High concordance of subtypes of childhood acute lymphoblastic leukemia within families: lessons from sibships with multiple cases of leukemia

Abstract

Polymorphic genes have been linked to the risk of acute lymphoblastic leukemia (ALL). Surrogate markers for a low burden of early childhood infections are also related to increased risk for developing childhood ALL. It remains uncertain, whether siblings of children with ALL have an increased risk of developing ALL. This international collaboration identified 54 sibships with two (N = 51) or more (N = 3) cases of childhood ALL (ages <18 years). The 5-year event-free survival for 61 patients diagnosed after 1 January 1990 was 0.83 ± 0.05. Ages at diagnosis (Spearman correlation coefficient, r(S) = 0.41, P = 0.002) were significantly correlated, but not WBCs (r(S) = 0.23, P = 0.11). In 18 sibships with successful karyotyping in both cases, six were concordant for high-hyperdiploidy (N = 3), t(12;21) [ETV6/RUNX1] (N = 1), MLL rearrangement (N = 1) or t(1;19)(q23/p13) (N = 1). Eleven sibships were ALL-subtype concordant, being T-cell ALL (T-ALL) (N = 5, of a total of six sibships, where the first-born had T-ALL) or B-lineage ALL belonging to the same cytogenetic subset (N = 6), a finding that differs significantly from the expected chance distribution (κ: 0.58; P < 0.0001). These data indicate strong genetic and/or environmental risk factors for childhood ALL that are restricted to specific ALL subtypes, which must be taken into account, when performing epidemiological studies to reveal etiological factors.

Rare allelic forms of PRDM9 associated with childhood leukemogenesis

“…Families with two cases of childhood ALL in a sibship are rare and it is not clear whether siblings of children with ALL have an increased risk of developing ALL themselves (Draper et al 1996;Winther et al 2001). From studies published between 1951 and 2009 and registry-based childhood ALL data, an international collaboration only identified three sibships that were concordant for hyperdiploid ALL (Schmiegelow et al 2012). However, the high concordance rate in ALL subtype within sibships is somewhat incompatible with a scenario where all cases in sibships occur randomly through independent events.…”

Concordant B-cell precursor acute lymphoblastic leukemia in non-twinned siblings

“…One cannot exclude that this event occurred by chance in these sibs. However, based on a registry of double-ALL siblings, only 11% of them would harbor the same driving leukemia aberration by chance assuming an overall frequency of 20% for ETV6-RUNX1, (calculated as, 0.2 * 0.2/(0.2 * 0.8 + 0.8 * 0.2 + 0.2 * 0.2)), as previously discussed by Schmiegelow et al [15,28]. The age of the children at the diagnosis being less than one-year apart, and the differences on time to the clinical onset of the BCP-ALL with ETV6/RUNX1 fusion gene are also of biological interest.…”

“…The concordance of childhood leukemia among siblings is a rare event [14]. In a recent publication Schmiegelow et al have reviewed data from an international collaborative series of ALL that identified 54 sib ships with two or more cases of childhood ALL, proposing that strong genetic risk factors for childhood ALL might be restricted to specific subtypes [15]. Besides, the familial history of cancer has been associated with increased risk of childhood leukemia [16].…”

Five Most Common Prognostically Important Fusion Oncogenes are Detected in the Majority of Pakistani Pediatric Acute Lymphoblastic Leukemia Patients and are Strongly Associated with Disease Biology and Treatment Outcome

“…This heterogeneity is likely to be due to genetic, racial and geographic variations that exist among different populations (Pui et al, 2003;Treviño et al, 2009;Iacobucci et al, 2012;Schmiegelow et al, 2012;Xu et al, 2012). Therefore, the distribution of genetic and molecular subtypes may not be uniform in different parts of the world (Romana., 1995;Ariffin et al, 2007).…”

“…Therefore, the distribution of genetic and molecular subtypes may not be uniform in different parts of the world (Romana., 1995;Ariffin et al, 2007). Moreover, gene-environment interactions, which are critical in leukemogenesis, may differently contribute in defining the relative proportions of molecular subgroups in different geographic regions (Iqbal et al, 2006;Siddique et al, 2010;Faiz et al, 2011;Schmiegelow et al, 2012;Schrappe et al, 2012). The most common oncogenes found in leukemia patients are the fusion genes, which are formed as a result of different genetic abnormalities at the chromosomal level (Zelent et al, 2004).…”