Developmental timing of mutations revealed by whole-genome sequencing of twins with acute lymphoblastic leukemia

Abstract

Acute lymphoblastic leukemia (ALL) is the major pediatric cancer. At diagnosis, the developmental timing of mutations contributing critically to clonal diversification and selection can be buried in the leukemia's covert natural history. Concordance of ALL in monozygotic, monochorionic twins is a consequence of intraplacental spread of an initiated preleukemic clone. Studying monozygotic twins with ALL provides a unique means of uncovering the timeline of mutations contributing to clonal evolution, pre- and postnatally. We sequenced the whole genomes of leukemic cells from two twin pairs with ALL to comprehensively characterize acquired somatic mutations in ALL, elucidating the developmental timing of all genetic lesions. Shared, prenatal, coding-region single-nucleotide variants were limited to the putative initiating lesions. All other nonsynonymous single-nucleotide variants were distinct between tumors and, therefore, secondary and postnatal. These changes occurred in a background of noncoding mutational changes that were almost entirely discordant in twin pairs and likely passenger mutations acquired during leukemic cell proliferation.

Fig. 1.

Summary of lesions found in acute lymphoblastic leukemia. Shown are Circos plots (19) of somatic mutations in the each of the twin pairs. CNVs and LOH are depicted for each twin with regions of gain shown in blue, loss in red, and LOH in purple. Validated structural variations are depicted as colored ribbons in the interior of the plot. Panels refer to twin pair 1 and twin pair 2, and patients A and B in each twin pair.

Fig. 2.

Developmental timeline of acute lymphoblastic leukemia in the two twin pairs revealed by whole-genome sequencing.