Risk of Second Primary Cancers After a Diagnosis of First Primary Cancer: A Pan-Cancer Analysis and Mendelian Randomization Study

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    This study presents a valuable finding on the associations and causal relationship between second primary cancers and the initial diagnosis of a primary cancer via using a large database. The evidence supporting the claims of the authors is solid. The work will be of interest to cancer clinicians.

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Abstract

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. 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) 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 =1.24, 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.

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  1. eLife assessment

    This study presents a valuable finding on the associations and causal relationship between second primary cancers and the initial diagnosis of a primary cancer via using a large database. The evidence supporting the claims of the authors is solid. The work will be of interest to cancer clinicians.

  2. Reviewer #1 (Public Review):

    The authors used pan-cancer Standardized Incidence Ratio analyses and Mendelian Randomization analysis to reach the causal relationships between first primary cancers and second primary cancers, proving that a primary cancer may cause another type of primary cancer. The results supported that pharynx cancer, ovary cancer, kidney cancer may cause non-Hodgkin lymphoma, soft tissue cancer, lung cancer and myeloma, respectively. This research provides a useful direction for further elucidation of profound mechanisms of secondary primary tumors, and guide the community to attach importance to the prevention of secondary primary tumors. According to previous researches, the number of patients with multiple primary cancers is growing rapidly and second solid tumors are a leading cause of mortality among several populations of long-term survivors, which shed light on the significance of this work.

    The methods of the work are logically rigorous, which revealed the incidence relationship among numerous types of cancers using SEER database analyses and further confirmed the causal relationship between first primary cancers and second primary cancers through MR analysis utilizing GWAS as an exposure database and UK Biobank as an outcome database. Then, 2 outlier-detected methods were used and validate the harmonization between SIR and MR analyses, making the results more solid.

    Nonetheless, SEER SIR analyses might be affected by confounding factors of screening and did not represent the whole population. In addition, too few SNPs were included in part of cancer types mentioned in the research, such as larynx, stomach and male breast cancer.

  3. Reviewer #2 (Public Review):

    This study investigates the associations and causal relationship between second primary cancers and the initial diagnosis of a primary cancer, utilizing a large-scale database. The study's unique contribution lies in its combination of pan-cancer analysis and the incorporation of Mendelian randomization, which adds novelty and enhances the value of the research.

    Furthermore, the findings of this study have the potential to provide valuable insights into important clinical considerations, such as patients' prognosis, treatment decisions, and survivorship care.