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Rise and fall of subclones from diagnosis to relapse in pediatric B-acute lymphoblastic leukaemia.

Ma X, Edmonson M, Yergeau D, Muzny DM, Hampton OA, Rusch M, Song G, Easton J, Harvey RC, Wheeler DA, Ma J, Doddapaneni H, Vadodaria B, Wu G, Nagahawatte P, Carroll WL, Chen IM, Gastier-Foster JM, Relling MV, Smith MA, Devidas M, Guidry Auvil JM, Downing JR, Loh ML, Willman CL, Gerhard DS, Mullighan CG, Hunger SP, Zhang J - Nat Commun (2015)

Bottom Line: Half of the leukaemias had multiple subclonal mutations in a pathway or gene at diagnosis, but mostly with only one, usually minor clone, surviving therapy to acquire additional mutations and become the relapse founder clone.Relapse-specific mutations in NT5C2 were found in nine cases, with mutations in four cases being in descendants of the relapse founder clone.These results provide important insights into the genetic basis of treatment failure in ALL and have implications for the early detection of mutations driving relapse.

View Article: PubMed Central - PubMed

Affiliation: Computational Biology, St Jude Children's Research Hospital, Memphis, Tennessee 38105, USA.

ABSTRACT
There is incomplete understanding of genetic heterogeneity and clonal evolution during cancer progression. Here we use deep whole-exome sequencing to describe the clonal architecture and evolution of 20 pediatric B-acute lymphoblastic leukaemias from diagnosis to relapse. We show that clonal diversity is comparable at diagnosis and relapse and clonal survival from diagnosis to relapse is not associated with mutation burden. Six pathways were frequently mutated, with NT5C2, CREBBP, WHSC1, TP53, USH2A, NRAS and IKZF1 mutations enriched at relapse. Half of the leukaemias had multiple subclonal mutations in a pathway or gene at diagnosis, but mostly with only one, usually minor clone, surviving therapy to acquire additional mutations and become the relapse founder clone. Relapse-specific mutations in NT5C2 were found in nine cases, with mutations in four cases being in descendants of the relapse founder clone. These results provide important insights into the genetic basis of treatment failure in ALL and have implications for the early detection of mutations driving relapse.

No MeSH data available.


Related in: MedlinePlus

Three subclonal JAK2 mutations in patient PAPSPN.(a) Alignment of sequencing reads that harbour the three mutations present at diagnosis. (b) Sequencing read count of mutant (to the right of y axis) and wild-type (to the left of y axis) alleles of the three mutations categorized into diagnosis (black), remission (blue) and relapse (red) classes in the discovery sequencing (WXS, left) and verification sequencing (right). Colour code of mutations matches that of a.
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f2: Three subclonal JAK2 mutations in patient PAPSPN.(a) Alignment of sequencing reads that harbour the three mutations present at diagnosis. (b) Sequencing read count of mutant (to the right of y axis) and wild-type (to the left of y axis) alleles of the three mutations categorized into diagnosis (black), remission (blue) and relapse (red) classes in the discovery sequencing (WXS, left) and verification sequencing (right). Colour code of mutations matches that of a.

Mentions: Multiclonal mutations were observed in six genes in 10 cases at diagnosis or relapse: NT5C2 (n=3), KRAS (n=3), NRAS (n=2), JAK2 (n=2), CREBBP (n=1) and PAX5 (n=1) (Supplementary Data 5). Multiclonal mutations in NT5C2 and CREBBP were relapse specific, while multiclonal mutations in KRAS, NRAS, JAK2 and PAX5 at diagnosis exhibited variable persistence. Case PAPSPN is illustrative of the dynamic population changes of multiclonal mutations. This case had multiclonal mutations in three genes (JAK2, KRAS and PAX5), all of which showed switching of the predominant mutation site from diagnosis to relapse. Three mutations affecting JAK2 p.Arg683, a known hotspot of mutation in B-ALL121314, were present at diagnosis (Fig. 2a). JAK2 p.Arg683Ser was the predominant clonal mutation (MAF=0.42), while p.Arg683Gly (MAF=0.007) and p.Ile682_Glu684>GlyGly (MAF=0.005) were minor subclonal mutations (Fig. 2a). Only JAK2 p.Arg683Gly persisted to relapse to become a clonal mutation with MAF of 0.44. Importantly, the MAFs detected by WXS were verified by deep sequencing (Fig. 2b). Similarly, the dominant clonal mutation in KRAS switched from p.Gly12Asp at diagnosis to p.Ala146Thr at relapse, while the frameshift mutation PAX5 p.Glu97fs at diagnosis was replaced by a relapse-specific in-frame insertion p.Gly48>ValMetIleIleLysValSer. In addition to sequence mutations, we also detected multiclonal SVs in PAX5 (n=2) and CDKN2A (n=1; Supplementary Figs 6,7 and 16).


Rise and fall of subclones from diagnosis to relapse in pediatric B-acute lymphoblastic leukaemia.

Ma X, Edmonson M, Yergeau D, Muzny DM, Hampton OA, Rusch M, Song G, Easton J, Harvey RC, Wheeler DA, Ma J, Doddapaneni H, Vadodaria B, Wu G, Nagahawatte P, Carroll WL, Chen IM, Gastier-Foster JM, Relling MV, Smith MA, Devidas M, Guidry Auvil JM, Downing JR, Loh ML, Willman CL, Gerhard DS, Mullighan CG, Hunger SP, Zhang J - Nat Commun (2015)

Three subclonal JAK2 mutations in patient PAPSPN.(a) Alignment of sequencing reads that harbour the three mutations present at diagnosis. (b) Sequencing read count of mutant (to the right of y axis) and wild-type (to the left of y axis) alleles of the three mutations categorized into diagnosis (black), remission (blue) and relapse (red) classes in the discovery sequencing (WXS, left) and verification sequencing (right). Colour code of mutations matches that of a.
© Copyright Policy - open-access
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC4377644&req=5

f2: Three subclonal JAK2 mutations in patient PAPSPN.(a) Alignment of sequencing reads that harbour the three mutations present at diagnosis. (b) Sequencing read count of mutant (to the right of y axis) and wild-type (to the left of y axis) alleles of the three mutations categorized into diagnosis (black), remission (blue) and relapse (red) classes in the discovery sequencing (WXS, left) and verification sequencing (right). Colour code of mutations matches that of a.
Mentions: Multiclonal mutations were observed in six genes in 10 cases at diagnosis or relapse: NT5C2 (n=3), KRAS (n=3), NRAS (n=2), JAK2 (n=2), CREBBP (n=1) and PAX5 (n=1) (Supplementary Data 5). Multiclonal mutations in NT5C2 and CREBBP were relapse specific, while multiclonal mutations in KRAS, NRAS, JAK2 and PAX5 at diagnosis exhibited variable persistence. Case PAPSPN is illustrative of the dynamic population changes of multiclonal mutations. This case had multiclonal mutations in three genes (JAK2, KRAS and PAX5), all of which showed switching of the predominant mutation site from diagnosis to relapse. Three mutations affecting JAK2 p.Arg683, a known hotspot of mutation in B-ALL121314, were present at diagnosis (Fig. 2a). JAK2 p.Arg683Ser was the predominant clonal mutation (MAF=0.42), while p.Arg683Gly (MAF=0.007) and p.Ile682_Glu684>GlyGly (MAF=0.005) were minor subclonal mutations (Fig. 2a). Only JAK2 p.Arg683Gly persisted to relapse to become a clonal mutation with MAF of 0.44. Importantly, the MAFs detected by WXS were verified by deep sequencing (Fig. 2b). Similarly, the dominant clonal mutation in KRAS switched from p.Gly12Asp at diagnosis to p.Ala146Thr at relapse, while the frameshift mutation PAX5 p.Glu97fs at diagnosis was replaced by a relapse-specific in-frame insertion p.Gly48>ValMetIleIleLysValSer. In addition to sequence mutations, we also detected multiclonal SVs in PAX5 (n=2) and CDKN2A (n=1; Supplementary Figs 6,7 and 16).

Bottom Line: Half of the leukaemias had multiple subclonal mutations in a pathway or gene at diagnosis, but mostly with only one, usually minor clone, surviving therapy to acquire additional mutations and become the relapse founder clone.Relapse-specific mutations in NT5C2 were found in nine cases, with mutations in four cases being in descendants of the relapse founder clone.These results provide important insights into the genetic basis of treatment failure in ALL and have implications for the early detection of mutations driving relapse.

View Article: PubMed Central - PubMed

Affiliation: Computational Biology, St Jude Children's Research Hospital, Memphis, Tennessee 38105, USA.

ABSTRACT
There is incomplete understanding of genetic heterogeneity and clonal evolution during cancer progression. Here we use deep whole-exome sequencing to describe the clonal architecture and evolution of 20 pediatric B-acute lymphoblastic leukaemias from diagnosis to relapse. We show that clonal diversity is comparable at diagnosis and relapse and clonal survival from diagnosis to relapse is not associated with mutation burden. Six pathways were frequently mutated, with NT5C2, CREBBP, WHSC1, TP53, USH2A, NRAS and IKZF1 mutations enriched at relapse. Half of the leukaemias had multiple subclonal mutations in a pathway or gene at diagnosis, but mostly with only one, usually minor clone, surviving therapy to acquire additional mutations and become the relapse founder clone. Relapse-specific mutations in NT5C2 were found in nine cases, with mutations in four cases being in descendants of the relapse founder clone. These results provide important insights into the genetic basis of treatment failure in ALL and have implications for the early detection of mutations driving relapse.

No MeSH data available.


Related in: MedlinePlus