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

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

doi:10.1200/po.17.00009

Abstract

PurposeIdentification of single-gene biomarkers that are prognostic of outcome can shed new insights on the molecular mechanisms that drive breast cancer and other cancers.MethodsExploratory 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.ResultsA 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 = 3.8E-14) outperformed MKI67 (P = 1.06E-8) and AURKA (P = 2.61E-5). A comparison of the Stouffer P value in four ER-negative cohorts showed that FGD3 (P = 3.88E-5) outperformed MKI67 (P = .477) and AURKA (P = .820).ConclusionFGD3 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.

Highlights

An increasing collection of breast cancer cohorts have been molecularly profiled on Affymetrix and Illumina platforms, so it is feasible to conduct an exploratory analysis to identify single-gene biomarkers in which messenger RNA expression is prognostic of outcome.[1]
A meta-analysis of Cox regression of faciogenital dysplasia 3 (FGD3) messenger RNA (mRNA) as a continuous variable for overall survival of estrogen receptor (ER)–positive samples in METABRIC discovery, METABRIC validation, The Cancer Genome Atlas (TCGA) breast cancer, and Combination Chemotherapy in Treating Women With Breast Cancer (E2197) cohorts resulted in a combined hazard ratio (HR) of 0.69, indicating better outcome with high expression
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

Summary

Introduction

An increasing collection of breast cancer cohorts have been molecularly profiled on Affymetrix and Illumina platforms, so it is feasible to conduct an exploratory analysis to identify single-gene biomarkers in which messenger RNA (mRNA) expression is prognostic of outcome.[1] By limiting the exploratory analysis to a single gene, we intended to identify novel gene(s) that might provide insight into biological mechanisms that drive breast cancer metastasis.[2] The starting point for this analysis was the Molecular Taxonomy of Breast Cancer International Consortium (METABRIC) data set, which contains clinical traits, expression data, copy number variation profiles, and single nucleotide polymorphism genotypes derived from breast tumors collected from participants in the METABRIC trial.[3] We used the Genomic Data Commons, which incorporates The Cancer Genome Atlas (TCGA) cancer cohorts and currently spans 21 cancer types suitable for survival analysis. ESR1 transcriptional regulation of FGD3 mRNA expression in the breast cancer cell line ZR-75-1 was confirmed

Methods

Results

Conclusion