A Study of Molecular and Genetic Factors for Liver Cancer in the Greater Baltimore Area

BACKGROUND:

Liver cancer is the third most deadly and fifth most common cancer worldwide. Hepatocellular
carcinoma (HCC) is the most frequent primary cancer of the liver with rising incidence in the
United States. HCC patients have a dismal outcome and are an underserved cancer population.
We are proposing a liver cancer case-control and case-case study to be conducted in
Baltimore, Maryland.

OBJECTIVES:

Our research is aimed to identify genetic and genomic changes that might explain the
aggressive nature of liver cancer. We will test the primary hypothesis that HCC biomarkers
exist in blood products (or mouth wash), urine and/or tissues that can be used for early
diagnosis and prevention. A unique study factor is the use of urine samples for biomarker
identification. A secondary goal will be to examine whether certain genetic and genomic
factors modify liver cancer susceptibility using candidate and genome wide association study
approaches. Although other studies have investigated genetic susceptibility, large scale
studies have not been conducted for liver cancer. Our study will also be valuable due to
access to frozen tumor specimens from pre-therapy resection, whose collection is required for
gene expression analysis. If certain genes are related to HCC risk and progression, this
tissue resource will be used to further validate our findings with laboratory investigations.
The proposed study is designed to be exploratory and hypothesis generating.

ELIGIBILITY:

The participants will reside in Baltimore City and surrounding areas. Cases will have
pathologically confirmed liver cancer or risk factors for HCC development. Risk factors
include chronic liver disease due to hepatitis B and/or C viral infection, nonalcoholic
steatohepatitis or alcoholic cirrhosis. The study will be supported by an epidemiological
infrastructure developed by our University of Maryland School of Medicine resource contractor
for ongoing lung and prostate cancer case-control studies. The enrollment of controls will
begin concurrently with case accrual, and will continue for 5 years. Population-based
controls will be recruited using a triple eligibility criterion, such that controls eligible
for the lung/prostate study will be asked to complete a supplemental questionnaire for the
liver study.

DESIGN:

The study will include 400 primary HCC cases, 800 patients with chronic liver disease (high
risk non-cancer cases) and a sample of 800 population-based controls. The HCC and high risk
non-cancer cases will be recruited at two Baltimore hospitals, the Veterans Affairs Medical
Center, and the University of Maryland School of Medicine over a period of 13-15 years.
Controls will be identified through a Department of Motor Vehicle database and match cases by
age, gender, race and county of residency. The study will involve administration of a
questionnaire and collection of blood (or mouth wash) from all study subjects. Fresh-frozen
tumor and tumor surrounding non-cancerous specimens will be obtained from approximately 20
percent of the cancer patients. The cases will receive one questionnaire.

- INCLUSION CRITERIA:

SELECTION OF CASE SUBJECTS (HCC AND HIGH RISK NON-CANCER CASES)

We will recruit incident cases of pathologically confirmed primary liver cancer or risk
factors for liver cancer (patients with chronic liver disease due to hepatitis B and/or C
viral infection, nonalcoholic steatohepatitis or alcoholic cirrhosis) at all stages of the
disease that are age greater than or equal to 18 years or less than or equal to 90 years.
Treatment can be surgery or therapy. The following check list will be used to verify
eligibility of a case subject.

ELIGIBILITY CRITERIA- HCC CANCER CASES

1. Diagnosed with primary liver cancer (HCC) within the last two years

2. Physician diagnosis based on AFP and ultrasound/imaging or Pathological diagnosis of
primary liver cancer made at the local hospital pathology department

3. Resides in Maryland or surrounding states

4. Has a residential working phone within his/her home (*The reason for a participant
having a residential working phone is that the matching population controls are
selected through the Department of Motor Vehicles records and must have a residential
telephone number to be selected as part of the random sample.)

5. Age is greater than or equal to 18 years and less than or equal to 90 years

6. A non-objection statement by the physician from the hospital where the patient was
identified, or listed as the treating physician by the tumor registry or surgical
pathology report, to contact the patient is obtained

7. Is not currently residing in an institution, such as a prison, nursing home, or
shelter

8. Is not a severely ill patient in the intensive care unit

9. Is able to give informed consent

10. Is physically and mentally capable of performing the interview

11. Must understand English well enough to be interviewed

12. Has never been interviewed as a control for this study

13. Subject provides informed consent and signs form.

ELIGIBITY CRITERIA HIGH RISK NON-CANCER CASES

1. Has been diagnosed with chronic Hepatitis B or C, NASH or alcoholic liver disease with
chronicity present at least for a 6 month period

2. Resides in Maryland or surrounding states

3. Has a residential working phone within his/her home

4. Age greater than or equal to 18 years and less than or equal to 90 years

5. A non-objection statement by the physician from the hospital where the patient was
identified or is being treated or by the surgical pathology report, to contact the
patient is obtained

6. Is not currently residing in an institution, such as a prison, nursing home, or
shelter

7. Is not a severely ill patient in the intensive care unit

8. Is able to give informed consent

9. Is physically and mentally capable of performing the interview

10. Must understand English well enough to be interviewed

11. Has never been interviewed as a control for this study

12. Subject provides informed consent and signs form.

SELECTION OF POPULATION-BASED CONTROLS

Population-based controls will be identified through the Motor Vehicle Administration
(MVA), and matched on age (year of birth), race, gender and geography to cases. We sample
controls in proportion to the population size of their county of residence. Recruitment of
controls will start concurrently with case accrual, using the age, race and gender
frequency distribution of cancer patients in previous years. The sampling frame is
continually updated as we accrue information on the case distribution of age, race and
gender. We will exclude controls that do not have a listed home phone number. The following
check list will be used to verify eligibility of a control subject.

ELIGIBILITY CRITERIA - POPULATION-BASED CONTROLS

1. Resides in Baltimore City, Anne Arundel, Baltimore, Caroline, Carroll, Cecil,
Dorchester, Harford, Howard, Kent, Queen Anne s, Somerset, Talbot, Wicomica and
Worchester County.

2. Has a residential working phone within his/her home

3. Age greater than or equal to 18 years and less than or equal 90 years

4. Have never had radiation therapy or chemotherapy

5. Is not currently residing in an institution, such as a prison, nursing home, or
shelter

6. Is physically and mentally capable of performing the interview

7. Must understand English well enough to be interviewed

8. Has never been interviewed as a control for the study

9. Subject provides informed consent and signs form.

EXCLUSION CRITERIA:

Exclusion Criteria-HCC CANCER CASES

1. Liver cancer patients who are older than 90 years are excluded because of co-morbidity
considerations and the difficulty of matching those cases with population-based
controls.

2. Children and institutionalized patients are excluded from the proposed study. Very few
HCC patients at the 3 participating hospitals are younger than 18 years of age and HCC
incidence mainly occurs in adults.

Exclusion Criteria-HCC HIGH-RISK NON-CANCER CASES

1. High Risk Non-Cancer patients who are older than 90 years are excluded because of
co-morbidity considerations and the difficulty of matching those cases with
population-based controls.

2. Children and institutionalized patients are excluded from the proposed study. Very few
HCC patients at the 3 participating hospitals are younger than 18 years of age and HCC
incidence mainly occurs in adults. High-Risk Non-Cancer cases who are younger than 18
years are excluded due to the need of matching with HCC cases and population controls.

Exclusion Criteria-POPULATION BASED CONTROLS

1. Population based controls who are older than 90 years are excluded because of
co-morbidity considerations and the difficulty of matching with HCC cases and high
risk non-cancer cases.

2. Population controls who are younger than 18 years or are institutionalized are
excluded due to the need of matching with HCC cases and high-risk non-cancer cases.

3. Population controls with prior cancer with the exception of non-melanomic skin cancer
(squamous or basal cell).