A pilot genome-wide association study shows genomic variants enriched in the non-tumor cells of patients with well-differentiated neuroendocrine tumors of the ileum.
Genetic studies of midgut carcinoid cancer have exclusively focused on genomic changes of the tumor cells. We investigated the role of constitutional genetic polymorphisms in predisposing individuals to ileal carcinoids. In all, 239 cases and 110 controls were collected from three institutions: the Uppsala University Hospital; the Dana-Farber Cancer Institute; and the MD Anderson Cancer Center, and were genotyped using microarrays assaying >300 000 single nucleotide polymorphisms. Association with rs2208059 in KIF16B approached statistical significance (Mantel-Haenszel odds ratio=2.42, P=4.16×10(-7)) at a Bonferroni-corrected level (<1.62×10(-7)). Using two computational algorithms, four copy-number variants (CNVs) were identified in multiple cases that were absent in study controls and markedly less frequent in ∼1500 population-based controls. Of these four constitutional CNVs identified in blood-derived DNA, a 40 kb heterozygous deletion in Chr18q22.1 corresponded with a region frequently showing loss of heterozygosity (LOH) in ileal carcinoid tumor cells based on our meta-analysis of previously published cytogenetic studies (69.7% LOH, 95% confidence interval=60.0-77.9%). We analyzed the constitutional 40 kb deletion on chr18 in our study samples with a real-time quantitative PCR assay; 14/226 cases (6.19%) and 2/97 controls (2.06%) carried the CNV, although the exact boundaries of each deletion have not been determined. Given the small sample size, our findings warrant an independent cohort for a replication study. Owing to the rarity of this disease, we believe these results will provide a valuable resource for future work on this serious condition by allowing others to make efficient use of their samples in targeted studies.
Department of Epidemiology and Public Health, Yale University, 60 College Street, New Haven, Connecticut 06520, USA.
Kyle M
KM
Walsh
Murim
M
Choi
Kjell
K
Oberg
Matthew H
MH
Kulke
James C
JC
Yao
Chengqing
C
Wu
Magdalena
M
Jurkiewicz
Ling-I
LI
Hsu
Susanne M
SM
Hooshmand
Manal
M
Hassan
Eva T
ET
Janson
Janet L
JL
Cunningham
Evan
E
Vosburgh
Richard S
RS
Sackler
Richard P
RP
Lifton
Andrew T
AT
Dewan
Josephine
J
Hoh
D016022:Case-Control Studies; D002454:Cell Differentiation; D002477:Cells / Q000378:metabolism / Q000473:pathology*; D056915:DNA Copy Number Variations / Q000235:genetics / Q000502:physiology; D005260:Female; D014644:Genetic Variation; D055106:Genome-Wide Association Study; D006801:Humans; D007078:Ileal Neoplasms / Q000235:genetics* / Q000473:pathology; D008297:Male; D015201:Meta-Analysis as Topic; D046228:Microarray Analysis; D009367:Neoplasm Staging; D018358:Neuroendocrine Tumors / Q000235:genetics* / Q000473:pathology; D010865:Pilot Projects; D020641:Polymorphism, Single Nucleotide; D012196:Review Literature as Topic