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

Abstract

Small intestine 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 1,000 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 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) relative risk, suggesting both genetic and environmental influences. The risk extends out to 3rd degree relatives with a 2.3-fold relative risk (p=0.008). Metachronous cancers were also reported in 26% of the SI-NET cases demonstrating an increased relative risk 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.

Landscape of CDKN1B Mutations in Luminal Breast Cancer and Other Hormone-Driven Human Tumors

“…These cells contain a large amount of our body storage of serotonin. Clear information about how these tumors develop is limited ( 68 ), but recent studies tried to shed light on the genomic landscape of SI-NETs. Banck and colleagues have first analyzed 48 SI-NETs by massive parallel exome sequencing, both in tumors and in their normal tissue counterpart.…”

GEP- NETS UPDATE: Genetics of neuroendocrine tumors

“…Small intestinal NETs (SI-NETs) have also been described to occur with familial aggregation in a small fraction of patients (133,134). Despite substantial efforts no definitive genetic basis for this phenomenon has been described.…”

TSC2 rare germline variants in non-tuberous sclerosis patients with neuroendocrine neoplasias

“…Notably, epidemiological studies have demonstrated that non-syndromic individuals with an affected relative are at an increased risk of developing gastroenteropancreatic (GEP) NENs. In individuals with affected siblings, the relative risk of GEP NEN increases by 13.4-fold, and an increased risk (2.3-fold) is present even in third-degree relatives ( Neklason et al . 2016 ).…”