# Presentation: 262274

## Disclosure

**I have financial relationships with commercial entities and the content of my presentation does not include discussion of off-label/investigative use of medicine(s), medical devices, or procedures. **
_**Research Grants**_
**AstraZeneca**
** ****TAP Pharmaceuticals**

## NIDDKNetwork of Research Minority InvestigatorsAnnual Workshop

**Familial Barrett’s Esophagus**
- Yvonne Romero, M.D.
- Assistant Professor
- Division of Gastroenterology & Hepatology
- Department of Epidemiology
- Department of Otolaryngology
- April 19, 2007

## Outline

- Phenotypes
- Evidence for familial aggregation
- GERD Symptoms
- Reflux esophagitis
- Barrett’s esophagus
- Barrett’s Esophagus Genomic Study Group
- Susceptibility loci for familial GERD
- Esophageal Adenocarcinoma & Barrett’s Esophagus Registry

## Normal Anatomy

## Erosive  Reflux Esophagitis –Los Angeles Classification 

**Erosive  Reflux Esophagitis –****Los Angeles Classification**** **

**Notes:**
Erosive esophagitis – summary of Los Angeles classification
 This slide summarises the information provided in the previous four slides. 

## Slide 6

## Slide 8

## Slide 9

## 1

**CP1020012-6**

**1**

**2**

**3**

**4**

## Slide 11

## Incidence of Adenocarcinoma of theEsophagus in Population-Based Studies

**CP1020012-1**

- Incidence of Adenocarcinoma of theEsophagus in Population-Based Studies

**Cases/100,000/year**

**Olmsted County**
**Connecticut Cancer Registry**
**Natl Cancer Institute**
**Birmingham, England**
**Vaud, Switzerland**

**Median year of observation period**

## Barrett’s Esophagus and Endoscopy

**CP1020012-9**

- Olmsted County

**Upper endoscopy/100,000**

**Endoscopy**
**Long Barrett’s**
**Short Barrett’s**

**Year**

**New diagnosis Barrett’s/100,000**

## Outline

- Phenotypes
- Evidence for familial aggregation
- GERD Symptoms
- Reflux esophagitis
- Barrett’s esophagus
- Barrett’s Esophagus Genomic Study Group
- Susceptibility loci for familial GERD
- Esophageal Adenocarcinoma & Barrett’s Esophagus Registry

## Known Risk Factors

_**Barrett’s esophagus**_
**Age**
**Sex**
**Ethnicity**
**GERD symptoms**
**Tobacco**

_**Esoph adenocarcinoma**_
**Age **
**Sex**
**Ethnicity**
**GERD symptoms**
**Tobacco**
**Obesity**
**Barrett’s esophagus**

## Case Reports of GERD in families

**Twins**
**Henry, 1954**
**Carre ́, 1957**
**Masse and Badder, 1957**
**Sidd, Gilliam and Bushueff, 1966**
**Gelfand, 1983**
**Fahmy and King, 1993**
**One generation**
**Clerf and Manges, 1934  ****	**
**Wamberg, 1947****	****	**
**Thomsen, 1955****	****	**
**Bouma, 1962****	****	**
**Chaiken, 1968****	****	**
**Carre ́, 1965****	****	**
**Prior and Whorwell, 1986****	**

**Two generations**
**Myles, 1939**
**Seé, 1947**
**Roviralta, 1952**
**Chaiken, 1968****	****	**
**Goodman, **
**Everhart, 1978**
**Lehman, 1979**
**Eng, 1993**
**Three generations**
**Chaiken, 1968**
**Carre ́and Froggart, 1970**
**Schulze-Delrieu and Anuras, 1983**
**Crabb, et al, 1985**
**Jochem, et al, 1992**
**Four generations**
**Fahmy and King, 1993**

## GERD Symptoms - Swedish Twin Study

- _Nationwide Swedish Twin Registry_
- Sample Size: N = 2178 MZ, N = 6223 DZ twin pairs
- Concordance for GERD symptoms: MZ >> DZ
- Obesity, smoking and ETOH, not significant
**Heritability for GERD symptoms is 31%**
- Cameron AJ, Gastroenterology 2002

## Familial Aggregation of GERD Symptoms

- N = 243 adult first-degree relatives of index patients
- N = 230 relatives of spouses (controls)
- The parents and siblings of Barrett’s esophagus or esophageal adenocarcinoma index patients met criteria for GERD symptoms twice as often as did the parents and siblings of their spouses
_**Conclusion**_**  **
**GERD symptoms aggregate in families**
- 						Romero, et al, Gastroenterology 1997
- 						Trudgill, et al, Am J Gastro 1999
- 						Chak, et al., Gut 2002

## Familial Aggregation of Barrett’s Esophagus and Reflux Esophagitis 

- Prospective Cohort Study
- Inclusion criteria:
- No prior upper endoscopy
- Sx:		weekly heartburn or acid regurg  			Controls GERD symptoms
- Non-Sx:  	asymptomatic or rare symptoms
- 			Controls scoped for diarrhea_ _

## Results

- 260 of 529 (49%) Barrett’s esophagus index patients
- 1014 of 1606 (63%) living adult first-degree relatives
**Results:****	****315 of 808 (39%) relatives **
**	****	****	****360 of 360 (100%) controls **
**   ****	****	**underwent endoscopy

## Results: Symptomatic Subjects

## Non-Symptomatic Subjects: Do Not Meet Criteria for GERD & Completely Asymptomatic Subjects

## Results

- _Independent predictors of Barrett’s esophagus_
-  Age (p=0.001)
-  Male sex (p=0.005)
-  GERD symptom duration  (p=0.001)
- After adjustment there was an over **2-fold increase in risk for relatives to have Barrett’s esophagus compared to controls.**** **

## Outline

- Phenotypes
- Evidence for familial aggregation
- GERD Symptoms
- Reflux esophagitis
- Barrett’s esophagus
- Barrett’s Esophagus Genomic Study Group
- Susceptibility loci for familial GERD
- Esophageal Adenocarcinoma & Barrett’s Esophagus Registry

## Barrett’s Esophagus Genomic Study (BEGS) Group

## Barrett’s Esophagus Genomic StudyGroup

- Established in August 1998
- 156 physicians
- Collaborate to identify families
- 		**101 informative families**

## Outline

- Phenotypes
- Evidence for familial aggregation
- GERD Symptoms
- Reflux esophagitis
- Barrett’s esophagus
- Barrett’s Esophagus Genomic Study Group
- Susceptibility loci for familial GERD
- Esophageal Adenocarcinoma & Barrett’s Esophagus Registry

## Aim

-   **To map susceptibility loci in familial Barrett’s esophagus pedigrees by genome-wide linkage analysis using ****phenotype(s):**
**GERD symptoms**
**Hiatal hernia**
**Reflux esophagitis**
**Barrett’s esophagus**
**Esophageal adenocarcinoma****  **

## Methods

**Endoscopy and surgery reports**
**Pathology slides reviewed**
**Prioritize kindreds **
**potential informativeness**
**affected members**
**blood available for analysis**

## Methods

**278/440 individuals provided blood samples for DNA analysis**
**ABI PRISM® Linkage Mapping Set version 2.5 **
**Genome-wide screen using 403 ****microsatellite**** ****markers covering all autosomes ****at ~10cM resolution**

**Methods**

## Genotyping Methods

**Genotypes were assigned using ABI GeneMapper (v 3.5) software package**

**Genotyping Methods**

## Linkage Analysis

- Model-based (parametric) approach
- Autosomal dominant inheritance
- Reduced penetrance of a rare gene
- SIMWALK
- Two-point and multipoint analyses
- Various combinations of clinically meaningful phenotypes were tested

## Slide 33

## LOD scores

-   _LOD score_		_Result is due to chance_
- 		2 				1/100
- 		3				1/1000
- 		-2			  	excludes linkage
- Heterogeneity (HLOD) score:
- Accounts for variation among families

## Results

## D2S2259 

**HLOD = 3.07**
**D2S2259**** **

**Barrett’s Esophagus: Chromosome 2p16**

**2p16**

## Slide 37

## Main Linkage Results for Barrett’s Esophagus

| Chromosome | cM | Marker | HLOD |
| --- | --- | --- | --- |
| 2p16 | 66.9 | D2S2259 | 3.07
2.79 (BE or ACA) |
| 2p11 | 79.43 |  D2S391-337 | 2.51 |
| 2p25 | 8.64 | D2S2211 | 1.57 |
| 12q13 | 73.55 | D12S368 | 1.52 |
| 19q12 | 43.9 | D19S414 | 1.41 |
| 19q13 | 71.06 | D19S902 | 1.47 |
| 13 | -- | all | ~0 |

## Main Linkage Results for Barrett’s Esophagus

| Chromosome | cM | Marker | HLOD |
| --- | --- | --- | --- |
| 2p16 | 66.9 | D2S2259 | 3.07
2.79 (BE or ACA) |
| 2p11 | 79.43 |  D2S391-337 | 2.51 |
| 2p25 | 8.64 | D2S2211 | 1.57 |
| 12q13 | 73.55 | D12S368 | 1.52 |
| 19q12 | 43.9 | D19S414 | 1.41 |
| 19q13 | 71.06 | D19S902 | 1.47 |
| 13 | -- | all | ~0 |

## Main Linkage Results for Barrett’s Esophagus

| Chromosome | cM | Marker | HLOD |
| --- | --- | --- | --- |
| 2p16 | 66.9 | D2S2259 | 3.07
2.79 (BE or ACA) |
| 2p11 | 79.43 |  D2S391-337 | 2.51 |
| 2p25 | 8.64 | D2S2211 | 1.57 |
| 12q13 | 73.55 | D12S368 | 1.52 |
| 19q12 | 43.9 | D19S414 | 1.41 |
| 19q13 | 71.06 | D19S902 | 1.47 |
| 13 | -- | all | ~0 |

## Slide 41

## Slide 42

## Slide 43

## Summary of Linkage Findings

- Linkage to chromosome 2p for Barrett’s esophagus and esophageal adenocarcinoma
- Potential regions on chromosomes 12q and 19q for Barrett’s esophagus

## Summary of Linkage Findings

- Linkage to chromosome 12q for hiatal hernia and GERD symptoms
- Potential regions on chromosome 7q for hiatal hernia and esophagitis

## Conclusions based on Linkage Analysis

- These results provide strong evidence for major susceptibility genes for familial
-  Barrett’s esophagus
-  Esophageal adenocarcinoma
-  Hiatal hernia
-  GERD symptoms

## Outline

- Phenotypes
- Evidence for familial aggregation
- GERD Symptoms
- Reflux esophagitis
- Barrett’s esophagus
- Barrett’s Esophagus Genomic Study Group
- Susceptibility loci for familial GERD
- Esophageal Adenocarcinoma & Barrett’s Esophagus Registry

## EABE Registry Consortia

**90 members**
- 19 Departments/Divisions
- Mayo Clinic Arizona
- Mayo Clinic Jacksonville
- Mayo Clinic Rochester
_**Industry Partners**_
- Affymetrix
- AstraZeneca
- Eisai
- TAP
- Wyeth

- Biostatistics
- Gastroenterology
- Genetic Epidemiology
- Medical Oncology
- Molecular Biology/Genetics
- Pathology
- Psychiatry
- Pulmonary
- Radiation Oncology
- Thoracic Surgery
- Mayo Clinic Cancer Center

## EABE Registry

- Large bank
- Fresh-frozen & formalin-fixed tissue
- Blood
- Demographic, symptom and risk factor data
- To facilitate identification of:
- Genetic pathways important in the neoplastic transformation from Barrett’s to cancer
- Novel biomarkers of risk, early detection, response to treatment
- Novel therapeutic or chemoprevention targets

## EABE Registry

- Large bank
- Fresh-frozen & formalin-fixed tissue
- Blood
- Demographic, symptom and risk factor data
- To facilitate identification of:
- Genetic pathways important in the neoplastic transformation from Barrett’s to cancer
- Novel biomarkers of risk, early detection, response to treatment
- Novel therapeutic or chemoprevention targets

## EABE Registry

- Large bank
- Fresh-frozen & formalin-fixed tissue
- Blood
- Demographic, symptom and risk factor data
- To facilitate identification of:
- Genetic pathways important in the neoplastic transformation from Barrett’s to cancer
- Novel biomarkers of risk, early detection, response to treatment
- Novel therapeutic or chemoprevention targets

## “Ultra Rapid”Consent Process

- Patients located anywhere on campus
- Takes 15-45 minutes, family process
- Education about Barrett’s esophagus** **

## Consented Patients

- Blood collected once
- Questionnaires collected by Survey Research
- baseline
- annual
*Tissue collected every opportunity*** **

## Slide 54

## Mayo Clinic RochesterAs of April 18, 2007(Consecutive recruitment since Sept. 10, 2001)N = 2787 Met Entry Criteria

**1569 (56%) Consent**
-   636 (23%) declined
-   428 evaluation in progress

## MCR PhenotypesN = 1569LSBE         =   827 (53%)BE + ACA  =   283 (18%)ACA only   =   187 (12%)Squamous =   105 (  7%)

-   Blood and tissue collected _at least once_ from 1353 and 659 patients, respectively

## Mayo Clinic JacksonvilleAs of April 18, 2007(Recruitment September 13, 2005 to February 1, 2006,April 18, 2006 – to present)N = 71 Met Entry Criteria

**51 (72%) Consent**
-   5 (  7%) declined
- 15 evaluation in progress

## Take Home Points

- Increase in esophageal adenocarcinoma not due to Barrett’s esophagus
- GERD aggregates in families
- Susceptibility loci for _familial_ Barrett’s esophagus and esophageal adenocarcinoma are on different chromosomes than loci for _familial_ hiatal hernia and GERD symptoms

## Take Home Points

- Increase in esophageal adenocarcinoma not due to Barrett’s esophagus
- GERD aggregates in families
- Susceptibility loci for _familial_ Barrett’s esophagus and esophageal adenocarcinoma are on different chromosomes than loci for _familial_ hiatal hernia and GERD symptoms

## Take Home Points

- Increase in esophageal adenocarcinoma not due to Barrett’s esophagus
- GERD aggregates in families
- Susceptibility loci for _familial_ Barrett’s esophagus and esophageal adenocarcinoma are on different chromosomes than loci for _familial_ hiatal hernia and GERD symptoms

## Conclusion

- Multi-center, multi-disciplinary  Academic-NIH-Industry collaboration will facilitate discoveries that translate into improved patient outcomes

## Acknowledgments

- _Genotyping Core Lab_
- Julie Cunningham, PhD
- _Genetic Biostatisticians_
- Mariza de Andrade, Ph.D.
- Joshua P. Slusser, B.S.
- _Gastroenterology_
- Alan J. Cameron, M.D.

- _Genetic Epidemiology_
- Gloria M. Petersen, Ph.D.
- _Study Coordinators_
- Betsy Cayer
- Mary Fredericksen, C.C.R.P.
- Deb Geno, C.C.R.P
**286 Clinicians & Scientists of the EABE Registry & the BEGS Group**
**Partners in Industry**
**Supporters at the NIH**

## Gracias!

**Gracias!**

## ROCHESTER

**ROCHESTER**
**  ****MN**

**ROCHESTER**
**  ****MN**

## Slide 65

## Simple (Monogenic) disorder

**Simple (Monogenic) disorder**

**Peltonen & McKusick, Science 291:1224, 2001**

## Complex disorder

**Complex disorder**

**Peltonen & McKusick, Science 291:1224, 2001**