Recurrent DGCR8, DROSHA, and SIX homeodomain mutations in favorable histology Wilms tumors

Amy L Walz; Ariadne Ooms; Samantha Gadd; Daniela S Gerhard; Malcolm A Smith; Jaime M Guidry Auvil; Daoud Meerzaman; Qing-Rong Chen; Chih Hao Hsu; Chunhua Yan; Cu Nguyen; Ying Hu; Reanne Bowlby; Denise Brooks; Yussanne Ma; Andrew J Mungall; Richard A Moore; Jacqueline Schein; Marco A Marra; Vicki Huff; Jeffrey S Dome; Yueh-Yun Chi; Charles G Mullighan; Jing Ma; David A Wheeler; Oliver A Hampton; Nadereh Jafari; Nicole Ross; Julie M Gastier-Foster; Elizabeth J Perlman

doi:10.1016/j.ccell.2015.01.003

Recurrent DGCR8, DROSHA, and SIX homeodomain mutations in favorable histology Wilms tumors

Cancer Cell. 2015 Feb 9;27(2):286-97. doi: 10.1016/j.ccell.2015.01.003.

Authors

Amy L Walz¹, Ariadne Ooms², Samantha Gadd³, Daniela S Gerhard⁴, Malcolm A Smith⁵, Jaime M Guidry Auvil, Daoud Meerzaman⁶, Qing-Rong Chen⁶, Chih Hao Hsu⁶, Chunhua Yan⁶, Cu Nguyen⁶, Ying Hu⁶, Reanne Bowlby⁷, Denise Brooks⁷, Yussanne Ma⁷, Andrew J Mungall⁷, Richard A Moore⁷, Jacqueline Schein⁷, Marco A Marra⁸, Vicki Huff⁹, Jeffrey S Dome¹⁰, Yueh-Yun Chi¹¹, Charles G Mullighan¹², Jing Ma¹², David A Wheeler¹³, Oliver A Hampton¹³, Nadereh Jafari¹⁴, Nicole Ross¹⁵, Julie M Gastier-Foster¹⁵, Elizabeth J Perlman¹⁶

Affiliations

¹ Division of Hematology-Oncology and Transplantation, Ann and Robert H. Lurie Children's Hospital of Chicago, Northwestern University's Feinberg School of Medicine, Chicago, IL 60611, USA.
² Department of Pathology, Josephine Nefkens Institute, Erasmus Medical Center, Rotterdam CA 3000, the Netherlands.
³ Department of Pathology and Laboratory Medicine, Lurie Children's Hospital, Northwestern University's Feinberg School of Medicine and Robert H. Lurie Cancer Center, Chicago, IL 60611, USA.
⁴ Office of Cancer Genomics, National Cancer Institute, Bethesda, MD 20892, USA.
⁵ Cancer Therapy Evaluation Program, National Cancer Institute, Bethesda, MD 20892, USA.
⁶ Center for Biomedical Informatics and Information Technology, National Cancer Institute, Bethesda, MD 20892, USA.
⁷ Canada's Michael Smith Genome Sciences Centre, British Columbia Cancer Agency, Vancouver, BC V5Z 4S6, Canada.
⁸ Canada's Michael Smith Genome Sciences Centre, British Columbia Cancer Agency, Vancouver, BC V5Z 4S6, Canada; Department of Medical Genetics, University of British Columbia, Vancouver, BC V6H 3N1, Canada.
⁹ Department of Genetics, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA.
¹⁰ Division of Pediatric Hematology/Oncology, Children's National Medical Center, Washington, DC 20010, USA.
¹¹ Department of Biostatistics, University of Florida, Gainesville, FL 32610, USA.
¹² Department of Pathology, St. Jude Children's Research Hospital, Memphis, TN 38105, USA.
¹³ Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX 77030, USA.
¹⁴ Center for Genetic Medicine, Northwestern University, Chicago, IL 60611, USA.
¹⁵ Department of Pathology and Laboratory Medicine, Nationwide Children's Hospital, Ohio State University College of Medicine, Columbus, OH 43205, USA.
¹⁶ Department of Pathology and Laboratory Medicine, Lurie Children's Hospital, Northwestern University's Feinberg School of Medicine and Robert H. Lurie Cancer Center, Chicago, IL 60611, USA. Electronic address: [email protected].

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.

Publication types

Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't

MeSH terms

Gene Expression Regulation, Neoplastic
Homeodomain Proteins / genetics*
Humans
Loss of Heterozygosity / genetics
MicroRNAs / genetics
Mutation
Neoplasm Recurrence, Local / genetics
Neoplasm Recurrence, Local / pathology
Nerve Tissue Proteins / genetics*
Polymorphism, Single Nucleotide
RNA-Binding Proteins / genetics*
Ribonuclease III / genetics*
Wilms Tumor / genetics*
Wilms Tumor / pathology

Substances

DGCR8 protein, human
Homeodomain Proteins
MicroRNAs
Nerve Tissue Proteins
RNA-Binding Proteins
SIX1 protein, human
SIX2 protein, human
mirnlet7 microRNA, human
DROSHA protein, human
Ribonuclease III

Abstract

Publication types

MeSH terms

Substances

Grants and funding