Identification of TP53 as an acute lymphocytic leukemia susceptibility gene through exome sequencing - PubMed (original) (raw)

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Identification of TP53 as an acute lymphocytic leukemia susceptibility gene through exome sequencing

Bradford C Powell et al. Pediatr Blood Cancer. 2013 Jun.

Abstract

Although acute lymphocytic leukemia (ALL) is the most common childhood cancer, genetic predisposition to ALL remains poorly understood. Whole-exome sequencing was performed in an extended kindred in which five individuals had been diagnosed with leukemia. Analysis revealed a nonsense variant of TP53 which has been previously reported in families with sarcomas and other typical Li Fraumeni syndrome-associated cancers but never in a familial leukemia kindred. This unexpected finding enabled identification of an appropriate sibling bone marrow donor and illustrates that exome sequencing will reveal atypical clinical presentations of even well-studied genes.

Copyright © 2012 Wiley Periodicals, Inc.

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Conflict of interest statement

CONFLICT OF INTEREST STATEMENT

Dr. Richard Gibbs receives compensation as a consultant for GE Healthcare. Donna Muzny has been a co-owner of SeqWright, which also held investments in Lasergen and Visigen. She divested from SeqWright and Visigen in 2012. The authors declare no other potential conflict of interest.

Figures

Figure 1

Figure 1

Clinical pedigree of the individuals involved in this study. Arrows indicate consultands who presented for genetic evaluation and “dx.” indicates age at cancer diagnosis. This kindred includes five individuals who had developed leukemia with only one other individual being affected with esophageal carcinoma. Exome sequence analysis was performed the affected individuals III-7 (patient 1) and IV-2 (patient 2) as well as the familial control (mother of patient 1; individual II-5) who did not transmit the cancer risk. Targeted analysis for the TP53 familial mutation by Sanger sequencing subsequently revealed that individual IV-4 carries the mutation (E+(TP53)) but individuals IV-1 and IV-3 do not (E−(TP53)).

Figure 2

Figure 2

The heterozygous TP53 mutation c.916C>T was present in the two affected individuals but not in the nontransmitting parent. (A) Germline variants were filtered by familial relationships, rarity (allele frequency <= 0.01 in 1000 Genomes Project data and NIEHS Environmental Genome Project) and potential for functional change to protein sequence (missense, nonsense, frameshift, codon insertion/deletion or splice-altering). 231 rare variants (72 predicted to change protein sequence) were present in both affected individuals but not in the familial control. Further details regarding these variants are given in Supplementary Table 1. (B) The variant c.916C>T was present in two patients but not in the familial control through whole exome sequencing. Sequence reads near this mutation are displayed using the Integrative Genomics Viewer, with reads colored by strand (red and blue for positive and negative strand, respectively). The view is centered at cDNA position 916 of TP53 and variant (non-reference) base calls are highlighted for each subject.

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