To further dissect the genetic architecture of colorectal cancer (CRC), we performed whole-genome sequencing of 1,439 cases and 720 controls, imputed discovered sequence variants and Haplotype Reference Consortium panel variants into genome-wide association study data, and tested for association in 34,869 cases and 29,051 controls. Findings were followed up in an additional 23,262 cases and 38,296 controls. We discovered a strongly protective 0.3% frequency variant signal at CHD1. In a combined meta-analysis of 125,478 individuals, we identified 40 new independent signals at P < 5 × 10-8, bringing the number of known independent signals for CRC to ~100. New signals implicate lower-frequency variants, Krüppel-like factors, Hedgehog signaling, Hippo-YAP signaling, long noncoding RNAs and somatic drivers, and support a role for immune function. Heritability analyses suggest that CRC risk is highly polygenic, and larger, more comprehensive studies enabling rare variant analysis will improve understanding of biology underlying this risk and influence personalized screening strategies and drug development.

The PREDIMED (in Spanish: PREvención con DIeta MEDiterránea) primary prevention trial ^1–3 reported in 2013 that long-term adherence to an energy-unrestricted Mediterranean diet (MedDiet), supplemented with either extra-virgin olive oil (EVOO) or nuts, reduced cardiovascular disease (CVD). PREDIMED showed a 30% relative reduction in the composite cardiovascular primary endpoint (stroke, myocardial infarction or cardiovascular death). ^{2,, 3} However, the PREDIMED trial tested only the composition of the diet, but did not test other lifestyle interventions (i.e. energy reduction, increased physical activity (PA) and behavioural modification) frequently applied in the context of the current unprecedented obesity pandemic. ^{4,, 5} With the exception of the null results of the Look-AHEAD trial, ⁶ and the successful results of the EXERDIET-HTA study that found improvements in blood pressure, cardio-respiratory fitness and body composition (though they encouraged adherence to an hypocaloric DASH diet, instead of a Mediterranean diet), ⁷ lifestyle interventions including such components have never been tested in long-term randomized trials using hard cardiovascular events as endpoints.

Night shift work, exposure to light at night (ALAN) and circadian disruption may increase the risk of hormone-dependent cancers. We evaluated the association of exposure to ALAN during sleeping time with breast and prostate cancer in a population based multicase-control study (MCC-Spain), among subjects who had never worked at night. We evaluated chronotype, a characteristic that may relate to adaptation to light at night. We enrolled 1,219 breast cancer cases, 1,385 female controls, 623 prostate cancer cases, and 879 male controls from 11 Spanish regions in 2008-2013. Indoor ALAN information was obtained through questionnaires. Outdoor ALAN was analyzed using images from the International Space Station (ISS) available for Barcelona and Madrid for 2012-2013, including data of remotely sensed upward light intensity and blue light spectrum information for each geocoded longest residence of each MCC-Spain subject. Among Barcelona and Madrid participants with information on both indoor and outdoor ALAN, exposure to outdoor ALAN in the blue light spectrum was associated with breast cancer [adjusted odds ratio (OR) for highest vs. lowest tertile, OR=1.47; 95% CI: 1.00, 2.17] and prostate cancer (OR=2.05; 95% CI: 1.38, 3.03). In contrast, those exposed to the highest versus lowest intensity of outdoor ALAN were more likely to be controls than cases, particularly for prostate cancer. Compared with those who reported sleeping in total darkness, men who slept in "quite illuminated" bedrooms had a higher risk of prostate cancer (OR=2.79; 95% CI: 1.55, 5.04), whereas women had a slightly lower risk of breast cancer (OR=0.77; 95% CI: 0.39, 1.51). Both prostate and breast cancer were associated with high estimated exposure to outdoor ALAN in the blue-enriched light spectrum. https://doi.org/10.1289/EHP1837.