Population-Based Evidence of Familial Clustering in Pulmonary Carcinoid Tumors: Insights From the Utah Population Database

Abstract

Background: Pulmonary carcinoid tumors are rare neuroendocrine neoplasms. While gastrointestinal carcinoids have established familial clustering, the heritable component of pulmonary carcinoids, particularly outside of multiple endocrine neoplasia type 1 (MEN1) syndrome, remains poorly defined. Utah's unique linked genealogy-cancer registry enables population-based assessment of familial risk.

Methods: We used the Utah Population Database (UPDB) linked to the Utah Cancer Registry (a Surveillance, Epidemiology, and End Results (SEER) registry) to identify individuals diagnosed with pulmonary carcinoid tumors (International Classification of Diseases for Oncology, Third Edition (ICD-O-3), histology codes 8240, 8249). The Genealogical Index of Familiality (GIF) test evaluated excess pairwise relatedness compared with 1,000 matched control sets. Relative risks (RRs) were estimated for first-, second-, and third-degree relatives, with expected cases based on cohort-specific incidence rates.

Results: A total of 232 pulmonary carcinoid cases with ≥3 generations of genealogy were identified. The GIF test demonstrated significant excess relatedness (GIF: 5.36 vs. 2.65; p=0.002), with excess in parent-offspring and avuncular pairs. RRs were significantly elevated for first-degree relatives (RR: 5.78; 95% CI: 1.03-18.21; p=0.048) and second-degree relatives (RR: 12.91; 95% CI: 6.42-23.29; p<0.0001), but not third-degree relatives. We identified 61 high-risk pedigrees with significantly more cases than expected. Incidence rates of pulmonary carcinoid were similar in Utah (0.8%) and the rest of SEER (0.7%), despite markedly lower overall lung cancer incidence in Utah.

Conclusions: Our findings demonstrate the significant familial clustering of pulmonary carcinoid tumors in a large, population-based resource, supporting a potential heritable contribution independent of MEN1 syndrome. These results justify further genetic and environmental investigations in high-risk pedigrees to identify susceptibility loci and modifiable exposures.

Keywords: familial clustering; genealogy; neuroendocrine tumors; pulmonary carcinoid; utah population database.

Figure 1. Familial clustering of pulmonary carcinoid tumors by genetic distance

Contributions to the GIF are shown for 232 pulmonary carcinoid cases (blue) and 1,000 matched control sets (red). Stronger clustering is observed among close relatives, particularly parent-offspring (distance=1) and avuncular (distance=3) pairs, suggesting possible hereditary or shared environmental influences. GIF: Genealogical Index of Familiality

Figure 2. An example of a Utah high-risk pulmonary carcinoid cancer pedigree

An example of a high-risk pedigree with four pulmonary carcinoid cases among descendants of a founder born in the 1830s. The observed-to-expected case ratio was 4/0.6 (p=0.003). Squares (□): male individuals; circles (○): female individuals; diagonal slash (∕): deceased individual; filled symbol (● or ■): affected individual (in this case, diagnosed with pulmonary carcinoid tumor); unfilled symbol: unaffected individual (no known pulmonary carcinoid); triangles (▵): represent founders or ancestral couples in earlier generations