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.

This content is only available via PDF.
©2025 The Authors; Published by the American Association for Cancer Research
2025
American Association for Cancer Research
This open access article is distributed under the Creative Commons Attribution-NonCommercial-NoDerivatives 4.0 International (CC BY-NC-ND 4.0) license.
This work is licensed under a Creative Commons Attribution-NonCommercial-NoDerivatives 4.0 International License .
Attribution-NonCommercial-NoDerivatives

Article PDF first page preview

First page of Risk Factors Associated with Gastroenteropancreatic and Lung Neuroendocrine Tumors: A Nested Case–Control Study from the <italic>All of Us</italic> Research Program<alt-title alt-title-type="short">Risk Factors of Developing NETs Using the <italic>All of Us</italic> Data</alt-title>

Supplementary data

Supplementary Figure 2

Supplementary Figure 2 shows study timeline for the nested case-control design.

- docx file
Supplementary Figure 1

Supplementary Figure 1 shows flow diagram outlining the cohort’s inclusion and exclusion criteria.

- docx file
Supplementary Table 9

Supplementary Table 9 demonstrates risk factors associated with pancreatic NETs and risk factors associated with GEP or lung NETs, excluding pancreatic NETs.

- docx file
Supplementary Table 6

Supplementary Table 6 reports risk factors associated with GEP and lung NETs stratified by sex at birth.

- docx file
Supplementary Table 8

Supplementary Table 8 is the sensitivity analysis in the conditional logistic regression model.

- docx file
Supplementary Table 7

Supplementary Table 7 reports risk factors associated with GEP or lung NETs in incident cases and corresponding controls.

- docx file
Supplementary Table 5

Supplementary Table 5 shows ICD 9 and 10 codes for identifying type 2 diabetes and name of relevant medications.

- docx file
Supplementary Table 4

Supplementary Table 4 shows ICD 9 and 10 codes for identifying immune-mediated diseases.

- docx file
Supplementary Table 3

Supplementary Table 3 shows exposure assessment methods.

- docx file
Supplementary Table 2

Supplementary Table 2 shows personal medical history survey questions and answers in the All of Us Research Program.

- docx file
Supplementary Table 1

Supplementary Table 1 shows ICD 9 and 10 codes for identifying GEP and lung NETs.

- docx file
Supplementary Figure 3

Supplementary Figure 3 shows Modified Directed acyclic graphs (DAGs). The DAGs illustrate selected risk factors (in black) and the outcome (in pink).

- docx file