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

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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

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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

• Tipo de documento: Artigo Científico
• Fonte: Nature Genetics; v. 51, n. 5, p. 815+, MAY 2019.
• Citações Web of Science: 1

Resumo

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)

• Processo FAPESP: 15/07925-5 - Softwares de código aberto contendo ferramentas estatísticas para análise e integração de conjuntos de dados epigenômicos produzidos em alta escala, a fim de decifrar e entender redes reguladoras de câncer
• Beneficiário: Houtan Noushmehr
• Linha de fomento: Auxílio à Pesquisa - Apoio a Jovens Pesquisadores
• Processo FAPESP: 17/08211-1 - Estudo da origem celular do câncer de ovário usando dados genômicos e epigenômicos em larga escala
• Beneficiário: Marcos Abraão de Souza Fonseca
• Linha de fomento: Bolsas no Brasil - Programa Capacitação - Treinamento Técnico