Risk assessment of secondary primary malignancies: results from two large prospective European cohorts.

Secondary primary malignancies (SPMs), new histologically distinct cancers that develop in patients with a history of primary tumors, represent a critical long-term adverse event in cancer survivorship. Although epidemiological studies have suggested associations between certain primary tumors and SPMs, systematic validation of their causal relationships is lacking. A Mendelian randomization analysis was employed to investigate the causal links between primary tumors and SPMs. This study systematically examined cancers spanning eight major human organ systems using data from two large European prospective cohorts: UK Biobank (31 cancer types) and FinnGen (28 cancer types). A meta-analysis of the two cohorts revealed that gastric cancer (GC) had a significant causal relationship with an increased risk of secondary esophageal cancer (odds ratio [OR] = 1.29, 95% confidence interval [95% CI]: 1.13-1.46, P < 0.001) and rectal cancer (OR = 1.13, 95% CI: 1.07-1.21, P < 0.001). Further, a single-cell sequencing analysis identified PLK1+ cancer stem cells as potential drivers of this causal relationship. Our findings provide important genetic evidence of the causal links between GC and specific SPMs, which may inform the optimization of precise follow-up strategies for GC survivors.