TY - JOUR
T1 - The prevalence of germline DICER1 pathogenic variation in cancer populations
AU - Kim, Jung
AU - Schultz, Kris Ann P.
AU - Hill, Dana Ashley
AU - Stewart, Douglas R.
N1 - Funding Information:
This work was supported by the Intramural Research Program of the Division of Cancer Epidemiology and Genetics of the National Cancer Institute, Bethesda, MD.
Funding Information:
DAH and KAS are supported by National Cancer Institute R01CA143167. The authors also wish to thank the Pine Tree Apple Tennis Classic and St. Baldrick's Foundation for their ongoing support of children's cancer research. The authors wish to thank the many patients, families and treating physicians who participate in the NCI DICER1‐ related Pleuropulmonary Blastoma Cancer Predisposition Syndrome study, the International OTST Registry and/or the International PPB/DICER1 Registry. This work utilized the computational resources of the NIH High Performance Computing Biowulf cluster. The results published here are in whole or part based upon data generated by the TCGA Research Network: http://cancergenome.nih.gov/ and the Therapeutically Applicable Research to Generate Effective Treatments (TARGET) initiative managed by the NCI. The data used for this analysis are available phs000218. Information about TARGET can be found at http://ocg. cancer.gov/programs/target
Publisher Copyright:
© 2019 The Authors. Molecular Genetics & Genomic Medicine published by Wiley Periodicals, Inc.
PY - 2019/3
Y1 - 2019/3
N2 - Background: The DICER1 syndrome is an autosomal dominant tumor-predisposition disorder associated with pleuropulmonary blastoma, a rare pediatric lung cancer. Somatic missense variation in “hotspot” codons in the RNaseIIIb domain (E1705, D1709, G1809, D1810, E1813) is observed in DICER1-associated tumors. Previously, we found the prevalence of germline pathogenic DICER1 variation in the general population is 1:10,600. In this study, we investigated the prevalence of pathogenic DICER1 germline variation in The Cancer Genome Atlas (TCGA; 32 adult cancer types; 9,173 exomes) and the Therapeutically Applicable Research to Generate Effective Treatment (TARGET; two pediatric cancer types; 175 exomes) cohorts. Methods: All datasets were annotated and binned into four categories: pathogenic, likely pathogenic, variant of unknown significance, or likely benign. Results: The prevalence of DICER1 pathogenic variants was 1:4,600 in TCGA. A single participant with a uterine corpus endometrial carcinoma harbored two pathogenic germline DICER1 (hotspot and splice-donor) variants, and a single participant with a rectal adenocarcinoma harbored a germline DICER1 stop-gained variant. In the smaller TARGET dataset, we observed no pathogenic germline variants. Conclusion: This is the largest comprehensive analysis of DICER1 pathogenic variation in adult and pediatric cancer populations using publicly available data. The observation of germline DICER1 variation with uterine corpus endometrial carcinoma merits additional investigation.
AB - Background: The DICER1 syndrome is an autosomal dominant tumor-predisposition disorder associated with pleuropulmonary blastoma, a rare pediatric lung cancer. Somatic missense variation in “hotspot” codons in the RNaseIIIb domain (E1705, D1709, G1809, D1810, E1813) is observed in DICER1-associated tumors. Previously, we found the prevalence of germline pathogenic DICER1 variation in the general population is 1:10,600. In this study, we investigated the prevalence of pathogenic DICER1 germline variation in The Cancer Genome Atlas (TCGA; 32 adult cancer types; 9,173 exomes) and the Therapeutically Applicable Research to Generate Effective Treatment (TARGET; two pediatric cancer types; 175 exomes) cohorts. Methods: All datasets were annotated and binned into four categories: pathogenic, likely pathogenic, variant of unknown significance, or likely benign. Results: The prevalence of DICER1 pathogenic variants was 1:4,600 in TCGA. A single participant with a uterine corpus endometrial carcinoma harbored two pathogenic germline DICER1 (hotspot and splice-donor) variants, and a single participant with a rectal adenocarcinoma harbored a germline DICER1 stop-gained variant. In the smaller TARGET dataset, we observed no pathogenic germline variants. Conclusion: This is the largest comprehensive analysis of DICER1 pathogenic variation in adult and pediatric cancer populations using publicly available data. The observation of germline DICER1 variation with uterine corpus endometrial carcinoma merits additional investigation.
KW - DICER1
KW - DICER1 syndrome
KW - TARGET
KW - TCGA
KW - cancer population
KW - prevalence estimate
UR - http://www.scopus.com/inward/record.url?scp=85062920057&partnerID=8YFLogxK
U2 - 10.1002/mgg3.555
DO - 10.1002/mgg3.555
M3 - Article
C2 - 30672147
AN - SCOPUS:85062920057
SN - 2324-9269
VL - 7
JO - Molecular Genetics and Genomic Medicine
JF - Molecular Genetics and Genomic Medicine
IS - 3
M1 - e555
ER -