High Expression of FGD3, a Putative Regulator of Cell Morphology and Motility, Is Prognostic of Favorable Outcome in Multiple Cancers

Scooter Willis; Yuliang Sun; Mark Abramovitz; Teng Fei; Brandon Young; Xiaoqian Lin; Min Ni; Justin Achua; Meredith M Regan; Kathryn P Gray; Robert Gray; Victoria Wang; Bradley Long; Roswitha Kammler; Joseph A Sparano; Casey Williams; Lori J Goldstein; Roberto Salgado; Sherene Loi; Giancarlo Pruneri; Giuseppe Viale; Myles Brown; Brian Leyland-Jones

doi:10.1200/PO.17.00009

High Expression of FGD3, a Putative Regulator of Cell Morphology and Motility, Is Prognostic of Favorable Outcome in Multiple Cancers

JCO Precis Oncol. 2017 Oct 13:1:PO.17.00009. doi: 10.1200/PO.17.00009. eCollection 2017.

Authors

Scooter Willis¹, Yuliang Sun¹, Mark Abramovitz¹, Teng Fei¹, Brandon Young¹, Xiaoqian Lin¹, Min Ni¹, Justin Achua¹, Meredith M Regan¹, Kathryn P Gray¹, Robert Gray¹, Victoria Wang¹, Bradley Long¹, Roswitha Kammler¹, Joseph A Sparano¹, Casey Williams¹, Lori J Goldstein¹, Roberto Salgado¹, Sherene Loi¹, Giancarlo Pruneri¹, Giuseppe Viale¹, Myles Brown¹, Brian Leyland-Jones¹

Affiliation

¹ , , , , , , , and , Avera Cancer Institute, Sioux Falls, SD; , , , , , and , Dana-Farber Cancer Institute, Boston, MA; , Children's Medical Center Research Institute, University of Texas Southwestern Medical Center, Dallas, TX; , Molecular Core, Scripps Florida, Jupiter, FL; , International Breast Cancer Study Group, Bern, Switzerland; , Montefiore Medical Center, Bronx, NY; , Fox Chase Cancer Center, Philadelphia, PA; , Breast Cancer Translational Research Laboratory/Institut Jules Bordet, Brussels, Belgium; , Peter MacCallum Cancer Centre, East Melbourne, VIC, Australia; and and , European Institute of Oncology, University of Milan, Milan, Italy.

Abstract

Purpose: Identification of single-gene biomarkers that are prognostic of outcome can shed new insights on the molecular mechanisms that drive breast cancer and other cancers.

Methods: Exploratory analysis of 20,464 single-gene messenger RNAs (mRNAs) in the Molecular Taxonomy of Breast Cancer International Consortium (METABRIC) discovery cohort indicates that low expression of FGD3 mRNA is prognostic for poor outcome. Prognostic significance of faciogenital dysplasia 3 (FGD3), SUSD3, and other single-gene proliferation markers was evaluated in breast cancer and The Cancer Genome Atlas (TCGA) cohorts.

Results: A meta-analysis of Cox regression of FGD3 mRNA as a continuous variable for overall survival of estrogen receptor (ER)-positive samples in METABRIC discovery, METABRIC validation, TCGA breast cancer, and Combination Chemotherapy in Treating Women With Breast Cancer (E2197) cohorts resulted in a combined hazard ratio (HR) of 0.69 (95% CI, 0.63 to 0.75), indicating better outcome with high expression. In the ER-negative samples, the combined meta-analysis HR was 0.72 (95% CI, 0.63 to 0.82), suggesting that FGD3 is prognostic regardless of ER status. The potential of FGD3 as a biomarker for freedom from recurrence was evaluated in the Breast International Group 1-98 (BIG 1-98; Letrozole or Tamoxifen in Treating Postmenopausal Women With Breast Cancer) study (HR, 0.85; 95% CI, 0.76 to 0.93) for breast cancer-free interval. In the Hungarian Academy of Science (HAS) breast cancer cohort, splitting on the median had an HR of 0.49 (95% CI, 0.42 to 0.58) for recurrence-free survival. A comparison of the Stouffer P value in five ER-positive cohorts showed that FGD3 (P = 3.8^E-14) outperformed MKI67 (P = 1.06^E-8) and AURKA (P = 2.61^E-5). A comparison of the Stouffer P value in four ER-negative cohorts showed that FGD3 (P = 3.88^E-5) outperformed MKI67 (P = .477) and AURKA (P = .820).

Conclusion: FGD3 was previously shown to inhibit cell migration. FGD3 mRNA is regulated by ESR1 and is associated with favorable outcome in six distinct breast cancer cohorts and four TCGA cancer cohorts. This suggests that FGD3 is an important clinical biomarker.