Risk of second primary cancers after a diagnosis of first primary cancer: A pan-cancer analysis and Mendelian randomization study

BACKGROUND: The risk of second primary cancers (SPC) is increasing after the first primary cancers (FPC) are diagnosed and treated. The underlying causal relationship remains unclear. METHODS: We conducted a pan-cancer association (26 cancers) study in the Surveillance, Epidemiology, and End Results (SEER) database (non-Hispanic whites). The standardized incidence ratio (SIR) was estimated as the risk of SPCs in cancer survivors based on the incidence in the general population. Furthermore, the causal effect was evaluated by two-sample Mendelian Randomization (MR, 13 FPCs) in the UK Biobank (UKB, n=459,136,, European whites) and robust analysis (radial MR and Causal Analysis Using Summary Effect estimates, CAUSE). RESULTS: We found 11 significant cross-correlations among different cancers after harmonizing SIR and MR results. Whereas only 4 of them were confirmed by MR to have a robust causal relationship. In particular, patients initially diagnosed with oral pharyngeal cancer would have an increased risk of non-Hodgkin lymphoma (SIR(SEER) = 1.18, 95%Confidence Interval [CI]:1.05–1.31, OR(radial-MR)=1.21, 95% CI:1.13–1.30, p=6.00 × 10(-3); OR(cause) = 1.17, 95% CI:1.05–1.31, p=8.90 × 10(-3)). Meanwhile, ovary cancer was identified to be a risk factor for soft tissue cancer (SIR(SEER) = 1.72, 95%Confidence Interval [CI]:1.08–2.60, OR(radial-MR)=1.39, 95% CI:1.22–1.58, p=1.07 × 10(-3); OR(cause) = 1.36, 95% CI:1.16–1.58, p=0.01). And kidney cancer was likely to cause the development of lung cancer (SIR(SEER) = 1.28, 95%Confidence Interval [CI]:1.22–1.35, OR(radial-MR)=1.17, 95% CI:1.08–1.27, p=6.60 × 10(-3); OR(cause) = 1.16, 95% CI:1.02–1.31, p=0.05) and myeloma (SIR(SEER) = 1.54, 95%Confidence Interval [CI]:1.33–1.78, OR(radial-MR)=1.72, 95% CI:1.21–2.45, p=0.02; OR(cause) = 1.49, 95% CI:1.04–2.34, p=0.02). CONCLUSIONS: A certain type of primary cancer may cause another second primary cancer, and the profound mechanisms need to be studied in the future. FUNDING: This work was in supported by grants from National Natural Science Foundation of China (Grant No. 81972645), Innovative research team of high-level local universities in Shanghai, Shanghai Youth Talent Support Program, intramural grant of The University of Hong Kong to Dr. Rong Na, and Shanghai Sailing Program (22YF1440500) to Dr. Da Huang.