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Old 02-26-2013, 02:47 AM
gdpawel gdpawel is offline
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Default Genetic evolution of chronic lymphocytic leukemia tracked

Kathy Boltz, PhD

Tumors are not factories for the mass production of identical cancer cells, but are, in reality, patchworks of cells with different patterns of gene mutations. A new study shows, more fully than ever before, how these mutations shift and evolve over time in chronic lymphocytic leukemia (CLL). This provides a strobe-like look at the genetic past, present, and future of CLL tumors.

Evolution may hold the key to understanding why CLL often recurs after treatment, and the key to developing better therapies. This study helps to explain why patients with seemingly similar diseases often do not derive the same benefit from therapy, why CLL recurs faster in some patients than others, and why therapy itself may speed the recurrence of the disease.

“One of the biggest challenges that patients with CLL and their physicians face is how to deal with relapse,” said study co-senior author, Catherine Wu, MD, of Dana-Farber Cancer Institute in Boston, Massachusetts. “It's been clear for some time that tumors are collections of different subgroups of cells, each with a particular set of gene mutations, and that, over time, some of these subgroups become more prevalent and some less. So the tumor that you initially treat can be quite different, from a genetic standpoint, from the tumor that recurs later on.”

This study, which was published in Cell (2013;152[4]:714-726), used next-generation gene-sequencing technology to chart changes in nearly 100 samples of CLL tissue. “From there,” Wu explained, “we began exploring how these different subgroups of cells influence the effectiveness of therapy. What can these subgroups tell us about how the cancer originated and developed, and how–and how long–it will respond to treatment before relapsing?”

Genetic material in CLL tissue from 140 patients was analyzed. The analysis focused just on the sections of DNA that hold code for making cell proteins. The cells' DNA was scoured for mutations in specific genes. For 18 patients, CLL samples taken several years apart were analyzed to track changes in the cells' genetic makeup over time. This allowed the researchers to reconstruct, in effect, a genetic biography of a patient's disease, identifying mutations that cropped up early or later in the disease.

Certain driver mutations—named for their ability to spur cancer formation and growth—tend to appear early in the disease's development, while others emerge over time. The researchers discovered that the initial driver mutations tend to be unique to malignancies that originate in immune system B cells (such as CLL), while those that arose later are often found in other malignancies.

Cell subgroups were identified that became more prominent in later stages of the disease. Some subgroups of cells that had a fairly minimal presence before treatment came to predominate after treatment. Cells from patients who received chemotherapy during the years between their cell samples underwent a great deal of genetic evolution, showing marked increases in some cell subgroups and decreases in others, whereas samples from patients who did not undergo such therapy were remarkably stable.
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Old 02-28-2013, 01:01 PM
gdpawel gdpawel is offline
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Default Clonal architecture of secondary acute myeloid leukemia

N Engl J Med. 2012 Mar 22;366(12):1090-8. doi: 10.1056/NEJMoa1106968. Epub 2012 Mar 14.

Clonal architecture of secondary acute myeloid leukemia.

Walter MJ, Shen D, Ding L, Shao J, Koboldt DC, Chen K, Larson DE, McLellan MD, Dooling D, Abbott R, Fulton R, Magrini V, Schmidt H, Kalicki-Veizer J, O'Laughlin M, Fan X, Grillot M, Witowski S, Heath S, Frater JL, Eades W, Tomasson M, Westervelt P, DiPersio JF, Link DC, Mardis ER, Ley TJ, Wilson RK, Graubert TA.

Department of Internal Medicine, Division of Oncology, Washington University School of Medicine, St. Louis, MO 63110, USA.

Abstract

BACKGROUND:

The myelodysplastic syndromes are a group of hematologic disorders that often evolve into secondary acute myeloid leukemia (AML). The genetic changes that underlie progression from the myelodysplastic syndromes to secondary AML are not well understood.

METHODS:

We performed whole-genome sequencing of seven paired samples of skin and bone marrow in seven subjects with secondary AML to identify somatic mutations specific to secondary AML. We then genotyped a bone marrow sample obtained during the antecedent myelodysplastic-syndrome stage from each subject to determine the presence or absence of the specific somatic mutations. We identified recurrent mutations in coding genes and defined the clonal architecture of each pair of samples from the myelodysplastic-syndrome stage and the secondary-AML stage, using the allele burden of hundreds of mutations.

RESULTS:

Approximately 85% of bone marrow cells were clonal in the myelodysplastic-syndrome and secondary-AML samples, regardless of the myeloblast count. The secondary-AML samples contained mutations in 11 recurrently mutated genes, including 4 genes that have not been previously implicated in the myelodysplastic syndromes or AML. In every case, progression to acute leukemia was defined by the persistence of an antecedent founding clone containing 182 to 660 somatic mutations and the outgrowth or emergence of at least one subclone, harboring dozens to hundreds of new mutations. All founding clones and subclones contained at least one mutation in a coding gene.

CONCLUSIONS:

Nearly all the bone marrow cells in patients with myelodysplastic syndromes and secondary AML are clonally derived. Genetic evolution of secondary AML is a dynamic process shaped by multiple cycles of mutation acquisition and clonal selection. Recurrent gene mutations are found in both founding clones and daughter subclones. (Funded by the National Institutes of Health and others.).

PMID: 22417201 [PubMed - indexed for MEDLINE] PMCID: PMC3320218

[url]http://www.ncbi.nlm.nih.gov/pubmed/22417201
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