Abstract
BACKGROUND: The incidence of neuroendocrine tumors (NET), which arise primarily in lung and gastroenteropancreatic (GEP) tissues, has increased dramatically in the past 50 years. However, the etiology of NETs remains inconclusive. METHODS: We conducted a nested case-control study using data from the All of Us Research Program (version 7; index dates: 2000-2022) to compare the odds of diagnosed GEP or lung NET in the presence or absence of various potential risk factors. One case was matched to five controls without cancer diagnoses by age at consent and sex. We used piecewise structural equation modeling to generate effect estimates. RESULTS: Of 2,180 individuals (including 366 with NETs), most were non-Hispanic White (62.8%) and female (61.0%). Individuals with a family history of any cancer [OR, 1.43; 95% confidence interval (CI), 1.06-1.95; P = 0.021], a past diagnosis of type 2 diabetes (OR, 1.46; 95% CI, 1.09-1.96; P = 0.012), and any immune-mediated disease (OR, 1.40; 95% CI, 1.11-1.76; P = 0.004) had higher odds of developing GEP or lung NETs. CONCLUSIONS: This study confirms prior evidence in less diverse cohorts that the risk of developing GEP or lung NETs is significantly associated with having a first-degree relative with any cancer or previous diagnosis of type 2 diabetes. IMPACT: Our findings are the first to demonstrate that a preexisting diagnosis of any immune-mediated disease is a risk factor for developing NETs. Together, our findings suggest that NET development may be influenced by unmodifiable factors as well as modifiable conditions.