Introduction
Somatic mutations in the Wnt signaling gene APC are known to be highly associated with metastatic prostate cancer progression. Less is known regarding the impact of germline APC mutations on prostate cancer outcomes such as aggressive variant prostate cancer (AVPC) including treatment-emergent neuroendocrine prostate cancer (t-NEPC). We sought to investigate the prostate cancer clinical outcomes of patients with the germline APC I1307K variant, an alteration found in 7% of Ashkenazi Jewish men.Methods
We reviewed records from 3 institutions to identify patients with the APC I1307K germline mutation. We also identified patients with somatic frameshift mutations in the APC gene at these same institutions to serve as a control cohort. Proportions of patients with AVPC among all the cases (or among only metastatic patients) were estimated along with 95% Clopper-Pearson exact confidence intervals. Odds ratios with 95% confidence intervals were provided for the prevalence of t-NEPC and AVPC in patients with germline APC I1307K compared to patients with frameshift alterations in APC (control cohort). One sample chi-square tests were used to assess differences in the proportions of genomic alterations in patients with the APC I1307K variant in our cohort compared with the expected proportions observed in unselected patients with metastatic prostate cancer available in cBioPortal.Results
From 2016-2022, 18 patients with prostate cancer at 3 institutions with the germline APC (I1307K) mutation were identified. Median age at diagnosis was 73.5 years. Most patients (15; 83%) developed metastatic disease (either de novo or metachronous). Clinically-defined AVPC was found in 8 of these 18 cases (44%; 95% CI: 21%-69%) and in 8 of the 15 cases with with metastatic disease (53%; 95% CI: 26%-79%). Combined somatic alterations in two or more of RB1, TP53 or PTEN (molecularly-defined AVPC) were found in 5/18 cases (28%; 95% CI: 10%-54%). None of these 18 cases had AR mutations. When compared to 20 patients with APC frameshift mutations, patients with the germline APC I1307K variant had a significantly increased odds of AVPC (OR 7.2; 95% CI 1.27, 40.68).Conclusions
Prostate cancers that develop in the presence of the germline APC I1307K mutation appear to be enriched for clinically-defined and molecularly-defined AVPC and in particular, for t-NEPC.Minas P. Economides, Mari Nakazawa, Jonathan W. Lee, Xiaochun Li, Lucas Hollifield, Rachelle Chambers, Michal Sarfaty, Judith D. Goldberg, Emmanuel S. Antonarakis, David R. Wise
Department of Medicine, Perlmutter Cancer Center, NYU Langone Medical Center, New York, NY, Department of Medicine, Johns Hopkins University, Baltimore, MD, Division of Biostatistics, Department of Population Health, NYU Grossman School of Medicine and Biostatistics Shared Resource, NYU Perlmutter Cancer Center, NY, NY, Department of Genetics, Perlmutter Cancer Center, NYU Langone Medical Center, New York, NY, Department of Medicine, University of Minnesota Masonic Cancer Center, Minneapolis, MN, Institute of Oncology, Sheba Medical Center, Israel Sackler Faculty of Medicine, Tel-Aviv, Israel
Source: Minas P. Economides et al. (2023) Case Series of Men with the Germline APC I 1307K Variant and Treatment-Emergent Neuroendocrine Prostate Cancer. Clinical Genitourinary Cancer.
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