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The landscape of somatic mutations in infant MLL-rearranged acute lymphoblastic leukemias.

Andersson AK, Ma J, Wang J, Chen X, Gedman AL, Dang J, Nakitandwe J, Holmfeldt L, Parker M, Easton J, Huether R, Kriwacki R, Rusch M, Wu G, Li Y, Mulder H, Raimondi S, Pounds S, Kang G, Shi L, Becksfort J, Gupta P, Payne-Turner D, Vadodaria B, Boggs K, Yergeau D, Manne J, Song G, Edmonson M, Nagahawatte P, Wei L, Cheng C, Pei D, Sutton R, Venn NC, Chetcuti A, Rush A, Catchpoole D, Heldrup J, Fioretos T, Lu C, Ding L, Pui CH, Shurtleff S, Mullighan CG, Mardis ER, Wilson RK, Gruber TA, Zhang J, Downing JR, St. Jude Children's Research Hospital–Washington University Pediatric Cancer Genome Proje - Nat. Genet. (2015)

Bottom Line: Our data show that infant MLL-R ALL has one of the lowest frequencies of somatic mutations of any sequenced cancer, with the predominant leukemic clone carrying a mean of 1.3 non-silent mutations.Despite this paucity of mutations, we detected activating mutations in kinase-PI3K-RAS signaling pathway components in 47% of cases.Surprisingly, these mutations were often subclonal and were frequently lost at relapse.

View Article: PubMed Central - PubMed

Affiliation: 1] Department of Pathology, St. Jude Children's Research Hospital, Memphis, Tennessee, USA. [2] Department of Clinical Genetics, Lund University, Lund, Sweden.

ABSTRACT
Infant acute lymphoblastic leukemia (ALL) with MLL rearrangements (MLL-R) represents a distinct leukemia with a poor prognosis. To define its mutational landscape, we performed whole-genome, exome, RNA and targeted DNA sequencing on 65 infants (47 MLL-R and 18 non-MLL-R cases) and 20 older children (MLL-R cases) with leukemia. Our data show that infant MLL-R ALL has one of the lowest frequencies of somatic mutations of any sequenced cancer, with the predominant leukemic clone carrying a mean of 1.3 non-silent mutations. Despite this paucity of mutations, we detected activating mutations in kinase-PI3K-RAS signaling pathway components in 47% of cases. Surprisingly, these mutations were often subclonal and were frequently lost at relapse. In contrast to infant cases, MLL-R leukemia in older children had more somatic mutations (mean of 6.5 mutations/case versus 1.3 mutations/case, P = 7.15 × 10(-5)) and had frequent mutations (45%) in epigenetic regulators, a category of genes that, with the exception of MLL, was rarely mutated in infant MLL-R ALL.

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Somatic mutations detected by whole genome sequencing of infant MLL-R ALL. (a–c) CIRCOS plots of somatic non-silent mutations in three infant MLL-R ALL cases. (a) INF006 contained a balanced t(4;11)(q21;q23) encoding the MLL-AFF1 and gain of chromosome X. (b) INF009 contained a balanced t(11;19)(q23;p13.3) with the break on chromosome 19 occurring 22.7kb 5` of MLLT1 resulting in a spliced in-frame MLL-MLLT1 chimeric gene. The translocation had an inverted intrachromosomal duplication spanning 0.3kb at the breakpoint on chromosome 19 that resulted in an out-of-frame RFX2-MLL fusion. In addition, an unrelated intrachromosomal deletion of 46bp was detected on chromosome 6. (c) INF004 contained a complex three-way translocation involving chromosomes 9, 10, and 11 that encoded the MLL-MLLT10 on the derivative chromosome 11, an out-of-frame MLLT10-CNTNAP3B chimeric gene on chromosome 9, and a truncated 3` MLL on chromosome 10. The case also contained a t(8;14)(q24;q11.2) that resulted in the juxtaposition of MYC to the T-cell antigen receptor alpha (TRA) gene as denoted by the ∧. In addition, a non-silent SNV in COL13A1 and a deletion on chromosome 9 disrupted PAX5. (d) Structure of the INF004 complex translocation involving chromosomes 9p11 (blue), 10p12 (yellow), and 11q14–23 (burgundy). The genomic coordinates (hg18) are indicated above each genomic segment. The MLL-MLLT10 fusion gene is depicted by the solid arrow and all other rearrangements by dotted arrows. Copy number gains (red) and losses (blue) at the respective break points are shown. The final genomic products on chromosomes 9, 10 and 11 are shown in Supplementary Fig. 9. Ter, terminus; Cen, centromere.
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Figure 1: Somatic mutations detected by whole genome sequencing of infant MLL-R ALL. (a–c) CIRCOS plots of somatic non-silent mutations in three infant MLL-R ALL cases. (a) INF006 contained a balanced t(4;11)(q21;q23) encoding the MLL-AFF1 and gain of chromosome X. (b) INF009 contained a balanced t(11;19)(q23;p13.3) with the break on chromosome 19 occurring 22.7kb 5` of MLLT1 resulting in a spliced in-frame MLL-MLLT1 chimeric gene. The translocation had an inverted intrachromosomal duplication spanning 0.3kb at the breakpoint on chromosome 19 that resulted in an out-of-frame RFX2-MLL fusion. In addition, an unrelated intrachromosomal deletion of 46bp was detected on chromosome 6. (c) INF004 contained a complex three-way translocation involving chromosomes 9, 10, and 11 that encoded the MLL-MLLT10 on the derivative chromosome 11, an out-of-frame MLLT10-CNTNAP3B chimeric gene on chromosome 9, and a truncated 3` MLL on chromosome 10. The case also contained a t(8;14)(q24;q11.2) that resulted in the juxtaposition of MYC to the T-cell antigen receptor alpha (TRA) gene as denoted by the ∧. In addition, a non-silent SNV in COL13A1 and a deletion on chromosome 9 disrupted PAX5. (d) Structure of the INF004 complex translocation involving chromosomes 9p11 (blue), 10p12 (yellow), and 11q14–23 (burgundy). The genomic coordinates (hg18) are indicated above each genomic segment. The MLL-MLLT10 fusion gene is depicted by the solid arrow and all other rearrangements by dotted arrows. Copy number gains (red) and losses (blue) at the respective break points are shown. The final genomic products on chromosomes 9, 10 and 11 are shown in Supplementary Fig. 9. Ter, terminus; Cen, centromere.

Mentions: WGS revealed that the infant MLL-R ALL genomes contained an average of 111 somatic sequence mutations (range 29–229) and 10 CNAs/SVs (range 2–26), per case (Supplementary Fig. 2 and Supplementary Tables 3 and 4), yielding a median somatic coding mutation rate of 7.30×10−8 per base (range 0–2.29×10−7). With the exception of pediatric low-grade glioma12, this is 2–180 fold lower than those reported in adult and pediatric cancers (Supplementary Table 5). The mutation spectrum across the cohort did not suggest any specific mutational mechanisms with the most common nucleotide changes being C>T/G>A transition (Supplementary Fig. 2). The number of somatic alterations affecting the coding region of annotated genes or regulatory RNAs averaged 8.2/case, including 2.2 non-silent SNVs (range 0–4) and 6.0 CNA/SVs (range 2–19) per case (Fig. 1a–c, Supplementary Tables 3, 4 and 6–8 and Supplementary Figs. 2–3). RNA sequencing (RNAseq) in 21/22 cases demonstrated 48% of the non-silent SNVs to be expressed (Supplementary Tables 9–11 and Supplementary Figs. 4 and 5). Despite the paucity of mutations, 81% of the expressed missense mutations were predicted to have a deleterious effect on protein function.


The landscape of somatic mutations in infant MLL-rearranged acute lymphoblastic leukemias.

Andersson AK, Ma J, Wang J, Chen X, Gedman AL, Dang J, Nakitandwe J, Holmfeldt L, Parker M, Easton J, Huether R, Kriwacki R, Rusch M, Wu G, Li Y, Mulder H, Raimondi S, Pounds S, Kang G, Shi L, Becksfort J, Gupta P, Payne-Turner D, Vadodaria B, Boggs K, Yergeau D, Manne J, Song G, Edmonson M, Nagahawatte P, Wei L, Cheng C, Pei D, Sutton R, Venn NC, Chetcuti A, Rush A, Catchpoole D, Heldrup J, Fioretos T, Lu C, Ding L, Pui CH, Shurtleff S, Mullighan CG, Mardis ER, Wilson RK, Gruber TA, Zhang J, Downing JR, St. Jude Children's Research Hospital–Washington University Pediatric Cancer Genome Proje - Nat. Genet. (2015)

Somatic mutations detected by whole genome sequencing of infant MLL-R ALL. (a–c) CIRCOS plots of somatic non-silent mutations in three infant MLL-R ALL cases. (a) INF006 contained a balanced t(4;11)(q21;q23) encoding the MLL-AFF1 and gain of chromosome X. (b) INF009 contained a balanced t(11;19)(q23;p13.3) with the break on chromosome 19 occurring 22.7kb 5` of MLLT1 resulting in a spliced in-frame MLL-MLLT1 chimeric gene. The translocation had an inverted intrachromosomal duplication spanning 0.3kb at the breakpoint on chromosome 19 that resulted in an out-of-frame RFX2-MLL fusion. In addition, an unrelated intrachromosomal deletion of 46bp was detected on chromosome 6. (c) INF004 contained a complex three-way translocation involving chromosomes 9, 10, and 11 that encoded the MLL-MLLT10 on the derivative chromosome 11, an out-of-frame MLLT10-CNTNAP3B chimeric gene on chromosome 9, and a truncated 3` MLL on chromosome 10. The case also contained a t(8;14)(q24;q11.2) that resulted in the juxtaposition of MYC to the T-cell antigen receptor alpha (TRA) gene as denoted by the ∧. In addition, a non-silent SNV in COL13A1 and a deletion on chromosome 9 disrupted PAX5. (d) Structure of the INF004 complex translocation involving chromosomes 9p11 (blue), 10p12 (yellow), and 11q14–23 (burgundy). The genomic coordinates (hg18) are indicated above each genomic segment. The MLL-MLLT10 fusion gene is depicted by the solid arrow and all other rearrangements by dotted arrows. Copy number gains (red) and losses (blue) at the respective break points are shown. The final genomic products on chromosomes 9, 10 and 11 are shown in Supplementary Fig. 9. Ter, terminus; Cen, centromere.
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Related In: Results  -  Collection

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getmorefigures.php?uid=PMC4553269&req=5

Figure 1: Somatic mutations detected by whole genome sequencing of infant MLL-R ALL. (a–c) CIRCOS plots of somatic non-silent mutations in three infant MLL-R ALL cases. (a) INF006 contained a balanced t(4;11)(q21;q23) encoding the MLL-AFF1 and gain of chromosome X. (b) INF009 contained a balanced t(11;19)(q23;p13.3) with the break on chromosome 19 occurring 22.7kb 5` of MLLT1 resulting in a spliced in-frame MLL-MLLT1 chimeric gene. The translocation had an inverted intrachromosomal duplication spanning 0.3kb at the breakpoint on chromosome 19 that resulted in an out-of-frame RFX2-MLL fusion. In addition, an unrelated intrachromosomal deletion of 46bp was detected on chromosome 6. (c) INF004 contained a complex three-way translocation involving chromosomes 9, 10, and 11 that encoded the MLL-MLLT10 on the derivative chromosome 11, an out-of-frame MLLT10-CNTNAP3B chimeric gene on chromosome 9, and a truncated 3` MLL on chromosome 10. The case also contained a t(8;14)(q24;q11.2) that resulted in the juxtaposition of MYC to the T-cell antigen receptor alpha (TRA) gene as denoted by the ∧. In addition, a non-silent SNV in COL13A1 and a deletion on chromosome 9 disrupted PAX5. (d) Structure of the INF004 complex translocation involving chromosomes 9p11 (blue), 10p12 (yellow), and 11q14–23 (burgundy). The genomic coordinates (hg18) are indicated above each genomic segment. The MLL-MLLT10 fusion gene is depicted by the solid arrow and all other rearrangements by dotted arrows. Copy number gains (red) and losses (blue) at the respective break points are shown. The final genomic products on chromosomes 9, 10 and 11 are shown in Supplementary Fig. 9. Ter, terminus; Cen, centromere.
Mentions: WGS revealed that the infant MLL-R ALL genomes contained an average of 111 somatic sequence mutations (range 29–229) and 10 CNAs/SVs (range 2–26), per case (Supplementary Fig. 2 and Supplementary Tables 3 and 4), yielding a median somatic coding mutation rate of 7.30×10−8 per base (range 0–2.29×10−7). With the exception of pediatric low-grade glioma12, this is 2–180 fold lower than those reported in adult and pediatric cancers (Supplementary Table 5). The mutation spectrum across the cohort did not suggest any specific mutational mechanisms with the most common nucleotide changes being C>T/G>A transition (Supplementary Fig. 2). The number of somatic alterations affecting the coding region of annotated genes or regulatory RNAs averaged 8.2/case, including 2.2 non-silent SNVs (range 0–4) and 6.0 CNA/SVs (range 2–19) per case (Fig. 1a–c, Supplementary Tables 3, 4 and 6–8 and Supplementary Figs. 2–3). RNA sequencing (RNAseq) in 21/22 cases demonstrated 48% of the non-silent SNVs to be expressed (Supplementary Tables 9–11 and Supplementary Figs. 4 and 5). Despite the paucity of mutations, 81% of the expressed missense mutations were predicted to have a deleterious effect on protein function.

Bottom Line: Our data show that infant MLL-R ALL has one of the lowest frequencies of somatic mutations of any sequenced cancer, with the predominant leukemic clone carrying a mean of 1.3 non-silent mutations.Despite this paucity of mutations, we detected activating mutations in kinase-PI3K-RAS signaling pathway components in 47% of cases.Surprisingly, these mutations were often subclonal and were frequently lost at relapse.

View Article: PubMed Central - PubMed

Affiliation: 1] Department of Pathology, St. Jude Children's Research Hospital, Memphis, Tennessee, USA. [2] Department of Clinical Genetics, Lund University, Lund, Sweden.

ABSTRACT
Infant acute lymphoblastic leukemia (ALL) with MLL rearrangements (MLL-R) represents a distinct leukemia with a poor prognosis. To define its mutational landscape, we performed whole-genome, exome, RNA and targeted DNA sequencing on 65 infants (47 MLL-R and 18 non-MLL-R cases) and 20 older children (MLL-R cases) with leukemia. Our data show that infant MLL-R ALL has one of the lowest frequencies of somatic mutations of any sequenced cancer, with the predominant leukemic clone carrying a mean of 1.3 non-silent mutations. Despite this paucity of mutations, we detected activating mutations in kinase-PI3K-RAS signaling pathway components in 47% of cases. Surprisingly, these mutations were often subclonal and were frequently lost at relapse. In contrast to infant cases, MLL-R leukemia in older children had more somatic mutations (mean of 6.5 mutations/case versus 1.3 mutations/case, P = 7.15 × 10(-5)) and had frequent mutations (45%) in epigenetic regulators, a category of genes that, with the exception of MLL, was rarely mutated in infant MLL-R ALL.

Show MeSH
Related in: MedlinePlus