Evidence for a heritable contribution to neuroendocrine tumors of the small intestine

Abstract

Small intestinal neuroendocrine tumors (SI-NETs) are rare tumors arising from the enterochromaffin cells of the gut. Having a first-degree relative with a SI-NET has been shown to confer a substantial risk arising from shared environment and genetics. Heritable risk was examined using a computerized genealogy linked to historical statewide cancer data. A population-based analysis of the observed familial clustering of SI-NETs was performed to assess the genetic risk in distant relatives. A test for significant excess relatedness of 384 individuals with genealogy data and histologically confirmed SI-NETs was performed by comparing pairwise relatedness of cases to 1000 sets of matched controls. Overall significant excess pairwise relatedness was found for the 384 cases (P<0.001) and was still observed when closer than first cousin relationships were ignored (P=0.041). Relative risks (RRs) for SI-NETs were estimated as a ratio of observed to expected number of SI-NET cases among each relationship class. Siblings have a 13.4-fold (P<0.0001) and parents have a 6.5-fold (P=0.143) RR, suggesting both genetic and environmental influences. The risk extends out to third-degree relatives with a 2.3-fold RR (P=0.008). Metachronous cancers were also reported in 26% of the SI-NET cases demonstrating an increased RR of colon, bladder, non-Hodgkin lymphoma, melanoma, and prostate cancers. Although SI-NETs are rare, relatives of these cases are at a significantly elevated risk of developing a SI-NET due to heritable genetic factors. Definition of the genetic risk factors will be an important tool for earlier diagnosis and better outcomes for SI-NETs.

Keywords: familial; genetics; neuroendocrine tumor; population; relative risk; small intestine.

Figure 1. Contribution to the GIF statistic by pairwise genetic distance for cases versus controls

Genetic distance between pairs is shown on the x-axis and represents an increasing measure of relatedness from close to distant (1 = parent/offspring; 2 = siblings, e.g.; 3 = uncle/niece, e.g.; 4 = first cousins, e.g.). The cumulative contribution to the GIF statistic for each relatedness (as measured by genetic distance) for all pairs identified at that genetic distance is represented on the y-axis. An excess of pairwise relationships was observed for first, second, and third degree relatives (pairwise genetic distance 1 to 4), as was observed in the RR analysis. Excess pairwise relationships were also observed for more distant pairs, including an excess for example for third cousins (genetic distance = 8).

Figure 2. Example high-risk SI-NET pedigree with 5 cases observed

The founding couple at the top of the pedigree has nearly 10,000 descendants and the pedigree is trimmed to only represent linear descent of the SI-NET cases. Only 0.78 SI-NETs would be expected in this large pedigree, however 5 are observed (p=1.4e⁻⁴) Circles represent females, squares represent males. A slash indicates deceased. SI-NETs are represented as shaded squares.