Abstract 2534: A comparative analysis of fraction genome altered vs tumor mutational count in prostate cancer
Authors: Chakraborty Goutam , Atiq Mohammad , Nandakumar Subhiksha , Mazzu Ying Z. , Armenia Joshua , Yoshikawa Yuki , Khan Nabeela , Lee Gwo-Shu M. , Mucci Lorelei , Kantoff Philip W. 
Published: August 2019

Prostate cancer is the second leading cause of cancer related death among men in the United States. Although 5 new life-prolonging agents have been FDA-approved for castration resistant prostate cancer in the past 8 years, drug resistance limits the durability of responses to these agents for most patients. We hypothesized that biomarkers of genomic alterations, defined as fraction genome altered (% of copy number altered chromosome regions out of measured regions) and mutational count (number of mutational events per cases), were prognostic biomarkers which might provide insights into resistance mechanisms. We used The Cancer Genome Atlas (TCGA; n= 490 primary prostate cancer) dataset to analyze fraction of genome altered and tumor mutational count in prostate tumors. Patients whose primary prostate cancer harbored a high frequency of fraction genome altered exhibited significant disease progression in TCGA cohort . In contrast, we did not observe a significant association between high tumor mutational count and disease progression. Fraction genome altered was more significantly associated with Gleason grade compare to tumor mutation count. Interestingly, our preliminary observation showed that primary prostate cancer patients who harbor high fraction genome altered (&gt;6%), but low tumor mutational count (&lt;30/cases) exhibited shorter disease-free survival, indicating that those primary prostate cancer patients who harbor high fraction genome altered but low mutational count may have more aggressive prostate cancer. We have also developed a transcriptional signature which is associated with high fraction genome altered. . A detailed understanding of these molecular features will help us to design appropriate therapeutic approaches for different subsets of the disease. We hypothesize that cases with a high fraction of genome altered are associated with aggressive disease and those with lower mutational count may be associated with a diminished immunoresponsiveness.

Tumor mutational count and fraction genome alteration in various stages TCGA prostate cancerDisease Status (Gleason unadjusted)p valueGleasonp value (trend)Disease FreeRecurred/ Progressed6 (n=45)7 (n=244)&gt;=8 (n=198)Fraction Genome Altered (Mean + SEM)0.08248 ± 0.00490.1254 ± 0.01120.00030.02504 ±0.00370.05985 ± 0.00390.1425 ± 0.0087&lt; 2.2e-16Mutational Count (Mean + SEM)35.05 ± 1.35439.88 ± 2.6550.394429.42 ± 1.749,34.69 ± 0.9089,38.58 ± 1.272,=9.971e-05 (7 vs &gt;=8; p value 0.0445)

Citation Format: Goutam Chakraborty, Mohammad Atiq, Subhiksha Nandakumar, Ying Z. Mazzu, Joshua Armenia, Yuki Yoshikawa, Nabeela Khan, Gwo-Shu M. Lee, Lorelei Mucci, Philip W. Kantoff. A comparative analysis of fraction genome altered vs tumor mutational count in prostate cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 2534.