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Implementation of array based whole-genome high-resolution technologies confirms the absence of secondary copy-number alterations in MLL-AF4-positive infant ALL patients

Leukemia volume 25, pages 175–178 (2011)Cite this article

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The current opinion in cancer research is that human tumors are the results of the progressive accumulation of subsequent multiple genetic lesions.1, 2 In many leukemias, the first transforming event has been demonstrated to occur prenatally in utero,1, 3 followed, several years later, by the subsequent post-natal acquisition of additional genetic mutations, leading to the overt leukemia development.1 In support to this hypothesis, several independent groups have identified the existence of ‘genetic hot spots’ in the human genome, regardless of the age of onset and the cytogenetic subgroups to which they belong, targeting non-random key genes with a crucial role in leukemogenesis.4, 5 However, for some subtypes of leukemia, such as Miked lineage leukemia (MLL) gene rearranged infant acute lymphoblastic leukemia (ALL), the pathogenetic mechanism remains still unclear. By applying the Affymetrix Human Mapping single-nucleotide polymorphism (SNP; Affymetrix, Santa Clara, CA, USA) 100K or 500K Array technology, we and others have recently reported an exceptionally limited number of copy-number alterations in high-risk infant ALL with MLL gene rearrangement, compared with other form of leukemia occurring in older children subsets.4, 6 This suggested that MLL rearrangement per se, as a first and sole hit, has a major role in driving and hastening the leukemogenic process in infant ALL, without the need of secondary cooperating mutations. It can be argued that, as a major limitation of this study, small lesions under the detection limit of the method applied might have potentially been missed.

Nowadays, the recent technology advancements give us the possibility to drastically increase the sensitivity, in a way that the re-evaluation of the same cases and the implementation of the data previously obtained with different, less sensitive platforms might be very helpful in reinforcing the recently published results. The new released Affymetrix Cytogenetics Whole-Genome 2.7 M Array (Affymetrix) provides, at present, the greatest power to detect known and novel aberrations across the entire genome, as the best available proxy to the high throughput whole genome sequencing. With unbiased, whole-genome coverage and the highest density of 2.7 million markers, including not only 400 000 SNPs, but also 2.3 millions of non-polymorphic copy-number markers, this array provides dense coverage of the annotated genes, cancer genes, micro RNA regions and haploinsufficiency genes, which are of particular relevance to cytogenetists, enabling to detect smaller submicroscopic aberrations as well as copy-number neutral loss of heterozygosity (LOH). As a major advantage, besides providing an high coverage of human genome, the array offers a better approach and a superior resolution, with a median distance between markers of 735 bp (compared with 2.5 Kb for the 500K arrays), that can be narrowed to 294 bp within the cancer genes loci, thus enabling the detection of very small structural changes.

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Acknowledgements

This study was supported by the FIRB-MIUR grant, Associazione Italiana per la Ricerca sul Cancro (AIRC), Fondazione Cariplo, Fondazione ‘M Tettamanti’ and Associazione ‘Sciare per la Vita’.

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  1. T A Gorletta

    Present address: 3Current address: Dipartimento di Biotecnologie e Bioscienze, Università di Milano-Bicocca, Milano, Italy.,

  2. A Biondi and G Cazzaniga: These authors share the seniorship of this paper.

Authors and Affiliations

  1. Centro Ricerca Tettamanti, Clinica Pediatrica Università Milano-Bicocca, Ospedale San Gerardo, Monza, Italy

    M Bardini, M Galbiati, A Lettieri, S Bungaro, A Biondi & G Cazzaniga

  2. Consorzio Genopolis, BTBS, Università di Milano-Bicocca, Milano, Italy

    T A Gorletta

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  1. M Bardini
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Correspondence to G Cazzaniga.

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Bardini, M., Galbiati, M., Lettieri, A. et al. Implementation of array based whole-genome high-resolution technologies confirms the absence of secondary copy-number alterations in MLL-AF4-positive infant ALL patients. Leukemia 25, 175–178 (2011). https://doi.org/10.1038/leu.2010.232

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