Genetic associations with neuroendocrine tumor risk: results from a genome-wide association study

Abstract

The etiology of neuroendocrine tumors remains poorly defined. Although neuroendocrine tumors are in some cases associated with inherited genetic syndromes, such syndromes are rare. The majority of neuroendocrine tumors are thought to be sporadic. We performed a genome-wide association study (GWAS) to identify potential genetic risk factors for sporadic neuroendocrine tumors. Using germline DNA from blood specimens, we genotyped 909,622 SNPs using the Affymetrix 6.0 GeneChip, in a cohort comprising 832 neuroendocrine tumor cases from Dana-Farber Cancer Institute and Massachusetts General Hospital and 4542 controls from the Harvard School of Public Health. An additional 241 controls from Dana-Farber Cancer Institute were used for quality control. We assessed risk associations in the overall cohort, and in neuroendocrine tumor subgroups. We identified no potential risk associations in the cohort overall. In the small intestine neuroendocrine tumor subgroup, comprising 293 cases, we identified risk associations with three SNPs on chromosome 12, all in strong LD. The three SNPs are located upstream of ELK3, a transcription factor implicated in angiogenesis. We did not identify clear risk associations in the bronchial or pancreatic neuroendocrine subgroups. This large-scale study provides initial evidence that presumed sporadic small intestine neuroendocrine tumors may have a genetic etiology. Our results provide a basis for further exploring the role of genes implicated in this analysis, and for replication studies to confirm the observed associations. Additional studies to evaluate potential genetic risk factors for sporadic pancreatic and bronchial neuroendocrine tumors are warranted.

Racial Disparity in Gastrointestinal Cancer Risk

“…It is unlikely, however, that celiac disease is a significant risk factor in Blacks given its low incidence in this population [55,56]. For small bowel neuroendocrine tumors, GWAS evaluations have identified risk variants upstream of ELK3 , though the impact of these variants by race is not known [57]. Additional risks for neuroendocrine tumors include family history, BMI, diabetes and tobacco [58].…”

Clinical Features, Management, and Molecular Characteristics of Familial Small Bowel Neuroendocrine Tumors

“…No other candidate gene mutations were identified in the other families. Subsequent studies have also not identified this IPMK mutation as a driving mutation in other familial SBNET candidate families (7,17,33).…”

“…Another large genome wide association study was performed looking at 293 sporadic SBNET. Three associated single nucleotide polymorphisms were identified on chromosome 12 just upstream of ELK3 , a transcription factor associated with angiogenesis ( 17 ). Earlier studies also identified APC and SRC mutations in 23 and 25% of SBNET although these have not been confirmed in more recent studies ( 14 , 18 ).…”

“…SBNET were previously thought to be rare sporadic tumors; however familial SBNET (defined as two cases in two first degree relatives with no other causative genetic syndrome) have been reported since the 1960s (5)(6)(7). In addition to case series, larger national epidemiological studies looking at neuroendocrine tumors have also looked at family associations and confirmed increased risks within familial cohorts (5,6,8,9). These larger studies showed a relative risk of 2.8 to 4.3 for the development of neuroendocrine tumors in familial cohorts (8,10,11).…”

Genetic Drivers of Ileal Neuroendocrine Tumors

“…No LOH of MUTYH was reported in the I-NET samples. Additional studies on SNP associations to I-NETs have focused on spontaneous and not familial I-NETs [106,107].…”