Background: To evaluate the utility of polygenic risk scores (PRS) in identifying high-risk individuals, different publicly available PRS for breast (n=85), prostate (n=37), colorectal (n=22) and lung cancers (n=11) were examined in a prospective study of 21,694 Chinese adults.

Methods: We constructed PRS using weights curated in the online PGS Catalog. PRS performance was evaluated by distribution, discrimination, predictive ability, and calibration. Hazard ratios (HR) and corresponding confidence intervals [CI] of the common cancers after 20 years of follow-up were estimated using Cox proportional hazard models for different levels of PRS.

Results: A total of 495 breast, 308 prostate, 332 female-colorectal, 409 male-colorectal, 181 female-lung and 381 male-lung incident cancers were identified. The area under receiver operating characteristic curve for the best performing site-specific PRS were 0.61 (PGS000873, breast), 0.70 (PGS00662, prostate), 0.65 (PGS000055, female-colorectal), 0.60 (PGS000734, male-colorectal) and 0.56 (PGS000721, female-lung), and 0.58 (PGS000070, male-lung), respectively. Compared to the middle quintile, individuals in the highest cancer-specific PRS quintile were 64% more likely to develop cancers of the breast, prostate, and colorectal. For lung cancer, the lowest cancer-specific PRS quintile was associated with 28-34% decreased risk compared to the middle quintile. In contrast, the hazard ratios observed for quintiles 4 (female-lung: 0.95 [0.61-1.47]; male-lung: 1.14 [0.82-1.57]) and 5 (female-lung: 0.95 [0.61-1.47]) were not significantly different from that for the middle quintile.

Conclusions: Site-specific PRSs can stratify the risk of developing breast, prostate, and colorectal cancers in this East Asian population. Appropriate correction factors may be required to improve calibration.

Funding This work is supported by the National Research Foundation Singapore (NRF-NRFF2017-02), PRECISION Health Research, Singapore (PRECISE) and the Agency for Science, Technology and Research (A*STAR). WP Koh was supported by National Medical Research Council, Singapore (NMRC/CSA/0055/2013). CC Khor was supported by National Research Foundation Singapore (NRF-NRFI2018-01). Rajkumar Dorajoo received a grant from the Agency for Science, Technology and Research Career Development Award (A*STAR CDA - 202D8090), and from Ministry of Health Healthy Longevity Catalyst Award (HLCA20Jan-0022). The Singapore Chinese Health Study was supported by grants from the National Medical Research Council, Singapore (NMRC/CIRG/1456/2016) and the U.S. National Institutes of Health [NIH] (R01 CA144034 and UM1 CA182876).

The development of tools to manipulate the mouse genome, including knockout and transgenic technology, has revolutionized our ability to explore gene function in mammals. Moreover, for genes that are expressed in multiple tissues or at multiple stages of development, the use of tissue-specific expression of the Cre recombinase allows gene function to be perturbed in specific cell types and/or at specific times. However, it is well known that putative tissue-specific promoters often drive unanticipated 'off target' expression. In our efforts to explore the biology of the male reproductive tract, we unexpectedly found that expression of Cre in the central nervous system resulted in recombination in the epididymis, a tissue where sperm mature for ~1-2 weeks following the completion of testicular development. Remarkably, we not only observed reporter expression in the epididymis when Cre expression was driven from neuron-specific transgenes, but also when Cre expression in the brain was induced from an AAV vector carrying a Cre expression construct. A surprisingly wide range of Cre drivers - including six different neuronal promoters as well as the adipose-specific Adipoq Cre promoter - exhibited off target recombination in the epididymis, with a subset of drivers also exhibiting unexpected activity in other tissues such as the reproductive accessory glands. Using a combination of parabiosis and serum transfer experiments, we find evidence supporting the hypothesis that Cre may be trafficked from its cell of origin to the epididymis through the circulatory system. Together, our findings should motivate extreme caution when interpreting conditional alleles, and suggest the exciting possibility of inter-tissue RNA or protein trafficking in modulation of reproductive biology.