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A Large Scale evaluation of SNP associations with Sporadic Neuroendocrine Tumors

A Large Scale evaluation of SNP associations with Sporadic Neuroendocrine Tumors. Monica Ter-Minassian, ScD Harvard School of Public Health. Objective. Determine genetic & other risk factors associated with sporadic neuroendocrine tumor risk

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A Large Scale evaluation of SNP associations with Sporadic Neuroendocrine Tumors

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  1. A Large Scale evaluation of SNP associations with Sporadic Neuroendocrine Tumors Monica Ter-Minassian, ScD Harvard School of Public Health

  2. Objective • Determine genetic & other risk factors associated with sporadic neuroendocrine tumor risk • Using a large scale single nucleotide polymorphism (SNP) genotyping approach of many candidate genes • Case-control study

  3. Age, sex and race Family history of any cancer Diabetes over a year Gastric & pancreatic NET Smoking Environmental Risk Factors

  4. Genetic risk factors • Sometimes seen in rare autosomal dominant familial syndromes related to the MTOR pathway • TSC1 and TSC2, VHL, NF1 and MEN2 genes • Very little known about heritable genetic risk factors for the much more common sporadic cases • Only previous study - tumor necrosis factor alpha, TNFA -1031 with a p-value less than 0.0005

  5. Study Population • 261 Neuroendocrine cases recruited from the Dana Farber Cancer Institute • Initial diagnosis from to 2003 to 2007 • 319 non-tumor controls from Harvard Lung Cancer Susceptibility study • conducted from 1992-2007 at the Massachusetts General Hospital/Harvard Cancer Center • similar catchment area as the DFCI • Restricted to Caucasians, sporadic cases, no missing data on age, sex and smoking status

  6. Descriptive characteristics of the study population a. median (range), significance calculated with Wilcoxon Rank Sum test

  7. Cases only

  8. SNP Genotyping • Designed an Illumina GoldenGate SNP chip with 1,536 candidate and tagging SNPs • QC elimination criteria: • More than 10% missing • Hardy Weinberg equilibrium c2 test p-value of <0.001 • minor allele frequency <0.01 in controls. • 1334 SNPs in 354 genes analyzed

  9. DNA Repair Cell Cycle Apoptosis MTOR Angiogenesis Cell Growth Inflammation Transporter Metastasis Metabolism Hormone Epigenetic Immunity Other Pathways

  10. Analysis • Logistic regression adjusting for age, sex and smoking status • Dominant and additive(trend) genetic models • Multiple Testing adjustment with Benjamini –Hochberg false discovery rate (FDR) • Pathway Analysis with the admixture maximum likelihood experiment-wise test (AML) • Can account for correlation among SNPs

  11. Genotyping results • Thirty-seven SNPs in 19 genes were associated with overall Neuroendocrine tumor risk at p<0.01, under either model. • The top 10 genes were • TSC2, IL1RN and CYP1B1, BIRC5, FRAP1(MTOR), AKAP9, SLC23A2, IL12A, BCL2, APAF1.

  12. TSC2 rs13337626 Phe860Phe • After multiple testing adjustment at p<0.01, only the TSC2 synonymous SNP rs13337626, Phe860Phe, remained significant overall • aOR= 2.81 (1.89, 4.19) • Pdominant =3.18E-07 • PFDR-dominant =0.0004 • F860F predicted to be an exonic splicing enhancer by the FASTSNP bioinformatic program • In LD with 6 potentially regulatory but no non-synonymous SNPs

  13. Pathway Results

  14. Cell Type Subgroup results

  15. MTOR, Apoptosis and Inflammation • MTOR pathway, in addition to TSC2 • FRAP1 (mTOR) in all cases • TSC1, VEGFR1 in pancreatic • IGFBP1 in small bowel • Apoptosis • CFLAR, DAD1, PIK3CA, TNFRSF6 stronger in small bowel • Inflammation • ALOX5 • IL1RN SNPs and haplotypes also stronger in small bowel

  16. Conclusions • First large scale evaluation of SNPs for neuroendocrine tumor risk in a large sample for this disease. • NET tended to occur at younger ages, in females and those not currently smoking compared to controls. • TSC2 strongly associated • Other genes in mTOR signaling, apoptosis, inflammation may be important as well • Replication of these findings are underway

  17. Acknowledgements Harvard School of Public Health • David C. Christiani • Immaculata De Vivo • Xihong Lin • Kofi Asomaning • Zhaoxi (Mike) Wang • Rihong Zhai • Li Su • Michael Wu • Chen-Yu Liu Dana Farber Cancer Institute • Matthew H. Kulke • Christine Frauenhoffer • Susanne M. Hooshmand • Jamie Silver

  18. Funding • Supported by NIH grant CA074386 • CDC/NIOSH grant T42-OH008416 • the John F. and Virginia B. Taplin Scholarship Fund Neuroendocrine study • a gift from Saul and Gitta Kurlat • the Stephen and Caroline Kaufer fund for neuroendocrine tumor research • Caring for Carcinoid Foundation • P50 CA127003 (DF/HCC SPORE in Gastrointestinal Cancer).

  19. Questions? Thank you!

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