Combating hereditary forms of colon cancer with the Familial Cancer Registry

It is not unusual for patients to approach Dr. C. Richard Boland, a gastroenterologist on the medical staff at Baylor University Medical Center with concerns that they may have a hereditary form of colorectal cancer.

And when you consider his history with familial ties to colon cancer, you can understand why they come to him for help:

“Dr. Boland resolved to solve the riddle behind his family’s history of colorectal cancer. His medical school thesis was titled “A Familial Cancer Syndrome,” focusing on his family’s medical pedigree. He accomplished his mission by 2001 by determining the gene mutation that ravaged his family and developed a way to detect it. He tested everyone in his family tree who was the child of a relative who developed the cancer. Those who had the mutation were urged to act. Men were told to have annual colonoscopies. Women were encouraged to have their uterus and ovaries removed after bearing children. Since then, none of his relatives has developed cancer.

Dr. Boland is writing a book about the family’s battle with the disease, and is credited with naming it Lynch syndrome. He has published more than 360 papers and written authoritative chapters in several textbooks.”

But he didn’t stop after solving his own family’s mystery. Now he’s helping other families with similar hereditary cancer ties break their family cycles too.

Fighting hereditary cancer ties

New strategies are developing to help Dr. Boland and others identify hereditary cancer — and fight it.

First, the patients are evaluated clinically and a careful family history is taken, including a pedigree, or “family tree,” that is drawn up using the information and inputed into a special computer program. The person in the family most likely to provide the critical information is selected for genetic testing for the disease in question. The most common conditions encountered are familial adenomatous polyposis (FAP) and Lynch Syndrome. These are relatively easy to distinguish and testing is only done for the appropriate condition.

There are three possible results of the testing: positive, negative or ambiguous. When Dr. Boland gets an ambiguous result, it means the reference laboratory is not sure whether this sequence variation in DNA is the cause of the disease in question.


“We invite people from all three categories to become ‘research subjects’ and join the Familial Colorectal Cancer Registry,” Dr. Boland said. “If the person agrees, we draw a tube of blood for extraction of DNA. In the case of those people who have a definite diagnosis, the DNA is used to look for other genetic variations that modify the clinical expression of that disease.”

Specifically, when there is one mutation in a family, some of the affected family members get a cancer of the colon and other relatives might develop cancer elsewhere. Family members can also get hereditary cancer when they are very young while others might not have issue until they are older.

“We are interested in understanding what modifies disease expression in those carrying the mutation.” Dr. Boland said.

Tackling ambiguous test results

In the case of ambiguous results, researchers can often do additional tests to make the ambiguous test more certain. Sometimes they can do testing on the tumor tissue itself, and that can help clarify the nature of the mutation. The reference laboratory only uses the genetic test and the presence or absence of certain tumors in developing their interpretation, so they have an advantage in formulating an interpretation.

If tests come back negative, they can test for other genes that could produce the same family history, or look for (and occasionally find) alterations in the gene that are not detectable by the reference laboratory.

“We can also perform tests in the future, when research progress alerts us to new ways that a gene can be altered to cause disease,” Dr. Boland said. “As a result, those who volunteer to be research subjects can help others who may be affected by a mutation that is difficult to interpret, and help with medical progress. On occasion, we can even solve the mystery in a family and help the research volunteers who may be affected by a familial predisposition to cancer.”

Dr. Boland provides some specifics about the registry:

Is there an official title to the cancer registry?

“It is our Familial Colorectal Cancer Registry, aka Registry for the Hereditary Colorectal Cancer Risk Program.”

Once an individual is registered in the cancer registry, are they in it forever? Does the information stay there to be used in the future?

Essentially, they are. (However long forever might be.) We keep testing since there are continuous advances, and we keep testing each person’s DNA when there is some chance that we might find something useful. We are always testing and looking for another type of mutation in a gene that has been newly linked to one form of cancer or another.

There are about 21,000 genes, and some of them are linked to cancer in a non-obvious way. We usually don’t find any mutations, but when we do, it’s an opportunity to help a family.

Also, when other researchers want information on familial cancer, we de-identify the information (i.e., make it impossible to trace back to the individuals involved) and share either the pedigrees (i.e., the information about which family members had what cancers, at what age, and with what outcomes), or we literally share a portion of the DNA (again, totally de-identified, to protect privacy). We also obtain informed consent from subjects to send de-identified samples outside of Baylor Scott & White through any collaborative research endeavors. A fully-executed Material Transfer Agreement (MTA) is completed prior to providing any de-identified pedigrees or DNA samples.”

How is the information in the cancer registry utilized?

“At this time, we are only using this to look for alterations in DNA that might help us understand why someone got a cancer and to help determine if that information might be useful to family members.

In some instances, we take one look at the genetic test results and know that we have an answer to the question about what caused that person’s cancer, and this translates into useful guidance for the rest of the family. In other instances, it is not obvious, and that requires more work for the proper interpretation. Some have remained a mystery for 10 years. We keep looking and testing.”

How has the registry grown?

“We have about 750 people now. The more we get, the more powerful the registry becomes. For example, if we have only one person or family with a given disease entity or family history, it can be hard to know for sure if an alteration in DNA is the source of the problem. However, if we have 10 people with an unexplained problem, and five to 10 have the same DNA alteration, and none of hundreds of unaffected ‘controls’ have the sequence variation, then we think that we might be on to something important. We have IRB approval to consent approximately 200 individuals annually for the research registry.”

Is this registry unique to Baylor Scott & White?

Other research-oriented medical centers may have similar registries, but there are actually only a few hereditary CRC registries like ours. We recently shared data with an international registry focused on a specific problem, and I noted that Baylor had one of the largest registries that was developed by a single researcher. Of course, places like the Mayo Clinic who have had many researchers working on this for many years (or decades), had the most. Our registry has been operational since the fall of 2003, and has been developed by one physician and one research nurse, but we have been very effective in getting people into the registry, and we have had some excellent successes at solving several types of challenging clinical problems.”

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Combating hereditary forms of colon cancer with the Familial Cancer Registry