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ALL: Molecular Characterization (Cytogenetics)
Note: This section has health/medical information. It was not written by a health care professional. The medical references are:
- Childhood Leukemias, edited by Ching-Hon Pui, 1999, Cambridge University Press
- NCI web site section on ALL, accessed 2010
- ALL translocation links (on this ped-onc web site)
- Dictionary of Genetic Terms
A full report of your child's ALL cells will include the cytogenetics of his or her disease. This at first will look like it is written in a foreign language, such as "t(17;19)(q22;p13.3), hyperdiploid". With a few clues, even the layman can decipher the important information in such reports. This section aims to give parents enough of the basics to understand what they need to know (plus links to informative web sites if you want to learn more).
The reason that it is useful to understand the cytogenetics, or the molecular characterization, of your child's leukemia is because in some cases, it directs the treatment plan, at least in the B-precursor leukemias. Beginning a couple of decades ago, whenever a child was put on a clinical trial, the researchers would carefully determine and record the cytogenetics of each child on the clinical trial. At the completion of the trial, they correlated the cytogenetics with the outcome of the treatment. Many children had cytogenetic patterns that were not seen in any other leukemias, however, certain patterns were seen again and again, and these particular patterns showed definite trends as to either successful or non-successful treatment. When the medical researchers designed the next set of clinical trials, written into the new trials was less aggressive treatment or more aggressive treatment depending on particular cytogenetic patterns.
ALL is called "clonal" because it (usually) arises when one cell becomes cancerous and grows out of control. This population of leukemic cells is called a "clone", hence the word clonal. The original leukemia cell usually has a distinct and detectable change in its DNA or chromosomes - note that this change might have nothing to do with the reason that the cell grows out of control. When the chromosomes of the leukemic clone are studied by molecular characterization techniques, a variety of deletions, insertions, translocations, and inversions are usually found.
Molecular characterization of ALL refers to the chromosome and DNA aberrations that are detected in a child's disease. The doctor takes a sample of the child's leukemia cells and sends it to a clinical lab, where they determine what is different in the DNA and chromosomes of the leukemia cells from DNA/chromosomes of normal cells. The results are reported as translocations, deletions, diploidy, trisomies, etc.
Translocations mean that one part of the chromosome is swapped with another part; they can be balanced (an even swap) or unbalanced (uneven swap), where there is both extra and missing information. A trisomy is a duplication of an area of a chromosome. Chromosomes come in pairs, so usually there are two copies of all genes, if duplication of one area is made, there are then three copies, thus, trisomy - three. Deletions indicate missing pieces and diploidy is explained in a separate section below.
Researchers have been studying molecular characterization data from children enrolled in clinical trials for years. They have found that certain chromosomal aberrations indicate a more or less virulent leukemia. Current protocols now screen new patients for these chromosomal aberrations, and if found, they put the child on more or less aggressive therapy accordingly. Note that the prognostic implications of most chromosomal changes is unknown.
Biology of childhood acute lymphoblastic leukemia. Lo Nigro L et al., J Pediatr Hematol Oncol. 2013 May;35(4):245-52. Abstract. Table entitled "Genetic and Clinical Characteristics of Specific Subtypes in Childhood ALL" and pie charts of the subtypes.
- translocation Abbreviated "t:", means that a chromosomal segment moves from one chromosome to another.
- p is the short arm of a chromosome
- q is the long arm of a chromosome
- insertion Abbreviated "ins:", means a chromosomal segment is in a new position in the same or another chromosome.
- inversion Abbreviated "inv:", means rotation of a chromosomal segment.
- deletion Abbreviated "del:", loss of a chromosomal segment.
- trisomy Means that there are 3 copies instead of the usual 2 of the named chromosome.
- hyper/hypodiploidy More than or less than 46 chromosomes (see below).
Trisomies and hyperdiploidy will be written out, and thus are obvious. Translocations are written like this:
- t(9;22), or in more detail: t(9;22)(q34;q11)
Note: At the moment, your author is not able to totally decipher this for you, except to state that this is a translocation involving chromosomes 9 and 22 and that it is the signature of the Philadelphia chromosome (below). When I really have to study one of these translocations, I pick up Pui's Childhood Leukemias book, and/or travel to a few informative web sites. Since I have such a large list of such web sites, I had to put them on a separate web page:
Some leukemic cells have extra chromosomes, or are "hyperdiploid", as determined by flow cytometry. "Modal number" is the most common chromosome number in a tumor population. The population is considered hyperdiploid when the modal number is greater than 46. Hyperdiploidy of over 50 is considered favorable; it is often expressed as a ratio of the modal number divided by 46. A ratio of 1.16 is considered favorable. Hypodiploidy is less than 45 chromosomes and is generally considered non-favorable. CCG 1991 directs children with "hypodiploidy with less than 45 chromosomes" to more aggressive treatment.
The following recurrent translocations are relevant almost solely to B-lineage ALL. In T-lineage ALL, they have studied chromosomal arrangements but have not yet associated with clinical significance with particular recurrent abnormalities. (2005 note: T-cell and pre-B cell molecular genetics are discussed in a review article [I have a copy]: Molecular Genetics of Acute Lymphoblastic Leukemia, Scott A. Armstrong and A. Thomas Look, J Clinical Oncology, Vol. 23, No. 26, Sept 10, 2005, 6306-6315.)
t(12;21) - known as the "tel-AML-1 fusion", now the ETV6-RUNX1 fusion
This is the most common translocation, comprising 20% of ALL cases. It is considered favorable. (Fusion of the TEL (ETV6) gene on chromosome 12 to the AML1 (CBFA2) gene on chromosome 21.) Children with TEL-AML1 fusion are generally 2 to 9 years of age. POG 9904 considered this enough of a good prognostic factor to make it a stipulation for the least aggressive trial offered.
As of 2010, this is referred to as the ETV6-RUNX1 fusion. COG trials consider this a highly favorable genetic factor.
trisomies 4 and 10, or simultaneous trisomy of 4 and 10, or TCF3-PBX1
This is considered favorable. It means that they see 3 copies each of the chromosomes numbers 4 and 10. POG 9904 considers this enough of a good prognostic factor to make it a stipulation for the least aggressive trial offered.
Reference: Blood, 1992, Jun 15;79 (12):3316-3324 "Trisomy of leukemic cell chromosomes 4 and 10 identifies children with B-progenitor cell acute lymphoblastic leukemia with a very low risk of treatment failure: a Pediatric Oncology Group study." Harris MB, Shuster JJ, Carroll A, Look AT, Borowitz MJ, Crist WM, Nitschke R, Pullen J, Steuber CP, Land VJ.
Intrachromosomal amplification of chromosome 21 (iAMP21)
This abnormality has multiple extra copies of the AML1 (RUNX1) gene on a single chromosome 21. It occurs in fewer than 5% of pre-B cell ALL. It has been associated with an inferior outcome. Moorman AV, Richards SM, Robinson HM et al. Prognosis of children with acute lymphoblastic leukemia (ALL) and intrachromosomal amplification of chromosome 21 (iAMP21). (Blood 2007;109(6):2327–30.)
t(1;19), or E2A-PBX1, t(1;19)
This translocation occurs in 5% to 6% of childhood ALL, and involves fusion of the E2A gene on chromosome 19 to the PBX1 gene on chromosome 1. This used to be considered an unfavorable translocation, but when treated with more intensive therapy, the EFS is similar to other common ALL sub classes. For instance, children with this translocation are placed on standard risk POG 9905 (if they qualify with other factors as well) rather than the low risk protocol (9904). CCG 1991 directs children with "balanced t(1;19)(q23;p13)" to more aggressive treatment.
This translocation occurs in about 5% of children with ALL and is considered favorable.
Rare, poor outcome. Hunger SP. Chromosomal translocations involving the E2A gene in acute lymphoblastic leukemia: clinical features and molecular pathogenesis. Blood. 1996;87:1211-1224.
Considered an unfavorable prognostic factor. CCG 1991 directs children with "t(4;11)(q21;q23)" to more aggressive treatment.
t(9;22), or Philadelphia chromosome, Ph+, BCR-ABL1
This is the Philadelphia chromosome (Ph) and accounts for 5% of cases and is considered very unfavorable. Also sometimes known as BCR/ABL fusion transcript. POG 9904, a very low risk protocol, directs children with this translocation to the very high risk protocol, POG 9906. CCG 1991 directs children with "t(9;22)(q34;q11)" to more aggressive treatment.
MLL (11q23) gene translocations
MLL stands for Myeloid Lymphoid Leukemia or Mixed Lineage Leukemia; is also called HRX or HTRX. There are several recurrent rearrangements all traced to this one gene on the q23 region of chromosome 11. These account for about 6% of childhood ALL cases and are generally considered as giving an increased risk for treatment failure. [HRX (MLL) rearrangement] POG 9904, a very low risk protocol, directs children with MLL rearrangements to more aggressive treatment. CCG 1991 directs children with "11q23 translocations involving MLL" to more aggressive treatment.
t(4;11) (q21;q23) or MLL-AF4, is the most common translocation in infants (under 12 months of age). Infants with t(4;11) generally present with high WBC count, and they are more likely than other children with ALL to have CNS disease and to have a poor response to initial therapy.
t(11;19) occurs in approximately 1% of cases and occurs in both B-precursor and T-cell ALL. Outcome for infants with t(11;19) is poor, but outcome appears relatively favorable for children with T-cell ALL and the t(11;19) translocation.
t(8;14)(q24;q32), MYC-IgH good prognosis with therapy that includes high dose methotrexate, ara C, cydlophosphamide
CRLF2 overexpression - poor prognosis
t(8;22)(q24;q11), and t(2;8)(p11-p12;q24) (characteristic of Burkitt's lymphoma) are high risk and not allowed on CCG 1991.
These pages are intended for informational purposes only and are not intended to render medical advice. The information provided on Ped Onc Resource Center should not be used for diagnosing or treating a health problem or a disease. It is not a substitute for professional care. If you suspect your child has a health problem, you should consult your health care provider.