Computational approaches to identify functional genetic variants in cancer genomes

Gonzalez-Perez, Abel, Mustonen, Ville, Reva, Boris, Ritchie, Graham R. S., Creixell, Pau, Karchin, Rachel, Vazquez, Miguel, Fink, J. Lynn, Kassahn, Karin S., Pearson, John V., Bader, Gary D., Boutros, Paul C., Muthuswamy, Lakshmi, Ouellette, B. F. Francis, Reimand, Jüri, Linding, Rune, Shibata, Tatsuhiro, Valencia, Alfonso, Butler, Adam, Dronov, Serge, Flicek, Paul, Shannon, Nick B., Carter, Hannah, Ding, Li, Sander, Chris, Stuart, Josh M., Stein, Lincoln D. and Lopez-Bigas, Nuria (2013) Computational approaches to identify functional genetic variants in cancer genomes. Nature Methods, 10 8: 723-729. doi:10.1038/nmeth.2562

Author Gonzalez-Perez, Abel
Mustonen, Ville
Reva, Boris
Ritchie, Graham R. S.
Creixell, Pau
Karchin, Rachel
Vazquez, Miguel
Fink, J. Lynn
Kassahn, Karin S.
Pearson, John V.
Bader, Gary D.
Boutros, Paul C.
Muthuswamy, Lakshmi
Ouellette, B. F. Francis
Reimand, Jüri
Linding, Rune
Shibata, Tatsuhiro
Valencia, Alfonso
Butler, Adam
Dronov, Serge
Flicek, Paul
Shannon, Nick B.
Carter, Hannah
Ding, Li
Sander, Chris
Stuart, Josh M.
Stein, Lincoln D.
Lopez-Bigas, Nuria
Title Computational approaches to identify functional genetic variants in cancer genomes
Journal name Nature Methods   Check publisher's open access policy
ISSN 1548-7091
Publication date 2013-08-01
Year available 2013
Sub-type Article (original research)
DOI 10.1038/nmeth.2562
Open Access Status Not Open Access
Volume 10
Issue 8
Start page 723
End page 729
Total pages 7
Place of publication London, United Kingdom
Publisher Nature Publishing Group
Language eng
Subject 1305 Biotechnology
1303 Biochemistry
1312 Molecular Biology
1307 Cell Biology
Abstract The timing of puberty is a highly polygenic childhood trait that is epidemiologically associated with various adult diseases. Using 1000 Genomes Project-imputed genotype data in up to ∼370,000 women, we identify 389 independent signals (P < 5 × 10(-8)) for age at menarche, a milestone in female pubertal development. In Icelandic data, these signals explain ∼7.4% of the population variance in age at menarche, corresponding to ∼25% of the estimated heritability. We implicate ∼250 genes via coding variation or associated expression, demonstrating significant enrichment in neural tissues. Rare variants near the imprinted genes MKRN3 and DLK1 were identified, exhibiting large effects when paternally inherited. Mendelian randomization analyses suggest causal inverse associations, independent of body mass index (BMI), between puberty timing and risks for breast and endometrial cancers in women and prostate cancer in men. In aggregate, our findings highlight the complexity of the genetic regulation of puberty timing and support causal links with cancer susceptibility.
Formatted abstract
The International Cancer Genome Consortium (ICGC) aims to catalog genomic abnormalities in tumors from 50 different cancer types. Genome sequencing reveals hundreds to thousands of somatic mutations in each tumor but only a minority of these drive tumor progression. We present the result of discussions within the ICGC on how to address the challenge of identifying mutations that contribute to oncogenesis, tumor maintenance or response to therapy, and recommend computational techniques to annotate somatic variants and predict their impact on cancer phenotype.
Keyword Single nucleotide polymorphisms
TERT promoter mutations
Somatic mutations
Missense mutations
Protein function
Transcription factors
2008 update
Q-Index Code C1
Q-Index Status Confirmed Code
Grant ID R01 CA180006
U01 HG006517
Institutional Status UQ

Document type: Journal Article
Sub-type: Article (original research)
Collections: Official 2014 Collection
Institute for Molecular Bioscience - Publications
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Citation counts: TR Web of Science Citation Count  Cited 82 times in Thomson Reuters Web of Science Article | Citations
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