-Feature-1 ObjectType-News-3 content type line 23 ObjectType-Article-1 ObjectType-Feature-2
ISSN:	0732-183X 1527-7755
DOI:	10.1200/JCO.2012.48.5292