Bidirectional Mendelian randomization analysis of the genetic association between primary lung cancer and colorectal cancer

Abstract

Background With the development and popularization of low-dose chest CT technology, the diagnosis and survival rates of patients with early lung cancer (LC) have significantly improved. The occurrence of colorectal cancer (CRC) as the second primary cancer (SPC) in primary lung cancer (PLC) survivors has become an essential factor affecting the prognosis of early LC. This study explored the potential association between PLC and CRC genetically, laying a foundation for developing SPC-CRC prevention strategies after primary early LC. Methods Based on a two-sample bidirectional Mendelian randomization (MR) design, this study systematically screened genetic instrumental variables (IVs) based on the genome-wide association studies (GWAS) of PLC and CRC, applied inverse variance weighted (IVW) as the main method to assess the incidence association between the two cancers, and used a variety of other MR methods for supplementary analysis. Finally, the Genetic Risk Scores (GRS) method was used for secondary analysis to verify the results robustness further. Results From LC to CRC forward MR analysis, 20 genetic IVs of overall LC, 15 genetic IVs of squamous cell lung carcinoma (LUSC), and 10 genetic IVs of adenocarcinoma of the lung (LUAD) were screened. In the reverse MR analysis from CRC to LC, 47 genetic IVs for overall CRC, 37 for colon cancer, and 25 for rectal cancer were screened. The IVW method and a variety of MR methods all found that overall LC and CRC were significantly associated at the genetic level. Subgroup analysis also showed that LUSC was associated with CRC. And the results of the GRS method were consistent with those of the main analysis, confirming the robustness of the study. Summary Our MR study found an association between LC and CRC, with an increased risk of SPC-CRC following PLC, especially LUSC. Our study provides an essential basis for the precise prevention of SPC-CRC after PLC, suggesting that we should pay more attention to the population with a history of PLC in clinical work, and pay close attention to the incidence of SPC-CRC, and carry out intervention and treatment as soon as possible.

Bidirectional Mendelian randomization analysis investigating the genetic association between primary breast cancer and colorectal cancer

“…This is due to their increased susceptibility to developing CRC. Previously, our team of researchers successfully established a noteworthy genetic correlation between primary lung cancer and CRC through MR method (25). However, in this study, our research team did not find a statistically significant association between PBC and CRC using MR approach.…”

“…To ensure the validity of IVs, the fulfillment of three assumptions is necessary: (a) the independence of the IVs from the outcome should be taken into account when evaluating the exposure, which is restriction; (b) the correlation between the IVs and the exposure is necessary, which is commonly referred to as the "relevance" assumption; and (c) the independence of the IVs from any potential confounding factors, whether observed or unobserved, should be ensured (referred to as the assumption of "exchangeability") (22,23). Therefore, genetic IVs for overall BC, ER-BC, ER+ BC, overall CRC, colon cancer, rectal cancer, left CRC and right CRC were constructed according to the following criteria (24,25): (a) LD, linkage disequilibrium among IVs is measured using the r 2 statistic, with a threshold of less than 0.001 within a window size of 500 kb (Genetic variants in close genomic regions have a tendency to co-inherit, which is referred to as LD. When the presence of LD is observed alongside genetic variants, the information provided by each variant does not exist in isolation from one another.…”

Exploring causal correlations of inflammatory biomarkers in idiopathic normal-pressure hydrocephalus: insights from bidirectional Mendelian randomization analysis

“…Subsequently, we clumped the selected SNPs with an r 2 = value of 0.001 and a distance of 10,000 kbto minimize the impact of linkage disequilibrium on the results (Chen et al, 2023). Additionally, a minor allele frequency (MAF) > 0.01 (mutations present in >1% of the population) was required (Xiao et al, 2023). The variation explained by each genetic instrument was determined using the following formula: 2 × EAF × (1 − EAF) × beta 2 , where EAF is the effect allele frequency and beta is the estimated effect.…”

Associations between ADHD and risk of six psychiatric disorders: a Mendelian randomization study

“…Since SNPs are formed during embryonic development and are independent of the environment and other acquired factors, the MR design provides a randomization procedure that also minimizes the interference of residual confounding and reverse causation [ 11 ]. In recent years, with further exploration of MR research methods, it has become increasingly confirmed as an ideal way to study and the pathogenic association between two complex diseases [ 12 ].…”