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Master of Public Health

Genetic Factors Associated with Prostate Cancer Conversion from Active Surveillance to Treatment

AUTHORS

Jiang Y , Meyers TJ , Emeka AA , Cooley LF , Cooper PR , Lancki N , Helenowski I , Kachuri L , Lin DW , Stanford JL , Newcomb LF , Kolb S , Finelli A , Fleshner NE , Komisarenko M , Eastham JA , Ehdaie B , Benfante N , Logothetis CJ , Gregg JR , Perez CA , Garza S , Kim J , Marks LS , Delfin M , Barsa D , Vesprini D , Klotz LH , Loblaw A , Mamedov A , Goldenberg SL , Higano CS , Spillane M , Wu E , Carter HB , Pavlovich CP , Mamawala M , Landis T , Carroll PR , Chan JM , Cooperberg MR , Cowan JE , Morgan TM , Siddiqui J , Martin R , Klein EA , Brittain K , Gotwald P , Barocas DA , Dallmer JR , Gordetsky JB , Steele P , Kundu SD , Stockdale J , Roobol MJ , Venderbos LDF , Sanda MG , Arnold R , Patil D , Evans CP , Dall'Era MA , Vij A , Costello AJ , Chow K , Corcoran NM , Rais-Bahrami S , Phares C , Scherr DS , Flynn T , Karnes RJ , Koch M , Dhondt CR , Nelson JB , McBride D , Cookson MS , Stratton KL , Farriester S , Hemken E , Stadler WM , Pera T , Banionyte D , Bianco FJ , Lopez IH , Loeb S , Taneja SS , Byrne N , Amling CL , Martinez A , Boileau L , Gaylis FD , Petkewicz J , Kirwen N , Helfand BT , Xu J , Scholtens DM , Catalona WJ , Witte JS , . HGG advances. 2021 11 19; 3(1).

ABSTRACT

Men diagnosed with low-risk prostate cancer (PC) are increasingly electing active surveillance (AS) as their initial management strategy. While this may reduce the side effects of treatment for prostate cancer, many men on AS eventually convert to active treatment. PC is one of the most heritable cancers, and genetic factors that predispose to aggressive tumors may help distinguish men who are more likely to discontinue AS. To investigate this, we undertook a multi-institutional genome-wide association study (GWAS) of 5,222 PC patients and 1,139 other patients from replication cohorts, all of whom initially elected AS and were followed over time for the potential outcome of conversion from AS to active treatment. In the GWAS we detected 18 variants associated with conversion, 15 of which were not previously associated with PC risk. With a transcriptome-wide association study (TWAS), we found two genes associated with conversion (, p = 6.9×10 and , p = 2.0×10). Moreover, increasing values of a previously validated 269-variant genetic risk score (GRS) for PC was positively associated with conversion (e.g., comparing the highest to the two middle deciles gave a hazard ratio [HR] = 1.13; 95% Confidence Interval [CI]= 0.94-1.36); whereas, decreasing values of a 36-variant GRS for prostate-specific antigen (PSA) levels were positively associated with conversion (e.g., comparing the lowest to the two middle deciles gave a HR = 1.25; 95% CI, 1.04-1.50). These results suggest that germline genetics may help inform and individualize the decision of AS-or the intensity of monitoring on AS- treatment for the initial management of patients with low-risk PC.

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