Abstract 972: MMR-deficiency is the most prominent genetic feature of prostate cancer metastases organotropism

Abstract Prostate cancer (PCa) is the most prevalent, non-cutaneous, cancer in men in the Western world. Disease confined to the prostate can be cured, but metastatic disease cannot. PCa metastases are found in bone, lymph-nodes, liver and other visceral organs (visceral), in decreasing order of frequency. After an initial response to androgen receptor directed therapy, metastatic disease will inevitably recur as metastatic castration resistant prostate cancer (mCRPC), which is hallmarked by high morbidity and mortality. Since it is previously established, that the site of metastasis correlates with prostate cancer survival, we need a better understanding of metastatic organotropism. Therefore, we took advantage of the largest Whole Genome Sequencing (HiSeq X Ten system using the paired-end sequencing protocol) data set of mCRPC metastases to date. Molecular profiling of 326 metastases (Bone: 105, Lymph-node: 149, Liver: 49, Visceral: 23) revealed genetic determinants associated with organ-specific metastasis. First, we assessed differential occurrence of mutations in genes associated with targetable pathways. RB1 alteration were enriched in liver (35%) and in visceral metastases (30%), while lower rates were found in bone (10%) and lymph-nodes (13%)(Fisher exact test, p: 0.012). Analysis of aggregated pathway alteration data revealed a trend for increased frequency of alterations in the DNA repair and PI3K pathways in lymph node vs. bone metastases (p: 0.066 and 0.066, respectively). Next, we explored differential tumor mutational burden (TMB) between the sites. A higher TMB was observed in liver and visceral metastases compared to bone and lymph node metastases, while there was no difference between liver and visceral. The increased TMB in liver and visceral samples was associated with an MMR-deficiency mutational signature. Alterations in MSH6, MLH1 and POLD3 characterized a significant proportion of high TMB liver metastases, whereas high TMB visceral metastases predominantly showed MSH2 and POLD1 alterations.In conclusion: Our findings implicate high TMB/MMR-deficiency is a characteristic feature of liver and visceral PCa metastases, potentially impacting disease progression. Moreover, since response to immune check-point inhibitors is associated with high TMB, our findings might direct choice of therapy. Citation Format: Daniel Vis, Sander Palit, Marie Corradi, Martijn Lolkema, Niven Mehra, Edwin Cuppen, Lodewyk FA Wessels, Rene Bernards, Wilbert Zwart, Michiel S. van der Heijden, Andries M. Bergman. MMR-deficiency is the most prominent genetic feature of prostate cancer metastases organotropism [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 972.