Journal Article

KRAS and CREBBP mutations: a relapse-linked malicious liaison in childhood high hyperdiploid acute lymphoblastic leukemia

Stanulla, M, Mecklenbräuker, A, Malinowska-Ozdowy, K, Eckert, C, Kneidinger, D, Frech, C, Panzer-Grümayer, R, Schrappe, M, Schuster, M, Bock, C, Haas, O A, Horstmann, M A, Mann, G, von Stackelberg, A, Schönegger, A, zur Stadt, U, Cazzaniga, G, Locatelli, F, Attarbaschi, A

2015

Overview

High hyperdiploidy defines the largest genetic entity of childhood acute lymphoblastic leukemia (ALL). Despite its relatively low recurrence risk, this subgroup generates a high proportion of relapses. The cause and origin of these relapses remains obscure. We therefore explored the mutational landscape in high hyperdiploid (HD) ALL with whole-exome ( n =19) and subsequent targeted deep sequencing of 60 genes in 100 relapsing and 51 non-relapsing cases. We identified multiple clones at diagnosis that were primarily defined by a variety of mutations in receptor tyrosine kinase (RTK)/Ras pathway and chromatin-modifying genes. The relapse clones consisted of reappearing as well as new mutations, and overall contained more mutations. Although RTK/Ras pathway mutations were similarly frequent between diagnosis and relapse, both intergenic and intragenic heterogeneity was essentially lost at relapse. CREBBP mutations, however, increased from initially 18–30% at relapse, then commonly co-occurred with KRAS mutations ( P <0.001) and these relapses appeared primarily early ( P =0.012). Our results confirm the exceptional susceptibility of HD ALL to RTK/Ras pathway and CREBBP mutations, but, more importantly, suggest that mutant KRAS and CREBBP might cooperate and equip cells with the necessary capacity to evolve into a relapse-generating clone.

• Publisher: Nature Publishing Group UK,Nature Publishing Group
• Subject: 45 / 45/47 / 631/208/514 / 631/67/1990/283 / 631/67/69 / 692/699/67/1990/283/2125 / 692/699/67/2332 / 692/699/67/68 / Acute lymphocytic leukemia / Adolescent / Antineoplastic Combined Chemotherapy Protocols - therapeutic use / Cancer Research / Case-Control Studies / Child / Clonal Evolution / CREB-Binding Protein - genetics / Critical Care Medicine / Development and progression / Diploidy / Female / Follow-Up Studies / Gene mutations / Genetic aspects / Health aspects / Hematology / Humans / Identification and classification / Intensive / Internal Medicine / Male / Medicine / Medicine & Public Health / Mutation - genetics / Neoplasm Recurrence, Local - drug therapy / Neoplasm Recurrence, Local - genetics / Neoplasm Recurrence, Local - mortality / Neoplasm Recurrence, Local - pathology / Neoplasm Staging / Oncology / Original / original-article / Precursor Cell Lymphoblastic Leukemia-Lymphoma - drug therapy / Precursor Cell Lymphoblastic Leukemia-Lymphoma - genetics / Precursor Cell Lymphoblastic Leukemia-Lymphoma - mortality / Precursor Cell Lymphoblastic Leukemia-Lymphoma - pathology / Prognosis / Proto-Oncogene Proteins - genetics / Proto-Oncogene Proteins p21(ras) / ras Proteins - genetics / Survival Rate