Abstract IA02: Prostate cancer: DNA-based risk assessment
Authors: Isaacs William 
Published: February 2019

Abstract
Due to intense and creative efforts by many investigators around the world, prostate cancer is transitioning from a common cancer about which relatively little was known genetically, particularly when compared to other common cancers of the breast, colon, and kidney, to a cancer for which breakthroughs, both conceptually and translationally, are occurring in all areas with some regularity.
The ability to sequence DNA rapidly, economically, and accurately has resulted in profound changes in the understanding and management of virtually all human cancers, with particularly robust progress made for prostate cancer. Many of the critical genetic and epigenetic pathways that drive prostate carcinogenesis and disease progression when altered somatically have been identified, providing mechanistic insight and novel therapeutic opportunities. Indeed, studies comparing aggressive to nonaggressive prostate cancer have unequivocally demonstrated the role of inactivation of TP53 and alterations in other key pathways including PTEN/AKT, MYC/8q, and AR signaling in the all-important determination of the aggressiveness of a given prostate cancer. Knowledge of the status of these risk factors is critical for optimal patient management. Furthermore, sequencing DNA from primary tumors and their multiple metastases has allowed for a better appreciation of the complexity of the genetic instability, clonal selection, metastatic dissemination, and the colonization process that makes the treatment of advanced prostate cancer such a difficult task.
Accurate disease risk assessment both before and after diagnosis can play a major role in determining who will benefit from early screening, who needs to be treated and how intensively, with what treatment, and eventually, ideally, who needs prevention. Sequencing germline genetic variants, both common and rare, can be used to identify men at elevated risk of prostate cancer, with some rare alleles providing valuable prognostic information. Common germline variants have the advantage that their facile multiplex assay provides quantitative risk information for each individual tested, regardless of family history or other factors. Cancer gene panel testing with a focus on DNA repair genes is becoming routine for men with mCRPC, as well as for men with high-risk, clinically localized disease. The findings from this testing can have immediate impact on which treatment may be most effective for an individual patient, as well as downstream for the patient’s family regarding cancer predisposition, including for potentially unsuspected cancer syndromes like Lynch and its immunotherapy implications. More widespread genetic testing is currently being considered in several realms, including family history of aggressive prostate cancer and/or other adenocarcinomas, as well as an aid in the critical decision of which prostate cancer patients can be managed safely with active surveillance. This question of who to test, when, and for what genes is a critical one without obvious resolution at present.
With respect to germline variants, BRCA2 and ATM appear to be the most important genes with respect to frequency of pathogenic mutations and magnitude of effect on treatment outcome and predisposition. CHEK2 can also be included in this list, although the frequencies of mutations in this gene vary substantially depending upon which populations are studied and which founder mutations are included as pathogenic. Many other DNA repair genes (and indeed thousands of others) are found to be mutated in the germline of men with advanced prostate cancer, although due to their rare occurrence and presumably smaller effects, the significance of these inherited variants is far from clear. Only when many more patients are sequenced will the clinical significance of mutations in genes like CHEK2, PALB2, and NBN1 be apparent. Hopefully, significant, clinically informative novel genes will emerge. This situation emphasizes the need for larger, well-controlled clinical research studies, with standardized sequencing platform and variant calling, extensive pathology characterization and outcomes to maximize the utility and benefit-to-cost ratio of all this sequence data for patient care and management.
Citation Format: William Isaacs. Prostate cancer: DNA-based risk assessment [abstract]. In: Proceedings of the AACR Special Conference: Prostate Cancer: Advances in Basic, Translational, and Clinical Research; 2017 Dec 2-5; Orlando, Florida. Philadelphia (PA): AACR; Cancer Res 2018;78(16 Suppl):Abstract nr IA02.