MACGN - APC I1307K

TABLE OF CONTENTS

Introduction
What is Colorectal Cancer?
What are Polyps?
What Is the Gastrointestinal Tract?
What Is Familial Colorectal Cancer?
What Is Hereditary Colorectal Cancer?
What Is the Difference Between thte APC I1307K Mutation and Other APC Mutations?
How Is the APC I1307K Mutation Inherited?
Is There a Test for the Newly Discovered APC I1307K Mutation?
Why Is This Mutation Most Common in People of Ashkenazi Jewish Descent?
Who Should Consider Testing for the APC I1307K Mutation?
Who Should Not Be Tested?
Who Needs Genetic Counseling?
What Does a Negative Gene Test Result Mean?
What Does a Positive Gene Test Result Mean?
What Should You Do If You Receive a Positive Gene Test Result?
Is Insurance Discrimination a Risk for Those Seeking Genetic Testing?
How Can the Gene Test Be Obtained?
How Much Does the Gene Test Cost?
Resources
Glossary
Appendix: Guidelines for Colon Screening

INTRODUCTION

The purpose of this booklet is to provide information about an inherited type of colon cancer that may be more common among men and women of Ashkenazi Jewish heritage (Jews of Eastern European or Russian ancestry). The information provided is intended to add to, and is not a substitute for, discussions with doctors, genetic counselors, nurses, and other members of the health care team.

We encourage you to read the entire booklet in the order in which it was written, since each section is built upon information in preceding sections. We emphasize the need for regularly scheduled, thorough medical examinations for persons who already have had colorectal cancer. Equally important, relatives at risk for this condition need to have regular examinations.

For additional information you are encouraged to contact your own personal health care provider or the Hereditary Colorectal Cancer Registry at the Johns Hopkins Hospital, (410) 955-3875 or toll free 1-888-77COLON (772-6566).

WHAT IS COLORECTAL CANCER?

Colorectal cancer occurs when the cells that line the colon (large bowel, large intestine) or the rectum (lower portion of the colon) become abnormal and grow out of control. Colorectal cancer is one of the most common cancers, with more than 130,000 new cases occurring each year. More than 46,000 men and women die from this cancer each year.

WHAT ARE POLYPS?

Polyps are abnormal, mushroom-like growths. They are found in the gastrointestinal tract (stomach, colon) and are most commonly seen in the colon. Polyps vary in size from less than one-tenth of an inch to 1-2 inches. In some people, polyps may be inherited while in others they are not. Polyps themselves are benign, but certain types of polyps are considered precancerous and can turn into colon cancer or rectal cancer.

WHAT IS THE GASTROINTESTINAL TRACT?

The gastrointestinal digestive tract is a hollow tube that begins at the mouth and ends at the anus. It has several parts including the esophagus, stomach, small intestine and colon (large intestine). Its total length is about 28 feet. The last 5-6 feet of the intestine is called the colon (large intestine, large bowel). The last 5 or 6 inches of the colon is the rectum. After food is digested, solid wastes move through the colon and rectum to the anus, where they are passed out of the body.

WHAT IS FAMILIAL COLORECTAL CANCER?

The presence of colorectal cancer in more than one family member may be sporadic, or due to chance. Factors such as diet or environment may contribute to the development of cancer. Alternatively, in some families the risk of developing this disease has been passed from one generation to the next. This means that the blood relatives of a person with colorectal cancer may have a greater chance of developing this cancer.

About 10-30% of colorectal cancers are familial. Familial colon cancer means that there is some tendency for colon cancer to develop within a family. A single gene or a combination of genes can lead to familial cancer. A combination of genes and environmental factors can also cause this cancer. We say a family may have familial colorectal cancer when it runs in the family and when no specific gene change has yet been identified. Usually, one or two members of these families have had colorectal cancer or precancerous polyps.

WHAT IS HEREDITARY COLORECTAL CANCER?

We say that a family has hereditary colorectal cancer when we know about the exact genetic change that causes the cancer. Several genetic changes that cause hereditary colorectal cancer have been found. There may be other gene mutations (changes) that we have not yet found.

We know of two other inherited colorectal cancer syndromes. These two conditions occur in both Jewish and non-Jewish families:

Hereditary Non-Polyposis Colorectal Cancer (HNPCC): Patients with HNPCC develop colon cancer at an early age, usually under the age of 50, and may have a strong family history of colorectal cancer.
Familial Adenomatous Polyposis (FAP): Patients with FAP develop many colon polyps at a young age and often have a strong family history of colorectal cancer.

In 1997, a Johns Hopkins research team found an inherited mutation called APC I1307K. Researchers believe that 6 percent of the Ashkenazi Jewish population have this gene mutation. People who inherit this gene mutation have an increased risk of developing colorectal polyps and cancer.

WHAT IS THE DIFFERENCE BETWEEN THE APC I1307K MUTATION AND OTHER APC MUTATIONS?

Both the APC I1307K mutation and mutations that cause FAP occur in the same gene, the APC (Adenomatous Polyposis Coli) gene. Individuals with FAP develop hundreds to thousands of polyps in the colon and rectum and have a very high risk of developing colorectal cancer.

The APC I1307K mutation is different from other APC mutations because the mutation itself does not cause colon cancer. Instead, this particular mutation creates an unstable spot in the gene that makes the gene more susceptible to additional genetic changes that may in turn lead to colon cancer.

Pie Chart

HOW IS THE APC I1307K MUTATION INHERITED?

People with the APC I1307K gene mutation have a 50% chance of passing the gene mutation to each of their children. Children who do not inherit the gene mutation cannot pass it to their own children.

IS THERE A TEST FOR THE FOR THE NEWLY DISCOVERED APC I1307K MUTATION?

Yes, a gene test has been developed to look for this inherited gene mutation. It is performed on a small sample of blood. However, this gene test does not look for gene mutations that cause other forms of hereditary colorectal cancer.

Jacob has colon cancer and carries the APC I1307K gene mutation. His wife Ruth does not have the gene mutation. They have three children, Steven, David and Susan. All had a 50% risk of inheriting the APC I1307K gene mutation from Jacob. In fact, both Steven and Susan do carry the mutation, and both have developed polyps.
Steven and his wife Elizabeth have two children. Although both children had a 50% chance of inheriting the gene mutation, neither one did.
David and his wife Deborah have two children. Since David does not have the gene mutation, his children had no risk of inheriting the gene mutation from him.
Susan and Adam have two children. Both children had a 50% chance of inheriting the gene mutation from Susan. Both do carry the gene mutation, but neither one has yet developed polyps or colon cancer.

WHY IS THIS MUTATION MOST COMMON IN PEOPLE OF ASHKENAZI JEWISH DESCENT?

Recent scientific studies tell us that certain groups of people, including Ashkenazi Jews, have unique genetic mutations that increase their risk of certain cancers or diseases. In most cases, doctors who study genetics believe that the first time a gene change occurs in a group of people, it occurs by chance. When this group is small and separate from other groups, by geography or culture for example, the gene change may become more frequent from one generation to the next. This is probably why the APC I1307K gene mutation is most commonly found in people of Ashkenazi Jewish descent.

WHO SHOULD CONSIDER TESTING FOR THE APC I1307K MUTATION?

Any person of Ashkenazi heritage who has a personal or family history of colon cancer or colon polyps may wish to consider testing. A family history means having at least one close family member with colon cancer or polyps. Ashkenazi Jews without a family history of colorectal cancer may still wish to obtain genetic counseling to learn the value of gene testing in their own unique circumstances.

WHO SHOULD NOT BE TESTED?

This test is not recommended for non-Ashkenazi Jewish people.

WHO NEEDS GENETIC COUNSELING?

Anyone who is thinking about having a gene test must receive genetic counseling. This is required because there are many issues to consider before testing. Genetic information can affect different people in many ways. Some people may feel relieved by the outcome of their gene test while others may feel upset or anxious. The genetic counselor will discuss the features of familial colon cancer and the individual"s; risk of colon cancer based on unique family information. The genetic counselor will discuss how APC I1307K is inherited in families as well as the risks and benefits of genetic testing.

WHAT DOES A NEGATIVE GENE TEST RESULT MEAN?

If a person receives a negative gene test result, there is a 99% chance that he or she does not carry the gene mutation. This person may still have a mutation in another gene that causes hereditary colon cancer. Other risk factors can be assessed during genetic counseling, where family history, lifestyle, and other issues may be discussed. Recommendations about future screening guidelines can then be made based on these factors.

A negative gene test result does not rule out the need for more frequent colon cancer screening. Colon cancer guidelines based on family history are described in the Appendix, page 18.

WHAT DOES A POSITIVE GENE TEST RESULT MEAN?

If a person tests positive for the APC I1307K gene mutation, that person has an estimated 10-20% risk of developing colorectal cancer in his or her lifetime. The APC I1307K test results are 99% accurate. A positive test result may affect screening (colon exam) recommendations. This test is only a gene test. It does not detect the presence of cancer or polyps.

WHAT SHOULD YOU DO IF YOU RECEIVE A POSITIVE GENE TEST RESULT?

It is important to detect colon polyps or cancer early. Routine screening is the best way to do this. At this time, experts recommend the following:

Persons with a positive gene test result, who do not already have colon cancer or polyps, should have a routine colonoscopy every 2 years beginning at age 35 OR 5 to 10 years before the earliest age at which colon cancer or polyps occurred in the family, whichever is younger.
Patients with a personal history of colon cancer or polyps should have a routine colonoscopy every 2 years, or more often at the recommendation of their doctor.
Relatives of people testing positive for this gene mutation should consider counseling and testing as well.

IS INSURANCE DISCRIMINATION A RISK FOR THOSE SEEKING GENETIC TESTING?

With any gene test, there is a risk of insurance (life or health) or employment discrimination. At this time, there are federal laws that offer some protection against the discrimination of people who already have medical insurance through a group health plan. Some states have other laws to protect people, but the laws on insurance and employment discrimination vary from state to state. The Americans with Disabilities Act may protect people with a positive gene test result from discrimination in the work place. These issues will be carefully explained during the genetic counseling session.

HOW CAN THE GENE TEST BE OBTAINED?

This gene test is performed at the Johns Hopkins University Pathology Molecular Diagnostics Laboratory in Baltimore, Maryland and at a few other laboratories in the country. People who wish to be tested but do not live near Baltimore may consult with local experts for genetic counseling. They may have a blood sample sent to Johns Hopkins for testing.

HOW MUCH DOES THE GENE TEST COST?

The cost of this gene test may vary. Genetic counseling may be required and would be an additional cost. Some insurance companies will pay for genetic counseling and testing, while others will not. People who are thinking about having a gene test done should check with their insurance company before making a final decision.

RESOURCES

THE AMERICAN CANCER SOCIETY
National Headquarters
1599 Clifton Road, N.E.
Atlanta, Georgia 30329
(404) 320-3333
1 -800-ACS-2345

The ACS can offer assistance if cancer should occur. Check the telephone directory for your local chapter.
HEREDITARY COLON CANCER REGISTRIES
Registries are located throughout the United States, Canada, and in some other countries. You may contact them for the names of experts in the management of colon cancer. Registries can also help to identify relatives at risk for the disorder. Further information concerning Hereditary Colon Cancer Registries or how to join one near you may be obtained by contacting:
CANCER INFORMATION SERVICE (CIS)
Toll Free: 1-800-4-CANCER

The Cancer Information Service is a national toll-free telephone inquiry system that provides information about cancer and cancer-related resources to the general public, patients and their families, as well as health professionals. Most CIS offices are associated with Comprehensive Cancer Centers or community hospitals. CIS offices provide support, understanding and rapid access to the latest information, as well as referral to local services and resources. They do not diagnose or recommend treatment for individuals. Telephone information may be supplemented by printed materials. All calls are kept confidential, and individuals do not need to give their name.

GLOSSARY

APC - The abbreviated name of the gene Adenomatous Polyposis Coli. It is located on chromosome 5.

At risk - A person "at risk" has the possibility of developing the condition which is present in his or her family.

Benign - Harmless, not cancerous.

Chromosome - The carrier of the genetic material of a cell (genes). The normal number of chromosomes in the human cell is 46 (23 pairs).

Colon - Large intestine or large bowel; the last portion of the intestine. It comprises the cecum, ascending colon, transverse colon, descending colon and sigmoid colon, and is 5-6 feet in length.

Colonoscopy - A test in which a flexible tube, about 5 feet in length, is used to examine the inside of the entire colon. The tube has a light source, a magnifying eyepiece, and an open channel through which air can be passed and a biopsy taken.

Familial colon cancer - Colon cancer that is more likely to develop within one family.

FAP (Familial Adenomatous Polyposis) - An inherited disorder of the gastrointestinal tract in which there are usually 100 or more precancerous polyps.

Flexible sigmoidoscopy - A test in which a flexible tube about 2.5 feet in length is used to examine the rectum and lower part of the large bowel. The tube has a light source, a magnifying eyepiece, and an open channel through which air can be passed and a biopsy taken.

Gastrointestinal (GI) tract - The digestive system, consists of the esophagus (the swallowing tube), stomach, small intestine (22-25 feet in length), and large intestine (5-6 feet in length).

Gene - The basic unit of heredity, each one occupying a certain place on a chromosome.

Hereditary - Genetically transmitted from parent to children.

HNPCC (Hereditary Nonpolyposis Colorectal Cancer) - An inherited disorder in which there is a small number of precancerous polyps in the colon and an increased tendency to develop colon or rectal cancer. Some other types of cancer can occur in families with HNPCC.

Mutation - A change in a gene which may result in a specific disorder.

Pedigree - A family tree; genealogy.

Polyps - Abnormal growths that can occur in the colon. While polyps themselves are harmless, some types are considered precancerous and can turn into cancer.

Precancerous - Condition of a tissue, such as a polyp, that can turn into cancer if not treated or removed.

Sporadic - Occurring by chance; occurring in an isolated case.

APPENDIX: GUIDELINES FOR COLON SCREENING

The American Gastroenterological Association and
The American Cancer Society
recommend the following guidelines for colon cancer screening:

People 50 Years of Age or Older Without Any Risk Factors for Colorectal Cancer

Fecal Occult Blood Screening every year
AND
Flexible Sigmoidoscopy every 5 years
OR
Double Contrast Barium Enema every 5 to 10 years
OR
Colonoscopy every 10 years

People With Close Relatives Who Have Had Colorectal Cancer or Polyps

Same as above but starting at least by the age of 40

People With a History of Adenomatous Polyps

Colonoscopy 3 years after the removal of a polyp
On occasion, your doctor will recommend a shorter interval.
The interval for the next examination will be based on the type, size, and number of polyps present.

People with a History of Colorectal Cancer

People who have had colon surgery for colorectal cancer should have a colonoscopy within 1 year after surgery.
If this is normal, colonoscopy should be done again in 3 years, and if this is normal, then every 5 years.

The above recommendations are only guidelines. We suggest that you talk with your doctor regarding a colon cancer screening plan that is right for you.

If you have any of the Seven Warning Signals listed below, see your doctor or go to your clinic without delay

CANCER'S SEVEN WARNING SIGNALS

Change in bowel or bladder habits
A sore that does not heal
Unusual bleeding or discharge
Thickening or lump in breast or elsewhere
Indigestion or difficulty in swallowing
Obvious change in wart or mole
Nagging cough or hoarseness

ACKNOWLEDGEMENTS

This booklet was prepared by members of The Johns Hopkins Hereditary Colorectal Cancer Program in 1998: Deborah Armstrong, M.D., Judith A. Bacon, B.S., Susan Viles Booker, B.A., Jill D. Brensinger, M.S., Ann-Marie Codori, Ph.D., Francis M. Giardiello, M.D., Constance A. Griffin, M.D., Karen A. Johnson, M.S., John W. Kim, M.P.H., Sharon Olsen, M.S., R.N., Gloria M. Petersen, Ph.D., Lynne Rosenblum-Vos, Ph.D., Candace Young, B.S.N, R.N., and Kristin L. Zawacki, M.S.N., R.N.

The gastrointestinal tract illustration on page 3 was reprinted with permission of Bonnie Sue Rolstad, R.N., B.A., E.T., from the booklet "Ileoanal Reservoir: A Patient Resource."

We would like to thank Marion Wasser and members of the Jewish Community Center in Owings Mills, Maryland for their help in pilot testing this booklet.

We would also like to thank the Mid-Atlantic Cancer Genetics Network and the Clayton Fund for their support in the development of this booklet.

To order copies of this booklet, please contact the Mid-Atlantic Cancer Genetics Network, Johns Hopkins School of Public Health, Department of Epidemiology, Room W6517, 615 N. Wolfe Street, Baltimore, MD 21205-2011, phone (410) 614-6334 or toll free (877) 880-6188, fax (410) 955-0863.

© 1999 The Johns Hopkins University