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Familial Barrett’s Esophagus & Esophageal Adenocarcinoma Amitabh Chak, MD Professor of Medicine & Oncology Case Western Re...
Pohl, H. et al. J Natl Cancer Inst 2005;97:142-146 EAC melanoma prostate breast/lung colon
Why Postulate A Genetic Basis? <ul><li>Sex (male) and race (white) predominance </li></ul><ul><li>BE restricted to a subse...
Evidence for Genetic Etiology <ul><li>Case Reports of Familial Clustering </li></ul><ul><li>Cross Sectional or Case Contro...
Case Reports of Familial Clusters Reference Proband GERD/BE/EAC Crabb et al., Ann Int Med, 1985 80    BE 3 generations, 7...
Pilot Cross Sectional Study – Familial Aggregation of BE/EAC  (Chak et al., Gut) p<0.005 p<0.001
CENTRAL HYPOTHESIS <ul><li>BE and associated cancers are complex genetic diseases. </li></ul><ul><li>Combined genetic and ...
 
RESULTS – Endoscopy ISOLATED RELATIVES (N = 35) FBE RELATIVES (N =27) P-value Hiatal hernia 14 (40%) 13 (48%) 0.70 Erosive...
 
Recruitment Of Pedigrees <ul><li>FBE Consortium </li></ul><ul><ul><li>University Hospitals Case Medical Center </li></ul><...
Prevalence of FBE (Chak et al., CEBP 2006) <ul><li>30 (7.3%) of 413 probands studied prospectively have a confirmed affect...
Age of Incidence Study <ul><li>Genetic diseases often have an earlier age of onset </li></ul><ul><li>Age of incidence of B...
 
Age of Cancers in Families with 3 or more affecteds Mean Age is 58.7 vs. 62.6 years, p < 0.05
Segregation Analysis
Segregation Analysis <ul><li>A statistical test of Mendel’s first law </li></ul><ul><li>Tests whether the aggregation of d...
Models in SEGREG <ul><li>One susceptibility type – no genetic transmission </li></ul><ul><li>Two susceptibility types – Me...
SEGREG – Preliminary Results <ul><li>881 pedigrees accrued at several centers </li></ul><ul><li>Trait defined as confirmed...
One Susceptibility
Mendelian Models
CONCLUSIONS <ul><li>Random environmental model insufficient to explain familial aggregation of BE, EAC, and EGJAC </li></u...
Linkage Studies Of BE
Linkage <ul><li>Relates sharing of chromosomal regions to sharing of trait </li></ul><ul><li>Model based methods define ex...
Romero et al. (DDW 2006) <ul><li>Genotyped 278 people in 31 families using microsatellite markers </li></ul><ul><li>Perfor...
FBEC linkage study <ul><li>-53 individuals typed in 15 pedigrees </li></ul><ul><ul><li>Average 3.5 per pedigree </li></ul>...
 
 
Model based linkage  Family AA-0009
Identification of Linked Haplotype
Summary of Family Studies <ul><li>BE and EAC proposed to be complex genetic diseases manifested as FBE. </li></ul><ul><li>...
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Endoscopy in Gastrointestinal Oncology - Slide 2

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Endoscopy in Gastrointestinal Oncology - Slide 2

  1. 1. Familial Barrett’s Esophagus & Esophageal Adenocarcinoma Amitabh Chak, MD Professor of Medicine & Oncology Case Western Reserve University
  2. 2. Pohl, H. et al. J Natl Cancer Inst 2005;97:142-146 EAC melanoma prostate breast/lung colon
  3. 3. Why Postulate A Genetic Basis? <ul><li>Sex (male) and race (white) predominance </li></ul><ul><li>BE restricted to a subset of GERD pts </li></ul><ul><li>Diseases with undefined etiologies, especially cancers, are likely “ Complex” (genetic + environmental) </li></ul>
  4. 4. Evidence for Genetic Etiology <ul><li>Case Reports of Familial Clustering </li></ul><ul><li>Cross Sectional or Case Control Studies of Familial Aggregation </li></ul><ul><li>Monozygotic vs. Dizygotic Twin Studies </li></ul><ul><li>Segregation Analysis </li></ul><ul><li>Linkage Analysis </li></ul><ul><li>Mapping of Genetic Mutation </li></ul>
  5. 5. Case Reports of Familial Clusters Reference Proband GERD/BE/EAC Crabb et al., Ann Int Med, 1985 80  BE 3 generations, 7/12 GER, 4/7 BE, multiple malignancies. Prior et al., Hepatogastro, 1986 66  BE Two sisters Jochem et al., Gastro, 1992 67  EAC 3 generations, 5 GER, 6 BE, 3 EAC Eng et al., Cancer Epi Bio Prev, 1993 EAC 3 generations, many GER(2 complicated GER), 7 BE, 2 EAC Fahmy et al., Am Jl Gastro, 1993 BE 4 families, multiple members with GER and BE
  6. 6. Pilot Cross Sectional Study – Familial Aggregation of BE/EAC (Chak et al., Gut) p<0.005 p<0.001
  7. 7. CENTRAL HYPOTHESIS <ul><li>BE and associated cancers are complex genetic diseases. </li></ul><ul><li>Combined genetic and environmental influences are responsible. </li></ul><ul><li>An inherited susceptibility to develop BE is present in a subset of affected patients. </li></ul>
  8. 9. RESULTS – Endoscopy ISOLATED RELATIVES (N = 35) FBE RELATIVES (N =27) P-value Hiatal hernia 14 (40%) 13 (48%) 0.70 Erosive esophagitis 4 (11%) 7 (26%) 0.25 Barrett ’ s epithelium: SSBE BE EAC Total no. 2 0 0 2 (6%) 5 5 1 11 (41%) 0.0023
  9. 11. Recruitment Of Pedigrees <ul><li>FBE Consortium </li></ul><ul><ul><li>University Hospitals Case Medical Center </li></ul></ul><ul><ul><li>Cleveland Clinic/HUP </li></ul></ul><ul><ul><li>Fred Hutch/UW </li></ul></ul><ul><ul><li>Creighton </li></ul></ul><ul><ul><li>Johns Hopkins </li></ul></ul><ul><ul><li>Mayo </li></ul></ul><ul><ul><li>U of Arizona </li></ul></ul><ul><ul><li>University of North Carolina </li></ul></ul>
  10. 12. Prevalence of FBE (Chak et al., CEBP 2006) <ul><li>30 (7.3%) of 413 probands studied prospectively have a confirmed affected first degree or second degree relative (BE or EAC): </li></ul><ul><ul><li>BE: 6.2% </li></ul></ul><ul><ul><li>EAC: 9.5% </li></ul></ul>
  11. 13. Age of Incidence Study <ul><li>Genetic diseases often have an earlier age of onset </li></ul><ul><li>Age of incidence of BE cannot be defined </li></ul><ul><li>Aim - To compare Age of Onset of Familial Barrett’s Cancer with “Sporadic” Cancers </li></ul>
  12. 15. Age of Cancers in Families with 3 or more affecteds Mean Age is 58.7 vs. 62.6 years, p < 0.05
  13. 16. Segregation Analysis
  14. 17. Segregation Analysis <ul><li>A statistical test of Mendel’s first law </li></ul><ul><li>Tests whether the aggregation of disease in families is consistent with an environmental factor or transmission of a factor according to Mendelian genetic models </li></ul>
  15. 18. Models in SEGREG <ul><li>One susceptibility type – no genetic transmission </li></ul><ul><li>Two susceptibility types – Mendelian dominant or recessive </li></ul><ul><li>Three susceptibility types – Co-dominant </li></ul><ul><li>Can also add polygenic loci with non-Mendelian transmission </li></ul><ul><li>Lower Akaike’s A information content (AIC) = better fitting model </li></ul>
  16. 19. SEGREG – Preliminary Results <ul><li>881 pedigrees accrued at several centers </li></ul><ul><li>Trait defined as confirmed BE (> 1 cm), EAC, EGJAC </li></ul><ul><li>Analysis assumed single ascertainment </li></ul><ul><li>Basic models were environmental only, polygenic only, dominant/recessive no polygenic, polygenic plus dominant/recessive, additive only, polygenic plus additive </li></ul>
  17. 20. One Susceptibility
  18. 21. Mendelian Models
  19. 22. CONCLUSIONS <ul><li>Random environmental model insufficient to explain familial aggregation of BE, EAC, and EGJAC </li></ul><ul><li>Incompletely dominant model with covariates for sex and founder status plus 3 polygenic loci provide best fit </li></ul><ul><li>Penetrance of dominant allele = 0.1005, sporadic rate = 0.0012 </li></ul><ul><li>Relative risk of dominant allele = 82.5 </li></ul><ul><li>These results support a linkage analysis to search for rare dominant incompletely penetrant allele(s) responsible for FBE </li></ul>
  20. 23. Linkage Studies Of BE
  21. 24. Linkage <ul><li>Relates sharing of chromosomal regions to sharing of trait </li></ul><ul><li>Model based methods define explicit relationship between phenotype and genotype </li></ul><ul><li>Model free methods test for increased sharing among affected individuals </li></ul>
  22. 25. Romero et al. (DDW 2006) <ul><li>Genotyped 278 people in 31 families using microsatellite markers </li></ul><ul><li>Performed Model Based Linkage Analysis using various traits including ECA, BE, and GERD </li></ul><ul><li>Identified linkage with BE on Chr 2, lod score of just over 3 </li></ul>
  23. 26. FBEC linkage study <ul><li>-53 individuals typed in 15 pedigrees </li></ul><ul><ul><li>Average 3.5 per pedigree </li></ul></ul><ul><ul><li>All Caucasian pedigrees </li></ul></ul><ul><ul><li>68% male </li></ul></ul><ul><ul><li>39 affected (BE or EAC), 14 unaffected </li></ul></ul><ul><ul><li>33 sibling pairs: </li></ul></ul><ul><ul><ul><li>21 concordantly affected pairs </li></ul></ul></ul><ul><ul><ul><li>11 discordant pairs </li></ul></ul></ul><ul><ul><ul><li>1 concordantly unaffected pair </li></ul></ul></ul><ul><li>-100K Affymetrix Array </li></ul>
  24. 29. Model based linkage Family AA-0009
  25. 30. Identification of Linked Haplotype
  26. 31. Summary of Family Studies <ul><li>BE and EAC proposed to be complex genetic diseases manifested as FBE. </li></ul><ul><li>FBE is restricted to a subset. The proportion of probands with confirmed FBE is less than 10%. </li></ul><ul><li>Pedigree analysis suggests FBE is caused by segregation of a transmissible (genetic) factor. </li></ul><ul><li>Linkage analysis has identified putative chromosomal regions linked to BE and EAC. </li></ul><ul><li>Sequencing is required to find the genetic variants that confer susceptibility to BE and EAC. </li></ul>

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