Identifying genetic determinants of Familial Barrett*s esophagus and adenocarcinoma of the gastro-esophageal junction

Worldwide esophageal cancer is a significant and an increasing health problem.
In 2005, there were 497,700 new cases, and the prevalence is expected to
increase by approximately 140% by 2025. Esophageal adenocarcinoma (EAC) account
for most cases of esophageal cancer in the Western world. Most esophageal
adenocarcinomas arise at the gastro-esophageal junction (GEJ) and are thought
to arise from Barrett*s epithelium, which is characterized by columnar
metaplasia with intestinal differentiation that has replaced the normal
squamous cell lining of the esophagus. Environmental factors as
gastro-esophageal reflux disease (GERD) and smoking contribute to chronic
inflammation, which promotes the transition from normal squamous cell
epithelium towards Barrett*s epithelium and ultimately leads to adenocarcinoma.
Circumstantial evidence on the role of genetics is provided by familial
clustering of BE and adenocarcinoma of the GEJ in certain families. Identifying
these families could be useful to study the exact phenotype of hereditary
Barrett*s esophagus (BE)/ adenocarcinoma of the GEJ and could be the key to the
identification of causal gene defects that underlie this condition. In the
current study we will explore the phenotype in families with multiple cases of
BE and EAC which enables genetic analysis in the near future aiming at
identifying putative susceptibility genes. Furthermore, it should allow (more
tailored) screening recommendations for relatives at increased risk.

The main goals of this study
1) To determine the prevalence of BE among first degree relatives of index
patients in families that fulfil criteria for familial BE/adenocarcinoma of the
GEJ
2) Collect tissues of the index patients and all first degree relatives (blood
or formalin fixed and paraffin embedded tissue) for genetic analyses in the
near future
3) Explore the phenotype of familial BE and adenocarcinoma of the GEJ

In a collaborative effort (with the Departments of Surgery and Medical
Genetics) we identified 20 families that met the criteria for familial BE or
adenocarcinoma of the GEJ.

Recruitment of the index patients
To ensure that only patients that are alive at baseline will be contacted, data
on vital status of these patients will obtained from the death register of the
Municipal Personal Records Database, which registers all deceased in the
Netherlands via the municipal civil registries. To ensure that only patients
that are alive at baseline will be contacted, data on vital status of these
patients will obtained from the death register of the Municipal Personal
Records Database, which registers all deceased in the Netherlands via the
municipal civil registries. The index patients from families meeting our
inclusion criteria will be invited to participate in this study by their
treating physician (surgeon, gastroenterologist, medical geneticist). If the
index patient is interested, he/she will receive an information letter. Within
one or two weeks, the patient will be contacted by telephone, by the
researcher. If the index patient is interested, he or she will be invited to
visit the outpatient clinic of the department of Gastroenterology. The patient
will receive together with a written confirmation of their outpatient clinic
visit, the *Barrett Esophagus* questionnaire, by mail. In one part of the
questionnaire, the patient is asked to fill in the contact information about
their first degree relatives (elder, siblings and children). At the outpatient
clinic, the study designs and implications will be discussed, and remaining
questions will be answered. If the patient is willing to participate, he/she
will be asked to sign the informed consent form, to sign the biobank form and
to provide the filled in *Barrett Esophagus* questionnaire. Directly after the
outpatient clinic visit, an experienced research nurse will take one blood
sample by venipuncture. This blood sample will be stored at the Central Biobank
at the UMC Utrecht and will be used in the next future for DNA research. After
informed consent, the first degree relatives will be invited for the study.
If the index patient is deceased, a first degree relative (in order of partner,
children or siblings) will be contacted, by the treating physician of the
deceased index patient (surgeon, gastroenterologist, medical geneticist). If
the individual is interested, he/she will receive an information letter and
will be contacted by telephone. If the individual is still interested, he/she
will be invited for an outpatient clinic visit to the department of
Gastroenterology. The individual will receive together with a written
confirmation of their outpatient clinic visit, the *Barrett Esophagus*
questionnaire, by mail. He or she will be asked to fill in the part of the
questionnaire that is about the contact information about the first degree
relatives (elders, siblings and children). He or she will receive a written
confirmation of their outpatient clinic visit. If the patient is willing to
participate, he/she will be asked to sign the informed consent and to provide
the filled in *Barrett Esophagus* questionnaire. After informed consent, the
first degree relatives will be invited for the study.

Recruitment of first degree relatives
All first degree individuals (alive and between 25 and 75 years old) will
receive an recruitment letter with a reply coupon on which they can indicate
whether they are interested in participating in this study. In case the first
degree relative is interested (thus reply their response form and indicate that
they are interested) , the study information and biobank information letter
will be sent. Within two weeks after receiving these letters, the individual
will be contacted by telephone. During this telephone consult, question of
individuals will be answered and (when applicable) the possibility of sedation
during the endoscopy will be discussed. If the individual underwent a
duodenoscopy in the past five years, he/she will be invited for an outpatient
clinic visit. Together with the written invitation to the outpatient clinic of
the department of Gastroenterology the individual will also receive the
*Barrett Esophagus* questionnaire. At the outpatient clinic remaining questions
will be answered. If the patient is willing to participate, he/she will be
asked to sign the informed consent form, to sign the biobank form and to
provide the filled in *Barrett Esophagus* questionnaire. Directly after the
outpatient clinic visit, an experienced research nurse will take one blood
sample by venipuncture.
When the individual had no prior duodenoscopy or more than five years ago,
he/she will be invited for a duodenoscopy at the endoscopy unit of the
department of Gastroenterology. Together with the written invitation for the
duodenoscopy, the individual will also receive the *Barrett Esophagus*
questionnaire. At the endoscopy unit, prior to endoscopy or venipunture, the
individuals will be asked to sign the study informed consent form, the biobank
form and to provide the filled in *Barrett Esophagus* questionnaire. At the
endoscopy unit the venipuncture will be carried out by an experienced research
nurse. After the duodenoscopy he/she (if preferred) will be informed directly
by the endoscopist about the findings. If biopsies are taken, the individual
will be invited for an outpatient clinic visit within two weeks to discuss the
pathological findings and further treatment.
If a first degree relative is deceased, the index patient will be asked
permission to obtain the medical record of the involved institution and
permission to check the PALGA database to search for (pre)malignant lesions and
if available to obtain tissue for DNA studies in the near future.

All individuals, index patients en first degree relatives, are asked permission
to check the PALGA database if patients are known with other (pre)malignant
lesions. This PALGA search will be repeated over 10 years.

For the index patient the burden consists of filling in the Barrett
questionnaire, one visit to the outpatient clinic and donation of one tube of
blood. This all together will take approximately 60 minutes and one extra
hospital visit.
For first degree family members the burden consists of filling in the Barrett
questionnaire, one telephone call, a duodenoscopy and donation of two tubes of
blood. This all together will take approximately 60 minutes, and one extra
hospital visit.

Venipuncture is a safe routine procedure and will be performed conform the
standard protocol. In approximately 10% of the venipunctures a hematoma may
develop, which heal scar less within a couple of days. Other complication such
as syncope and diaphoresis occur seldom. A duodenoscopy is considered as a safe
procedure. Complications are rare during and after upper endoscopy under local
anesthesia (1-2:1000 patients). The most common complain after the procedure is
a sore throat. Major complications such as an upper gastrointestinal bleeding
and perforation are rare (0.1% and 0.0001%, respectively).

The potential benefits for the participating individuals is early detection of
a BE. This premalignant requires treatment with a protonpomp inhibitor and
follow-up which will be done accordig the Dutch guidelines for BE.