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4. Network-Based Integration of GWAS and Gene Expression Identifies a HOX-Centric Network Associated with Serous Ovarian Cancer Risk

Author

Kar, S. P., Tyrer, J. P., Li, Qiyuan, Lawrenson, K., Aben, K. K. H., Anton-Culver, H., Antonenkova, N., Chenevix-Trench, G., Baker, H., Bandera, E. V., Bean, Y. T., Beckmann, M. W., Berchuck, A., Bisogna, M., Bjorge, L., Bogdanova, N., Brinton, L., Brooks-Wilson, A., Butzow, R., Campbell, I., Carty, K., Chang-Claude, J., Chen, Y. A., Chen, Z., Cook, L. S., Cramer, Daniel William, Cunningham, J. M., Cybulski, C., Dansonka-Mieszkowska, A., Dennis, J., Dicks, E., Doherty, J. A., Dork, T., du Bois, A., Durst, M., Eccles, D., Easton, D. F., Edwards, R. P., Ekici, A. B., Fasching, P. A., Fridley, B. L., Gao, Y.-T., Gentry-Maharaj, A., Giles, G. G., Glasspool, R., Goode, E. L., Goodman, M. T., Grownwald, J., Harrington, P., Harter, P., Hein, A., Heitz, F., Hildebrandt, M. A. T., Hillemanns, P., Hogdall, E., Hogdall, C. K., Hosono, S., Iversen, E. S., Jakubowska, A., Paul, J., Jensen, A., Ji, B.-T., Karlan, B. Y., Kjaer, S. K., Kelemen, L. E., Kellar, M., Kelley, J., Kiemeney, L. A., Krakstad, C., Kupryjanczyk, J., Lambrechts, D., Lambrechts, S., Le, N. D., Lee, A. W., Lele, S., Leminen, A., Lester, J., Levine, D. A., Liang, D., Lissowska, J., Lu, K., Lubinski, J., Lundvall, L., Massuger, L., Matsuo, K., McGuire, V., McLaughlin, J. R., McNeish, I. A., Menon, U., Modugno, F., Moysich, K. B., Narod, S. A., Nedergaard, L., Ness, R. B., Nevanlinna, H., Odunsi, K., Olson, S. H., Orlow, I., Orsulic, S., Weber, R. P., Pearce, C. L., Pejovic, T., Pelttari, L. M., Permuth-Wey, J., Phelan, C. M., Pike, M. C., Poole, Elizabeth M., Ramus, S. J., Risch, H. A., Rosen, B., Rossing, M. A., Rothstein, J. H., Rudolph, A., Runnebaum, I. B., Rzepecka, I. K., Salvesen, H. B., Schildkraut, J. M., Schwaab, I., Shu, X.-O., Shvetsov, Y. B., Siddiqui, N., Sieh, W., Song, H., Southey, M. C., Sucheston-Campbell, L. E., Tangen, I. L., Teo, S.-H., Terry, Kathryn Lynne, Thompson, P. J., Timorek, A., Tsai, Y.-Y., Tworoger, Shelley Slate, van Altena, A. M., Van Nieuwenhuysen, E., Vergote, I., Vierkant, R. A., Wang-Gohrke, S., Walsh, C., Wentzensen, N., Whittemore, A. S., Wicklund, K. G., Wilkens, L. R., Woo, Y.-L., Wu, X., Wu, A., Yang, H., Zheng, W., Ziogas, A., Sellers, T. A., Monteiro, A. N. A., Freedman, M. L., Gayther, S. A., and Pharoah, P. D. P.

Subjects
ovarian cancer, network analysis, GWAS, gene expression, transcription factors
Abstract

BACKGROUND: Genome-wide association studies (GWAS) have so far reported 12 loci associated with serous epithelial ovarian cancer (EOC) risk. We hypothesized that some of these loci function through nearby transcription factor (TF) genes and that putative target genes of these TFs as identified by coexpression may also be enriched for additional EOC risk associations. METHODS: We selected TF genes within 1 Mb of the top signal at the 12 genome-wide significant risk loci. Mutual information, a form of correlation, was used to build networks of genes strongly coexpressed with each selected TF gene in the unified microarray dataset of 489 serous EOC tumors from The Cancer Genome Atlas. Genes represented in this dataset were subsequently ranked using a gene-level test based on results for germline SNPs from a serous EOC GWAS meta-analysis (2,196 cases/4,396 controls). RESULTS: Gene set enrichment analysis identified six networks centered on TF genes (HOXB2, HOXB5, HOXB6, HOXB7 at 17q21.32 and HOXD1, HOXD3 at 2q31) that were significantly enriched for genes from the risk-associated end of the ranked list (P < 0.05 and FDR < 0.05). These results were replicated (P < 0.05) using an independent association study (7,035 cases/21,693 controls). Genes underlying enrichment in the six networks were pooled into a combined network. CONCLUSION: We identified a HOX-centric network associated with serous EOC risk containing several genes with known or emerging roles in serous EOC development. IMPACT: Network analysis integrating large, context-specific datasets has the potential to offer mechanistic insights into cancer susceptibility and prioritize genes for experimental characterization.

Published
2015
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6. LBA11Mainstreaming genetic counselling for genetic testing of BRCA1/2 in ovarian cancer patients in Malaysia (MaGIC study).

Author

Yoon, S Y Y, Wong, S W, Ahmad, N S, Mariapun, S, Hassan, T, Padmanabhan, H, Lim, J, George, A, Thong, M K, Chng, G S, Teo, S H, Bleiker, E, and Woo, Y L

Subjects
*GENETIC counseling, *GENETIC testing, *OVARIAN cancer, *COUNSELING, *CANCER patients
Abstract

Background Identification of germline BRCA mutations in ovarian cancer patients allows clinicians to make treatment decisions and manage risks. Due to the lack of genetic counsellors, clinical geneticists and awareness among clinicians, there is minimal testing regionally. Mainstreaming genetic counselling may improve this access. This study aims to determine the prevalence of BRCA mutations, feasibility of mainstreaming and the psychosocial impact of genetic testing in Malaysian ovarian cancer patients. Methods This study aimed to recruit 800 patients with non-mucinous epithelial ovarian, peritoneal or fallopian tube cancer regardless of age or family history, via mainstreaming or referral to genetic services. Genetic Counselling Satisfaction Scale (GCSS), Decisional Conflict Scale (DCS), Psychosocial Aspect of Hereditary Cancer (PAHC) and Cancer Worry Scale (CWS) were used to measure the feasibility and psychosocial outcomes. Mainstreaming clinicians provided feedback through a survey. Results 23/28 mainstreaming sites remained active and 47/68 trained clinicians continued to provide genetic counselling. 800 patients have been recruited, 690 via mainstreaming and 110 via genetics route. 790 have been tested, 110 (13.9%) have pathogenic variants, 90 (11.4%) VUS and 590 (74.7%) negative. Majority of the patients were satisfied with their pre-test GC (mean: 23.9; SD: 2.7) and post result disclosure (mean: 24.6; SD: 2.6). Large majority (86%) did not feel conflicted. Patients with no issues in 5 out of 6 PAHC domains increased from 46% at pre-test GC to 62% at result disclosure. However, only 16% of participants showed high distress level after result disclosure, 22% of these were carriers. Generally, there were no significant differences between mainstreaming and genetics pathways. 36/47 (80%) of clinician are confident to counsel patients and want to integrate BRCA testing into their clinical practice. Conclusions BRCA prevalence for ovarian cancer in Malaysia is 13.9%. There is satisfaction in counselling services, acceptable psychosocial impact with no significant differences between mainstreaming and genetics pathway. Mainstreaming may improve access to genetic testing in Malaysia. Legal entity responsible for the study Cancer Research Malaysia. Funding AstraZeneca. Disclosure S.Y.Y. Yoon: Research grant / Funding (institution), Investigator Initiated Research Grant: AstraZeneca. A. George: Research grant / Funding (institution): Wellcome Trust; Honoraria (institution): AstraZeneca; Honoraria (institution): Roche; Honoraria (institution): Tesaro. [ABSTRACT FROM AUTHOR]

Published
2019
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