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Poster display session

1838 - A Polymorphism in the Promoter of the FRAS1 Gene is Associated with Metastatic Prostate Cancer

Date

10 Sep 2017

Session

Poster display session

Topics

Translational Research;  Prostate Cancer

Presenters

Christopher Sweeney

Citation

Annals of Oncology (2017) 28 (suppl_5): v269-v294. 10.1093/annonc/mdx370

Authors

C.J. Sweeney1, M. Geybels2, S. Coseo-Markt3, V. Wang4, K. Penney5, T. Gerke6, M.M. Pomerantz7, G.M. Lee7, D. Nitsch8, C. Huttenhower9, L. Mucci3

Author affiliations

  • 1 Medical Oncology, Dana-Farber Cancer Institute, 02215 - Boston/US
  • 2 Division Of Public Health Sciences, Fred Hutchinson Cancer Research Center, Seattle/US
  • 3 Department Of Epidemiology, Harvard T.H. Chan School of Public Health, Boston/US
  • 4 Biostastatics, Dana Farber Cancer Institute, Boston/US
  • 5 Channing Division Of Network Medicine, Brigham Womens Hospital, Boston/US
  • 6 Epidemiology, Moffitt Cancer Center, Tampa/US
  • 7 Medical Oncology, Dana-Farber Cancer Institute, Boston/US
  • 8 Department Of General And Interventional Cardiology, University Heart Center Hamburg-Eppendorf, Hamburg/DE
  • 9 Department Of Biostatistics, Harvard T.H. Chan School of Public Health, Boston/US
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Resources

Abstract 1838

Background

Inflammation and one of its mediating transcription factors, NF-kappa B signaling (NFκB) have been implicated in prostate cancer (PrCa) carcinogenesis. We sought to define whether germline gene polymorphisms that interact with NFκB are associated with metastatic disease after prostatectomy (RP) or radiation (XRT) for localized disease.

Methods

Using a bioinformatics approach interrogating publicly available datasets, we defined a genome-wide functional association network specific to lethal PrCa consisting of 351 genes and 8,154,133 high-confidence functional associations related to the NFκB pathway. The dense module searching (DMS) method was used to analyze 419,461 SNPs from a previously conducted genome wide association study (GWAS) case-only study of 196 lethal PrCa cases compared to 368 indolent controls in the Harvard School of Public Heath (HSPH) Cohorts. Top hits from DMS were then tested in two independent PrCa cohorts: (i) ECOG/DFCI (n = 254 cases, 256 controls) and (ii) Fred Hutchinson Cancer Research Center (FH, n = 570 cases, 103 controls). In all 3 studies, “controls” were men with PrCa who are alive with no evidence of metastasis at least 8-years after RP or XRT and “cases” were men who developed metastatic disease after RP or XRT (FH, HSPH, ECOG) or with de novo presentation (ECOG).

Results

From the DMS, 40 SNPs with a minor allele frequency > 0.1 were associated with lethal PrCa. Of these, rs1910301 in the promoter region of FRAS1 was nominally associated with lethal disease in all 3 studies with similar size effects: the odds ratio (OR) for the A allele was 1.40 (p = 0.02) in HSPH, 1.35 in ECOG/Gelb (p = 0.04), and borderline significant in FH [OR 1.3, p = 0.07]. Fixed effects meta-analysis of all three cohorts found a significant association: OR = 1.38 95% CI: 1.15-1.66; p-value 0.005.

Conclusions

A SNP in the promoter region of FRAS1, which forms a gene unit with FREM2 and together regulate epidermal-basement membrane adhesion and cell migration, is associated with metastatic PrCa. FREM2 is an NFκB regulated gene and mutations in FREM2 and FRAS1 are associated with the Fraser syndrome. Further work is needed to determine the effect of rs1910301 on FRAS1 function and cellular adhesion and the metastatic process.

Clinical trial identification

Legal entity responsible for the study

Christopher Sweeney

Funding

US Department of Defense, NIH

Disclosure

C.J. Sweeney: Consultant with compensation and research: Janssen (C, R); Astellas (C, R); Sanofi (C, R); Bayer (C, R), Sotio (R), Pfizer (C). All other authors have declared no conflicts of interest.

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