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(Reference retrieved automatically from Web of Science through information on FAPESP grant and its corresponding number as mentioned in the publication by the authors.)

A transcriptome-wide association study of high-grade serous epithelial ovarian cancer identifies new susceptibility genes and splice variants

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Author(s):
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Gusev, Alexander [1, 2] ; Lawrenson, Kate [3, 4, 5] ; Lin, Xianzhi [3] ; Lyra, Jr., Paulo C. [6] ; Kar, Siddhartha [7] ; Vavra, Kevin C. [3] ; Segato, Felipe [8] ; Fonseca, Marcos A. S. [3] ; Lee, Janet M. [4] ; Pejovic, Tanya [9, 10] ; Liu, Gang [3] ; Karlan, Beth Y. [3] ; Freedman, Matthew L. [1] ; Noushmehr, Houtan [8, 11] ; Monteiro, Alvaro N. [6] ; Pharoah, Paul D. P. [7] ; Pasaniuc, Bogdan [12, 13, 5] ; Gayther, Simon A. [4] ; Consortium, Ovarian Can Assoc
Total Authors: 19
Affiliation:
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[1] Dana Farber Canc Inst, Dept Med Oncol, Boston, MA 02115 - USA
[2] Brigham & Womens Hosp, Div Genet, 75 Francis St, Boston, MA 02115 - USA
[3] Cedars Sinai Med Ctr, Womens Canc Program, Samuel Oschin Comprehens Canc Inst, Los Angeles, CA 90048 - USA
[4] Cedars Sinai Med Ctr, Dept Biomed Sci, Samuel Oschin Comprehens Canc Inst, Ctr Bioinformat & Funct Genom, Los Angeles, CA 90048 - USA
[5] Univ Calif Los Angeles, David Geffen Sch Med, Dept Biomath, Los Angeles, CA 90095 - USA
[6] H Lee Moffitt Canc Ctr & Res Inst, Canc Epidemiol Program, Tampa, FL - USA
[7] Univ Cambridge, CR UK Dept Oncol, Strangeways Res Lab, Cambridge - England
[8] Univ Sao Paulo, Ribeirao Preto Med Sch, Dept Genet, Sao Paulo - Brazil
[9] Oregon Hlth & Sci Univ, Knight Canc Inst, Portland, OR 97201 - USA
[10] Oregon Hlth & Sci Univ, Dept Obstet & Gynecol, Portland, OR 97201 - USA
[11] Henry Ford Hosp, Dept Neurosurg, Detroit, MI 48202 - USA
[12] Univ Calif Los Angeles, David Geffen Sch Med, Dept Human Genet, Los Angeles, CA 90095 - USA
[13] Univ Calif Los Angeles, David Geffen Sch Med, Dept Pathol & Lab Med, Los Angeles, CA 90095 - USA
Total Affiliations: 13
Document type: Journal article
Source: Nature Genetics; v. 51, n. 5, p. 815+, MAY 2019.
Web of Science Citations: 2
Abstract

We sought to identify susceptibility genes for high-grade serous ovarian cancer (HGSOC) by performing a transcriptome-wide association study of gene expression and splice junction usage in HGSOC-relevant tissue types (N = 2,169) and the largest genome-wide association study available for HGSOC (N =13,037 cases and 40,941 controls). We identified 25 transcriptome-wide association study significant genes, 7 at the junction level only, including LRRC46 at 19q21.32, (P=1 x 10(-9)), CHMP4C at 8q21 (P= 2 x 10(-11)) and a PRC1 junction at 15q26 (P=7 x 10(-9)). In vitro assays for CHMP4C showed that the associated variant induces allele-specific exon inclusion (P= 0.0024). Functional screens in HGSOC cell lines found evidence of essentiality for three of the new genes we identified: HAUS6, KANSL1 and PRC1, with the latter comparable to MYC. Our study implicates at least one target gene for 6 out of 13 distinct genome-wide association study regions, identifying 23 new candidate susceptibility genes for HGSOC. (AU)

FAPESP's process: 15/07925-5 - Open source software statistical tools to aid in analyzing and integrating large cancer epigenomic datasets in order to decipher and understand regulatory networks
Grantee:Houtan Noushmehr
Support Opportunities: Research Grants - Young Investigators Grants