Pan-cancer genomic analysis reveals FOXA1 amplification is associated with adverse outcomes in non-small cell lung, prostate, and breast cancers

Alexander G Goglia; Mohammed Alshalalfa; Anwar Khan; Danielle R Isakov; Helen Y Hougen; Nishwant Swami; Jasmine Kannikal; Sean M Mcbride; Daniel R Gomez; Sanoj Punnen; Paul L Nguyen; Puneeth Iyengar; Emmanuel S Antonarakis; Brandon A Mahal; Edward Christopher Dee

doi:10.1093/jnci/djae224

Pan-cancer genomic analysis reveals FOXA1 amplification is associated with adverse outcomes in non-small cell lung, prostate, and breast cancers

J Natl Cancer Inst. 2024 Sep 10:djae224. doi: 10.1093/jnci/djae224. Online ahead of print.

Authors

Affiliations

¹ Department of Radiation Oncology, Memorial Sloan Kettering Cancer Center, New York, NY, USA.
² Sylvester Comprehensive Cancer Center, University of Miami Miller School of Medicine, Miami, FL, USA.
³ Sylvester Comprehensive Cancer Center, University of Miami Miller School of Medicine, Miami, FL, USA/.
⁴ Human Oncology and Pathogenesis Program, Department of Neuro-Oncology, Memorial Sloan Kettering Cancer Center, New York, 10065, NY, USA.
⁵ Department of Urology, University of Iowa, Iowa City, 52242, IA, USA.
⁶ Division of Internal Medicine, University of Pennsylvania Health System, Pennsylvania, PA, USA.
⁷ Desai & Sethi Institute of Urology, Miller School of Medicine, University of Miami, Miami, 33136, FL, USA.
⁸ Department of Radiation Oncology, Dana-Farber Brigham Cancer Center, Boston, MA, USA.
⁹ Department of Medicine, University of Minnesota-Twin Cities, Minneapolis, 55455, MN, USA.
¹⁰ Department of Radiation Oncology, University of Miami Miller School of Medicine/Sylvester Comprehensive Cancer Center, Miami, FL, USA.

PMID: 39254651
DOI: 10.1093/jnci/djae224

Abstract

Introduction: Alterations in forkhead box A1 (FOXA1), a pioneer transcription factor, are associated with poor prognosis in breast cancer (BC) and prostate cancer (PC). We characterized FOXA1 genomic alterations and their clinical impacts in a large pan-cancer cohort from the AACR GENIE database.

Methods: FOXA1 alterations were characterized across >87,000 samples from >30 cancer types for primary and metastatic tumors alongside patient characteristics and clinical outcomes. FOXA1 alterations were queried in the MSK-MET cohort (a GENIE subset), allowing definition of hazard ratios (HRs) and survival estimates based on Cox proportional hazard models.

Results: FOXA1 was altered in 1,869 samples (2.1%), with distinct patterns across different cancers: PC enriched with indel-inframe alterations, BC with missense mutations, and lung cancers with copy number (CN) amplifications.Of 74,715 samples with FOXA1 CN profiles, amplification was detected in 834 (1.1%). Amplification was most common in non-small cell lung cancer (NSCLC, 3% in primary; 6% in metastatic) and small cell lung cancer (4.1% primary; 3.5% metastatic), followed by BC (2% primary; 1.6% metastatic) and PC (2.2% primary; 1.6% metastatic).CN amplifications were associated with decreased overall survival in NSCLC (HR: 1.45, 95%CI: 1.06-1.99, p = .02), BC (HR: 3.04, 95%CI: 1.89-4.89, p = 4e-6), and PC (HR: 1.94, 95%CI: 1.03-3.68, p = .04). Amplifications were associated with wide-spread metastases in NSCLC, BC, and PC.

Conclusions: FOXA1 demonstrates distinct alteration profiles across cancer sites. Our findings suggest an association between FOXA1 amplification and both enhanced metastatic potential and decreased survival, highlighting prognostic and therapeutic potential in breast cancer, prostate cancer, and NSCLC.