Recurrent DGCR8, DROSHA, and SIX homeodomain mutations in favorable histology Wilms tumors - PubMed (original) (raw)
. 2015 Feb 9;27(2):286-97.
doi: 10.1016/j.ccell.2015.01.003.
Ariadne Ooms 2, Samantha Gadd 3, Daniela S Gerhard 4, Malcolm A Smith 5, Jaime M Guidry Auvil, Daoud Meerzaman 6, Qing-Rong Chen 6, Chih Hao Hsu 6, Chunhua Yan 6, Cu Nguyen 6, Ying Hu 6, Reanne Bowlby 7, Denise Brooks 7, Yussanne Ma 7, Andrew J Mungall 7, Richard A Moore 7, Jacqueline Schein 7, Marco A Marra 8, Vicki Huff 9, Jeffrey S Dome 10, Yueh-Yun Chi 11, Charles G Mullighan 12, Jing Ma 12, David A Wheeler 13, Oliver A Hampton 13, Nadereh Jafari 14, Nicole Ross 15, Julie M Gastier-Foster 15, Elizabeth J Perlman 16
Affiliations
- PMID: 25670082
- PMCID: PMC4800737
- DOI: 10.1016/j.ccell.2015.01.003
Recurrent DGCR8, DROSHA, and SIX homeodomain mutations in favorable histology Wilms tumors
Amy L Walz et al. Cancer Cell. 2015.
Erratum in
- Cancer Cell. 2015 Mar 9;27(3):426. Guidry Auvil, Jamie M [corrected to Guidry Auvil, Jaime M]
Abstract
We report the most common single-nucleotide substitution/deletion mutations in favorable histology Wilms tumors (FHWTs) to occur within SIX1/2 (7% of 534 tumors) and microRNA processing genes (miRNAPGs) DGCR8 and DROSHA (15% of 534 tumors). Comprehensive analysis of 77 FHWTs indicates that tumors with SIX1/2 and/or miRNAPG mutations show a pre-induction metanephric mesenchyme gene expression pattern and are significantly associated with both perilobar nephrogenic rests and 11p15 imprinting aberrations. Significantly decreased expression of mature Let-7a and the miR-200 family (responsible for mesenchymal-to-epithelial transition) in miRNAPG mutant tumors is associated with an undifferentiated blastemal histology. The combination of SIX and miRNAPG mutations in the same tumor is associated with evidence of RAS activation and a higher rate of relapse and death.
Copyright © 2015 Elsevier Inc. All rights reserved.
Figures
Figure 1. Recurrent SIX1/2 Q177 mutations in FHWT
(A) Phyre2 images showing the Q177 residue of SIX1 to be located within a conserved region (top panel) and is predicted to be a specific DNA-contact base (bottom panel; blue and red indicate regions of low and high likelihood of DNA contact, respectively). (B) Coverage of the reference allele (blue bar) and variant allele (red bar) as determined by mRNA-sequencing for SIX1 and SIX2 mutant tumors. (C) Location of validation set variants within the SIX1 and SIX2 proteins; number of variants detected are provided in parenthesis. (D) Unsupervised NMF clustering of 75 FHWT with annotation of mutations identified (bottom, Red= somatic, Gray = germline) (E) Supervised hierarchical clustering of 75 FHWT according to the top 100 genes differentially expressed in _SIX1/2_-mutant tumors with annotation of tumors with SIX1/2 mutations and copy number changes (blue = gain; dark red = loss) shown at the bottom. (F) Boxplots of MEIS2 and CCND2 in _SIX1/2_-mutants versus wild-type FHWTs. The bottom and top of the box represent the first and third quartiles, respectively, the band inside the box represents the median, and the whiskers represent the maximum and minimum values. (G) Boxplots of MEIS2 and CCND2 in NMF cluster 2 _SIX1/2_-mutants versus wild-type tumors. See also Figure S1 and Tables S1–S3.
Figure 2. Recurrent miRNAPG hotspot mutations in FHWT
(A) Location of validation set variants within the DGCR8, DROSHA, XPO5, and DICER1 proteins; number of variants detected are provided in parenthesis. (B) Coverage of the reference allele (blue bar) and variant allele (red bar) as determined by mRNA-sequencing for DROSHA (top panel) and DGCR8 (bottom panel). (C) Supervised hierarchical clustering of 75 FHWT according to the top 100 genes differentially expressed in miRNAPG-mutant tumors with annotation of miRNAPG mutations (red= somatic, gray = germline) and copy number loss. (D) Mature Let-7a average ddCt (left panel) and primary Let-7a average ddCt (right panel) in FHWT with miRNAPG mutations (red bar), copy number loss (blue bar), and lacking both miRNAPG mutations and copy number loss (black bar). Error bars = +SEM. (E) Hierarchical analysis of the 43 miRNAs significantly differentially expressed in somatic miRNAPG mutant FHWTs compared with those lacking both miRNAPG mutations and copy number loss with annotation of miRNAPG mutations and copy number loss. Blue and yellow represent relatively high and low expression, respectively. Five clusters were observed, as indicated at the bottom. See also Tables S4–S6.
Figure 3. Integrative Analysis of Non-negative Matrix Factorization Clusters
Clinical, pathologic, and genetic features of FHWT arranged according to the NMF identified in Figure 1D. The key is illustrated at the bottom. See also Figure S2.
Figure 4. Disease Free Survival
Kaplan-Meier curve of disease free survival in the following four validation set groups: (1) tumors with SIX1/2 and miRNAPG-HS variants (black line), (2) tumors with miRNAPG-HS variants without SIX1/2 variants (blue line), (3) SIX1/2 variants without miRNAPG-HS variants (green line), and (4) all other validation set tumors (red line).
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