Constitutional Segmental Uniparental Disomy in a Twin Pair with t(12;21) Positive Acute Lymphoblastic Leukemia Characterized by the Same Prenatal Clone and Divergent Clonal Evolution.
Authors: Cazzaniga Giovanni , Irving Julie , Citterio Marco , Bungaro Silvia , Tussiwand Roxane , Mura Rossella , Hall Andrew G. , Biondi Andrea 
Published: October 2019

Abstract
We previously reported (Tussiwand R. et al., ASH 2002) the case of a monozygotic twin pair with concordant ALL aged 3.0 years at diagnosis, with only 13 days difference in latency. Twin 1 was classified as pre-B ALL and twin 2 as common-ALL, based on standard immunophenotyping criteria. A large screening for TcR and Ig gene rearrangements was performed, resulting in only one common VKII-Kde rearrangement, the others being not related to each others. Highly sensitive RQ-PCR was performed for all markers in both twins. The result of the crossed analysis was consistent with the hypothesis that after a prenatal event resulting in a preleukemic clone, at least a second independent event must have occurred before overt leukemia. To further identify markers of the clonal evolution, high-resolution single nucleotide polymorphisms (SNP) genotype analysis was performed on the DNA using the 10K SNP array (Affymetrix). Remission bone marrow was taken as a germ line samples. Array-based analysis of SNPs allows the rapid determination of genome-wide allelic information at high density, including the identification of submicroscopical copy number changes and/or loss of heterozygosity (LOH). SNP array analysis have been so far successfully applied to demonstrate allelic imbalance in ALL and AML blasts. A 12p12-13 deletion was observed on twin 2. The deletion of the TEL allele not involved in the t(12;21) was confirmed in twin 2 by FISH and microsatellite analyses. The twin 1 did not show any 12p deletion. Similar observations have been made in late-relapses occurring in ALL carrying the t(12;21) translocation: the predominant clone did not correspond to the same clone observed at diagnosis, but represented a second, independent transformation event within the fetal pre-leukemic clone, even when in the presence of the same genetic background. More interestingly, we found by SNP array a 13Mb area of LOH in remission and presentation samples of both twins involving the 2q13-14.3 region. As further confirmed by FISH with 2q probes, LOH was not associated with chromosomal loss, implying a recombination event resulting in Uniparental Isodisomy (UPD). The UPD area includes 57 known genes, several of them implicated in oncogenesis; they include translin, a gene involved in the control of chromosomal translocation and implicated in lymphoid malignancy. UPD of this region has not been reported in other tumors or in remission samples of leukemia; in genetic diseases few cases have been reported with maternal or paternal UPD 2, never associated with haematological disorders. By contrast, it has been shown that a transmitted deletion of 2q13 to 2q14.1 causes no phenotypic abnormalities. This is the first report on constitutional UPD in leukemia patients. Further analyses are necessary to understand the clinical meaning of this chromosomal abnormality; one hypothesis could be that the twins were born with a genetic predisposition to develop leukaemia. In this context, t(12;21) and additional events (i.e. TEL deletion) may be responsible for the overt leukemia.