After observing several patients in clinic with germline APC I1307K mutation (present in 7% of Ashkenazi Jewish men) developing AVPC we sought to determine if there is a potential association. Our investigation was motivated by the pressing need to better understand the biology and underlying genetic mechanisms of AVPC.
In our study, we retrospectively identified patients with germline APC I1307K mutation from 3 institutions (NYU, Johns Hopkins, Sheba Medical Center). Clinically-defined AVPC (mostly driven by treatment-related neuroendocrine transformation) was found in 8/18 cases and in 8/15 of those with metastatic disease.
Given that this mutation has been reported to generate canonical frameshift mutations in the APC gene, we compared the 18 cases with 20 controls with prostate cancer and APC frameshift mutations identified at NYU from 2016-2022 (control cohort). To our surprise, the odds of AVPC were significantly higher in our case cohort compared to our controls [8/18 cases (44%) vs 2/20 controls (10%), ORR: 7.2; 95% CI: 1.27, 40.6]. In addition, the odds of combined somatic alterations in two or more of RB1, TP53 or PTEN (molecularly defined AVPC) was 7.3 times greater in cases than in controls [5 cases (28%) and 1 control (5%); 95% CI: 0.76, 70.03]. These findings raise important questions regarding the mechanism of increased AVPC prevalence in our case cohort. A possible hypothesis is that germline APC I1307K mutation leads to a higher chance of dual tumor suppressor loss in the genes RB1, TP53 or PTEN (a molecular profile that is known to lead to lineage plasticity and androgen indifference). However, the genetic interplay that might lead to this genotype is unknown.
Finally, we compared these proportions of other somatic mutations among our 15 cases with metastatic disease with the expected proportions based on the largest metastatic cohort of prostate cancer patients available in cBioPortal. A notable finding was the absence of concurrent SPOP and AR mutations in our cohort (the latter being statistically significant), providing further proof of AR independent progression in these patients.
In conclusion, our study is the first to report an association between the germline APC I1307K mutation and AVPC. Given the poor prognosis and limited treatment options available for these patients, early identification of molecular predictors of progression to AVPC is important. It is possible that the germline APC I1307K mutation may be one such molecular indicator of AVPC development. Although we could not identify the precise molecular mechanism leading to this phenotype (it is not because of somatic APC frameshift mutation as originally hypothesized) the higher prevalence of clinical AVPC in patients with germline APC I1307K mutation warrants further investigation. Validation of this mutation as a biomarker for AVPC could potentially lead to a change in the prostate cancer surveillance strategy for Ashkenazi Jewish men undergoing treatment for prostate cancer.
Written by: Minas P. Economides,1 Mari Nakazawa,2 Jonathan W. Lee,1 Xiaochun Li,3 Lucas Hollifield,4 Rachelle Chambers,4 Michal Sarfaty,5 Judith D. Goldberg,3 Emmanuel S. Antonarakis,6 and David R. Wise1
- 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, New York, NY
- Department of Genetics, Perlmutter Cancer Center, NYU Langone Medical Center, New York, NY
- Sheba Medical Center, Institute of Oncology, Israel Sackler Faculty of Medicine, Tel-Aviv, Israel
- Department of Medicine, University of Minnesota Masonic Cancer Center, Minneapolis, MN