Occurrence of identical NOTCH1 mutation in non-twinned sisters with T-cell acute lymphoblastic leukemia

Sporadic cases of hematological malignancies in children or young adults or embryonic tumors in sibling pairs have raised speculation that genetic susceptibility factors may be associated with these diseases.1, 2 Recent genome-wide association studies in childhood acute lymphoblastic leukemia (ALL) have identified inherited gene variants associated with increased risk of disease.3 The excess of familial cancer occurrence may also be attributable to the fact that sibs share common environmental exposures, but studies to address this aspect are scarce.2

The acquired genetic aberrations in T-ALL include chromosomal translocations (frequently involving TCR) as well as gene rearrangements and mutations resulting in abnormal expression of genes such as NOTCH1, TAL1, HOX11, HOX11L2, LMO1 and LMO2.4 Acquired NOTCH1 mutations are present in 50% of T-ALL cases.5 NOTCH1 signaling is crucial for several steps in T-cell differentiation and also acts on proliferation and survival of these cells. Therefore, the mutational activation of this gene is an important factor in T-ALL pathogenesis.4 In one case of T-ALL, NOTCH1 mutation was pre-natal and preceded SIL–TAL fusion,6 suggesting that it might, at least in some cases, be an early and initiating genetic lesion. Animal models reveal that NOTCH1 mutations can initiate T-cell leukemia7 or arise as secondary, genetic lesions.8

We report a rare event of two non-twinned sisters with the same subtype of T-ALL harboring an identical NOTCH1 mutation (c.4735_4737 delGTG), who presented with onset of the disease 17 months apart from each other and with the same clinical features but with different outcomes. Sister 1 developed resistance to treatment and died, whereas sister 2 is still alive in complete continuous remission (20 years after diagnosis).

The clinical and laboratorial characteristics (Supplementary Table 1) and the details of methodological tests performed in samples from both sisters and their parents are summarized in the Supplementary Information available in the Leukemia website (http://www.nature.com/leu).

TCR analyses demonstrated monoclonality in both T-ALL sisters with, however, different rearrangement profiles, and direct sequencing of TCRG PCR products confirmed usage of different TCRG V regions (Figure 1a). These results ruled out the possibility of any technical cross-contaminations. No mutations were found in NOTCH1, PTEN and TP53 genes from the parents’ blood cell analysis. PTEN and TP53 genes were also wild type in malignant cells from sisters. The search for NOTCH1 mutations was performed in the heterodimerization (HD) and PEST/TAD domains and we observed the same alteration in the HD domain from both girls (Figure 1b). The mutation was characterized as a c.4735_4737 delGTG that results in valine deletion at 1578 position of NOTCH1 protein. This deletion was not found in the remission sample of sister 2 (or their parents) and was therefore somatic or acquired and not constitutive and inherited. Direct sequencing analyses were performed in different laboratory conditions and the same mutations were amplified on a separate occasion from additional independent leukemic DNA samples, suggesting that cross-contamination was unlikely.

Figure 1

Molecular analysis of the sisters: (a) TCR rearrangements of β (TCRB) and γ (TCRG) loci by Genemapper analysis show that the sister leukemias are monoclonal but harbor different rearrangements from each other; the methodology performed in this approach is described in Supplementary Information. (b) NOTCH1 mutations in both sisters compared with a normal sequence of NOTCH1. The graphic presents the specific point of deletion (c.4735_4737 delGTG) and highlights the equality of alterations between sisters. (c) Detection of TAL1 deletions to confirm the STIL loss found in SNP-array results. Both sisters presented TAL1 deletions, but with different breakpoints. WT, wild type.

To investigate the existence of other abnormalities shared or discordant between sisters, a high-density genome-wide SNP Array 6.0 assay (Affymetrix, Santa Clara, CA, USA) approach was used. Multiple copy-number abnormalities (CNAs), mostly deletions, were observed in both cases, but none was identical in the two patients, with the possible exception of 1p32/STIL (Table 1 and Supplementary Figure 1). However, when this genomic CNA—a SIL–TAL1 fusion—was sequenced (Figure 1c), it differed in the sibling pair with respect to N-region insertions.

Table 1 Copy number alterations in T-ALL sister cells

There is no other report of identical NOTCH1 mutation in non-twinned siblings in the literature. The c.4735_4737 delGTG has, however, been observed in other studies of T-ALL as an uncommon but recurrent mutation in unrelated cases.5

Identical (monozygotic) twins with concordant T- or B-cell precursor ALL share identical, clone-specific lesions, and this is interpreted as reflecting a single-cell origin in one twin in utero—followed by intraplacental spread to the second twin.9 Such a pre-natal scenario seems very unlikely for non-twinned siblings. We therefore conclude that the identical NOTCH1 mutations in the leukemias of the sibling pair occurred most probably at different times. Concordance of T-ALL in these siblings, we speculate, arose either because of shared genetic susceptibility and/or because of common environmental exposures. The medical, social and occupational history of the siblings and their family provided no clues in this regard. The divergent clinical responses in two siblings sharing the same NOTCH1 mutations may therefore reflect the impact of the additional genetics alterations we identified.


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MSPO has been supported by grants from INCT para Controle do Cancer, CNPq 573806/2008-0 and FAPERJ E26/170.026/2008. MBM is supported by the CAPES Foundation. ME is supported by INCA/MS. AMF and MG are supported by a programme grant from Leukaemia Lymphoma Research (London).

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Correspondence to M S Pombo-de-Oliveira.

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Supplementary Information accompanies the paper on the Leukemia website

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Mansur, M., Ford, A., van Delft, F. et al. Occurrence of identical NOTCH1 mutation in non-twinned sisters with T-cell acute lymphoblastic leukemia. Leukemia 25, 1368–1370 (2011). https://doi.org/10.1038/leu.2011.96

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