Mutational profiling of acute lymphoblastic leukemia with testicular relapse

Abstract

Relapsed acute lymphoblastic leukemia (ALL) is the leading cause of deaths of childhood cancer. Although relapse usually happens in the bone marrow, extramedullary relapse occasionally occurs including either the central nervous system or testis (<1-2%). We selected two pediatric ALL patients who experienced testicular relapse and interrogated their leukemic cells with exome sequencing. The sequencing results and clonality analyses suggest that relapse of patient D483 directly evolved from the leukemic clone at diagnosis which survived chemotherapy. In contrast, relapse leukemia cells (both bone marrow and testis) of patient D727 were likely derived from a common ancestral clone, and testicular relapse likely arose independently from the bone marrow relapsed leukemia. Our findings decipher the mutational spectra and shed light on the clonal evolution of two cases of pediatric ALL with testicular relapse. Presence of CREBBP/NT5C2 mutations suggests that a personalized therapeutic approach should be applied to these two patients.

Keywords: ALL; Acute lymphoblastic leukemia; Extramedullary relapse; Testicular relapse.

Fig. 1

Clonal evolution of ALL in patient D483. a Venn diagram shows mutations that occurred at leukemic diagnosis, bone marrow relapse, and testicular relapse in patient. b Cluster of mutations at initial marrow diagnosis, relapse of bone marrow, and testicle. c Clonal evolution lineage tree and sample composition of case D483. Lineage tree was constructed based on the constraint network using LICHeE [10]. Each node (circle) represents a sub-population of leukemic cells. Numbers inside circles indicate number of shared single nucleotide variants (SNVs, including synonymous SNVs and filtered with outliers of mutation cluster), numbers outside the circles show the mean VAF of each cluster. Color in each sample indicates mutational groups in that sub-population of cells, and the subdivision in a sample suggest potential mixed lineage pattern. GL germline, BM DX bone marrow at diagnosis, BM REL bone marrow at relapse, TES REL relapse in the testis

Fig. 2

Clonal evolution of ALL in patient D727. a Venn diagram shows mutations that occurred at leukemic diagnosis and relapse of bone-marrow and testicle in patient D727. b Cluster of mutations at diagnosis (DX), bone marrow relapse (REL), and testicular relapse (TES). c Clonal evolution lineage tree and sample composition of case D727. Lineage tree was constructed based on constraint network using LICHeE [10]. Each node (circle) represents a sub-population of leukemic cells. Numbers inside circles indicate number of shared SNVs (including synonymous SNVs and filtered with outliers of mutation cluster), numbers outside circles show mean VAF of each cluster. Color in each sample indicates mutational groups in that sub-population of cells, and subdivision in a sample suggest a potential mixed lineage pattern. GL germline, BM DX bone marrow at diagnosis, BM REL bone marrow at relapse, TES REL relapse at testis