Cancer therapy shapes the fitness landscape of clonal hematopoiesis.

Acquired mutations are pervasive across normal tissues. However, understanding of the processes that drive transformation of certain clones to cancer is limited. Here we study this phenomenon in the context of clonal hematopoiesis (CH) and the development of therapy-related myeloid neoplasms (tMNs). We find that mutations are selected differentially based on exposures. Mutations in ASXL1 are enriched in current or former smokers, whereas cancer therapy with radiation, platinum and topoisomerase II inhibitors preferentially selects for mutations in DNA damage response genes (TP53, PPM1D, CHEK2). Sequential sampling provides definitive evidence that DNA damage response clones outcompete other clones when exposed to certain therapies. Among cases in which CH was previously detected, the CH mutation was present at tMN diagnosis. We identify the molecular characteristics of CH that increase risk of tMN. The increasing implementation of clinical sequencing at diagnosis provides an opportunity to identify patients at risk of tMN for prevention strategies

Cancer therapy shapes the fitness landscape of clonal hematopoiesis.

Acquired mutations are pervasive across normal tissues. However, understanding of the processes that drive transformation of certain clones to cancer is limited. Here we study this phenomenon in the context of clonal hematopoiesis (CH) and the development of therapy-related myeloid neoplasms (tMNs). We find that mutations are selected differentially based on exposures. Mutations in ASXL1 are enriched in current or former smokers, whereas cancer therapy with radiation, platinum and topoisomerase II inhibitors preferentially selects for mutations in DNA damage response genes (TP53, PPM1D, CHEK2). Sequential sampling provides definitive evidence that DNA damage response clones outcompete other clones when exposed to certain therapies. Among cases in which CH was previously detected, the CH mutation was present at tMN diagnosis. We identify the molecular characteristics of CH that increase risk of tMN. The increasing implementation of clinical sequencing at diagnosis provides an opportunity to identify patients at risk of tMN for prevention strategies

Statins and prostate cancer—hype or hope? The epidemiological perspective

BACKGROUND: Men using cholesterol-lowering statin medications have been found to have lower risks of both advanced and fatal prostate cancer in multiple registry-based studies and prospective cohort studies. Statin use has also been associated with longer survival among men already diagnosed with prostate cancer. Mechanisms responsible for purported anti-cancer effects of statins are not well understood but may offer insight into prostate cancer biology. METHODS: We summarise epidemiological data from studies of statins and prostate cancer and discuss to what extent these findings can be interpreted as causal. Additionally, lipid-mediated and non-lipid-mediated mechanisms that may contribute to potential anti-cancer effects of statins are reviewed. Finally, we consider treatment settings and molecular subgroups of men who might benefit more than others from statin use in terms of prostate cancer-specific outcomes. RESULTS: Data from prospective observational studies generally reported a lower risk of fatal prostate cancer among statin users. There is some evidence for serum cholesterol-lowering as an indirect mechanism linking statins with advanced and fatal prostate cancer. Window-of-opportunity clinical trials show measurable levels of statins in prostate tissue highlighting potential for direct effects, whilst observational data suggest possible statin-driven modulation of prostate microenvironment inflammation. Additionally, emerging data from registry studies support a potential role for statins within the context of androgen deprivation therapy and anti-androgen treatment. CONCLUSION: Prospective and registry-based studies support a lower risk of advanced and fatal prostate cancer in statin users relative to non-users, as well as better outcomes among prostate cancer patients. The few randomised-controlled trials conducted so far have short follow-up, lack identified molecular subgroups, and do not provide additional support for the observational results. Consequently, additional evidence is required to determine which men may experience greatest benefit in terms of prostate cancer-specific outcomes and how statin effects may vary according to molecular tumour characteristics

Aneuploidy drives lethal progression in prostate cancer

Aneuploidy, defined as chromosome gains and losses, is a hallmark of cancer. However, compared with other tumor types, extensive aneuploidy is relatively rare in prostate cancer. Thus, whether numerical chromosome aberrations dictate disease progression in prostate cancer patients is not known. Here, we report the development of a method based on whole-transcriptome profiling that allowed us to identify chromosome-arm gains and losses in 333 primary prostate tumors. In two independent cohorts (n = 404) followed prospectively for metastases and prostate cancer-specific death for a median of 15 years, increasing extent of tumor aneuploidy as predicted from the tumor transcriptome was strongly associated with higher risk of lethal disease. The 23% of patients whose tumors had five or more predicted chromosome-arm alterations had 5.3 times higher odds of lethal cancer (95% confidence interval, 2.2 to 13.1) than those with the same Gleason score and no predicted aneuploidy. Aneuploidy was associated with lethality even among men with high-risk Gleason score 8-to-10 tumors. These results point to a key role of aneuploidy in driving aggressive disease in primary prostate cancer.National Institutes of Health (Grant GM118066)National Institutes of Health (Grant CA206157