Jacqueline Petkewicz

Germline Mutations in ATM and BRCA1/2 Distinguish Risk for Lethal and Indolent Prostate Cancer and are Associated with Early Age at Death

BACKGROUND Germline mutations in BRCA1/2 and ATM have been associated with prostate cancer (PCa) risk. OBJECTIVE To directly assess whether germline mutations in these three genes distinguish lethal from indolent PCa and whether they confer any effect on age at death. DESIGN, SETTING, AND PARTICIPANTS A retrospective case-case study of 313 patients who died of PCa and 486 patients with low-risk localized PCa of European, African, and Chinese descent. Germline DNA of each of the 799 patients was sequenced for these three genes. OUTCOME MEASUREMENTS AND STATISTICAL ANALYSIS Mutation carrier rates and their effect on lethal PCa were analyzed using the Fishers exact test and Cox regression analysis, respectively. RESULTS AND LIMITATIONS The combined BRCA1/2 and ATM mutation carrier rate was significantly higher in lethal PCa patients (6.07%) than localized PCa patients (1.44%), p=0.0007. The rate also differed significantly among lethal PCa patients as a function of age at death (10.00%, 9.08%, 8.33%, 4.94%, and 2.97% in patients who died ≤ 60 yr, 61-65 yr, 66-70 yr, 71-75 yr, and over 75 yr, respectively, p=0.046) and time to death after diagnosis (12.26%, 4.76%, and 0.98% in patients who died ≤ 5 yr, 6-10 yr, and>10 yr after a PCa diagnosis, respectively, p=0.0006). Survival analysis in the entire cohort revealed mutation carriers remained an independent predictor of lethal PCa after adjusting for race and age, prostate-specific antigen, and Gleason score at the time of diagnosis (hazard ratio=2.13, 95% confidence interval: 1.24-3.66, p=0.004). A limitation of this study is that other DNA repair genes were not analyzed. CONCLUSIONS Mutation status of BRCA1/2 and ATM distinguishes risk for lethal and indolent PCa and is associated with earlier age at death and shorter survival time. PATIENT SUMMARY Prostate cancer patients with inherited mutations in BRCA1/2 and ATM are more likely to die of prostate cancer and do so at an earlier age.

Nanocytological field carcinogenesis detection to mitigate overdiagnosis of prostate cancer: a proof of concept study.

Purpose To determine whether nano-architectural interrogation of prostate field carcinogenesis can be used to predict prognosis in patients with early stage (Gleason 6) prostate cancer (PCa), which is mostly indolent but frequently unnecessarily treated. Materials and Methods We previously developed partial wave spectroscopic microscopy (PWS) that enables quantification of the nanoscale intracellular architecture (20–200nm length scale) with remarkable accuracy. We adapted this technique to assess prostate needle core biopsies in a case control study from men with Gleason 6 disease who either progressed (n = 20) or remained indolent (n = 18) over a ~3 year follow up. We measured the parameter disorder strength (Ld) characterizing the spatial heterogeneity of the nanoscale cellular structure and nuclear morphology from the microscopically normal mucosa ~150 histologically normal epithelial cells. Results There was a profound increase in nano-architectural disorder between progressors and non-progressors. Indeed, the Ld from future progressors was dramatically increased when compared to future non-progressors (1±0.065 versus 1.30±0.0614, respectively p = 0.002). The area under the receiver operator characteristic curve (AUC) was 0.79, yielding a sensitivity of 88% and specificity of 72% for discriminating between progressors and non-progressors. This was not confounded by demographic factors (age, smoking status, race, obesity), thus supporting the robustness of the approach. Conclusions We demonstrate, for the first time, that nano-architectural alterations occur in prostate cancer field carcinogenesis and can be exploited to predict prognosis of early stage PCa. This approach has promise in addressing the clinically vexing dilemma of management of Gleason 6 PCa and may provide a paradigm for dealing with the larger issue of cancer overdiagnosis.

A comprehensive evaluation of CHEK2 germline mutations in men with prostate cancer

Germline mutations in CHEK2 have been associated with prostate cancer (PCa) risk. Our objective is to examine whether germline pathogenic CHEK2 mutations can differentiate risk of lethal from indolent PCa.

Germline mutations in ATM and BRCA1/2 distinguish risk for lethal and indolent prostate cancer and are associated with early age at death

Rong Na a,b,y, S. Lilly Zheng b,c,y, Misop Han d,y, Hongjie Yu , Deke Jiang , Sameep Shah , Charles M. Ewing , Liti Zhang , Kristian Novakovic b [5_TD

Germline Mutations in ATM and BRCA1/2 Are Associated with Grade Reclassification in Men on Active Surveillance for Prostate Cancer.

DIFF], Jacqueline Petkewicz [5_TD

MP57-01 GERMLINE MUTATIONS IN DNA REPAIR GENES ARE SIGNIFICANTLY ENRICHED IN LETHAL PROSTATE CANCER AND ARE ASSOCIATED WITH DISEASE SURVIVAL

DIFF], Kamalakar Gulukota , Donald L. Helseth Jr , Margo Quinn , Elizabeth Humphries , Kathleen E. Wiley [6_TD

MP17-02 TNFα ANTAGONISTS REDUCE INCIDENCE OF BPH IN PATIENTS WITH AUTOIMMUNE INFLAMMATORY CONDITIONS

DIFF], Sarah[7_TD

MP12-14 MODELS INTEGRATING MRI PREDICT PROSTATE CANCER UPGRADING ON CONFIRMATORY BIOPSY IN ACTIVE SURVEILLANCE PATIENTS

DIFF] D. Isaacs , Yishuo Wu , Xu Liu , Ning Zhang , Chi-Hsiung Wang , Janardan Khandekar , Peter J. Hulick , Daniel H. Shevrin , Kathleen A. Cooney , Zhoujun Shen , Alan W. Partin [8_TD

PD20-04 GERMLINE MUTATIONS IN DNA REPAIR GENES ARE INDEPENDENT PREDICTORS OF GRADE RECLASSIFICATION IN ACTIVE SURVEILLANCE FOR PROSTATE CANCER PATIENTS

DIFF], H [1_TD

Life after prostate cancer treatment: a mixed methods study of the experiences of men with sexual dysfunction and their partners

DIFF].[9_TD