December 5, 2011

Genetic Screening — Colorectal Cancer Test Shows Promise
By Carolyn Gutierrez
For The Record
Vol. 23 No. 22 P. 24

By identifying patients with Lynch syndrome, a genetic condition that greatly increases the risk of colon cancer, physicians can take preventive measures.

Researchers have found that genetic screening for hereditary colorectal cancer has proven to save lives while also being cost-effective. Over the past 15 years, advances in genetic testing have streamlined the diagnostic procedures for identifying families at risk, allowing for more options in preventive care.

The most common cause of hereditary colorectal cancer is Lynch syndrome, also known as hereditary nonpolyposis colorectal cancer. Although both sexes are affected equally, women with Lynch syndrome have an elevated risk of developing colorectal cancer as well as a very strong tendency to develop endometrial (or uterine) and ovarian cancer. Other cancers associated with Lynch syndrome include gastric, small bowel, kidney, bile duct, and even some brain and pancreatic cancers.

In the general public, the average age for the onset of colon cancer is 65. For those with Lynch syndrome, the average age of diagnosis is generally younger, typically around the age of 44. The polyps of those with Lynch syndrome are more likely to become cancerous, so physicians recommend that these patients begin screening colonoscopies as young as the age of 25.

If caught early, colon cancer is highly treatable, but for Lynch syndrome patients, there is a much greater chance of the cancer recurring in another part of the colon or rectum.

According to Michael Poles, MD, fellowship program director of the division of gastroenterology at NYU Langone Medical Center in New York City, “Lynch syndrome occurs when you have a genetically acquired mutation in proteins called the mismatch repair proteins.”

Hundreds of genetic mutations predisposing patients to colorectal cancer have been found, but the most significant number for Lynch syndrome have been discovered in four genes: MLH1, MSH2, MSH6, and PMS2. MLH1 and MSH2 genes account for 90% of the mutations.

“Normally, in your day-to-day existence, when you’re replicating cells, there are errors,” explains Poles, who is also an associate professor in the departments of gastroenterology, microbiology, and pathology at Langone. “The DNA polymerase is not going to be exact, so every time it tries to reproduce a gene, some errors happen, and naturally, the body has ways of identifying these errors. If it didn’t identify the errors, then everyone would develop cancer very quickly because cancer develops when you have errors in very important genes—genes that are controlling growth, etc. The gene that is damaged in Lynch syndrome, these mismatch repair proteins—MLH1 and MSH2—their job is to go ahead and proofread the DNA.”

As DNA is replicating a cell, the mismatch repair proteins created by the MLH1 and MSH2 genes verify that the sequence put in place on the new daughter strands of DNA are correct. When a mutation occurs, the proteins are either no longer made or a defective version of the protein is produced. Gradually, there is an accumulation of errors in the DNA, leading to a tumor in the colon or another part of the body.

Researchers have discovered that screening a colorectal cancer patient for these genetic mutations can drastically change the course of treatment.

According to Heather Hampel, MS, CGC, clinical associate director of the division of human genetics and a professor in the department of internal medicine at the Ohio State University Comprehensive Cancer Center, “We had studies here at Ohio State from 1999 through 2005 that proved it was feasible to screen all newly diagnosed colorectal cancer patients for Lynch syndrome, and since then, there have been several key papers that have supported our recommendations.”

In 2009, after reviewing the evidence put forth in studies by Hampel and other geneticists, the Evaluation of Genomic Applications in Practice and Prevention (EGAPP), a working group project developed by the National Office of Public Health Genomics, recommended newly diagnosed colorectal cancer patients receive across-the-board genetic screening for Lynch syndrome.

“The EGAPP paper was followed very closely by a paper that showed that it was cost-effective to do the screening, which is critical. Before everyone makes a change in standard of care, you have to make sure that it’s cost-effective,” Hampel says.

In findings reported in Cancer Prevention Research, a journal of the American Association for Cancer Research, scientists suggested that testing for Lynch syndrome could someday be as cost-effective as mammography in large patient populations.

Primary Screening for Lynch Syndrome
Before in-depth genetic sequencing is completed, two screening tests can be performed on a patient’s biopsy specimen to determine whether he or she is likely to have Lynch syndrome.

The first test is called microsatellite instability (MSI). “Throughout the genome, you have these little di- and trinucleotides called microsatellites, and when they show lots of mutations, that’s a suggestion that your mismatch repair proteins are not working,” Poles says.

MSI does not definitively determine if a patient has Lynch syndrome, but it does reveal whether a patient’s sequences of cellular DNA contain characteristics commonly seen in the syndrome. Approximately 95% of Lynch syndrome patients are MSI-positive.

“From our study,” says Hampel, “we now know that one out of every 35 colorectal cancer patients has Lynch syndrome. Then, if you have colorectal cancer and microsatellite instability, that increases your odds of having Lynch syndrome from one out of 35 to one out of five.”

The most cost-effective preliminary screening for Lynch syndrome is the immunohistochemistry (IHC) test. Like the MSI test, IHC analyzes a sample of the colorectal tumor specimen on a slide stain to detect if proteins are present. “If one of those genes is not working and the person has Lynch syndrome, they will have one or two of the proteins missing from their tumor,” Hampel says.

If a stain representing a protein is missing, it is a good indication that genetic sequencing should occur. Although slightly less sensitive than the MSI test, the IHC version is accessible to smaller hospitals because it can be performed in any pathology department alongside other standard immunohistochemistry studies.

“Every hospital, no matter what the size, can bring on the IHC staining, whereas it’s a little harder for smaller community hospitals to add on the MSI test because that one involves actually extracting DNA from the tumor—you need a molecular lab, which not all of the smaller hospitals have available to them,” Hampel says. “But the reason the IHC staining won in the cost-effectiveness analysis is because if the person is missing one or two stains, that tells me in genetics which gene is probably not working, which gene probably has a mutation that they inherited from their mom or their dad that gave them this susceptibility for Lynch syndrome. And that’s extremely helpful because gene testing is the most expensive part of the process. With MSI, you don’t know which of the four genes is responsible, so you might have to test all four of them to find the mutation, whereas with IHC, I would only have to test one or two of the genes.”

If possible, hospitals perform both the MSI and IHC tests for patients suspected of having Lynch syndrome.

At the Ohio State University Comprehensive Cancer Center, genetic counselors are actively involved with a patient’s surgeons, oncologists, and pathologists whenever a new case is reported as missing a stain in the IHC test. A genetic counselor will approach patients at one of their follow-up appointments—either a postoperative surgical visit or an oncology visit—and explain the preliminary screening results, offering full genetic counseling to help them better understand the implications of possibly having Lynch syndrome.

One of every five patients who is screened as being more likely to have Lynch syndrome will have his or her diagnosis confirmed when gene testing begins. For those patients, the screening is invaluable because it could lead to the prevention of a cancer recurrence. Female patients are advised to either get screened or have a hysterectomy to lower their risk of endometrial and ovarian cancer (if they are done having children).

All in the Family
Some of the most compelling findings by researchers advocating genetic screening for colorectal cancer patients cite the profound benefits to a patient’s relatives.

“I think the reason that EGAPP-recommended screening was the benefit to the family members—that is where you really exponentially increase the benefits,” Hampel says. “For example, in our study, we found that out of 1,566 colon cancer patients, 44 had Lynch syndrome. It doesn’t seem like much, but that’s 2.8%, which is where the one in 35 number comes from. But importantly, when we offered genetic counseling to the relatives, we tested an additional 249 relatives of the 44 people, and 109 of them tested positive.”

To illustrate the value in the testing of Lynch syndrome families, Hampel notes that of the 109 relatives who tested positive, one of them could very well have been a person in his or her 20s who, before the test, had no idea he or she had an 85% lifetime risk for colon cancer. If people in these circumstances began a series of preventive colonoscopies every one to two years at age 25, they could conceivably avoid getting colon cancer in their lifetime.

“Finding a family with Lynch syndrome is really an opportunity to do prevention for a high-risk group,” says Samir Gupta, MD, an assistant professor of internal medicine at the University of Texas Southwestern Medical Center and head of the high-risk colorectal cancer clinic at Parkland Memorial Hospital in Dallas.

Before the introduction of primary screening tests for hereditary conditions such as Lynch syndrome, physicians had to rely on patients’ sometimes-nebulous family histories to find out if there were multiple family members who had colon cancer. If they concluded a patient was at elevated risk, then physicians would refer the patient to a genetic counselor and proceed with genetic testing if it was deemed appropriate.

“There were two problems with the way that that was working,” says Gupta. “One was that if you just ask questions about family history and you don’t do the testing, you miss a substantial number of people who have Lynch syndrome because some patients who have Lynch syndrome don’t end up having a very striking family history—and that’s because they don’t know very much about their family and who died of cancer. For example, they might know that their grandfather died young … but they don’t really know of what. And some people have small families. A family history is most informative when people have multiple brothers and sisters, and multiple aunts and uncles, and so on.

“The second challenge is really one of knowledge,” he continues. “Taking the family history relies on someone thinking to do it and when a patient gets diagnosed with colorectal cancer, it’s a really busy time. Obviously, the primary goal of any doctor who’s involved with the care is ‘OK, how are we going to treat the patient’s cancer?’ Prevention doesn’t always rise to the forefront.”

To address these challenges, Gupta suggests establishing a system in the pathology lab where every patient who has colorectal cancer gets an initial screening test. “If it happens to be abnormal, you contact that patient’s doctor and the patient, advise them to do genetic counseling, and the patient decides if they want to have definitive testing to know whether or not they have Lynch syndrome. I think it’s both a system solution and a science solution,” he says.

DNA Analysis
Once a patient is identified as possibly having Lynch syndrome, gene sequencing is performed to definitively find the mutations in the mismatch repair genes. Depending on the number of genes that need to be sequenced, this can be time consuming and expensive.

“You have to look through the whole gene completely,” says Hampel. “I like to tell my patients it’s like going through an encyclopedia looking for a misspelled word—there are that many letters in the DNA code of the genes that we might be testing—and we don’t know if they have a mistake in those genes and, if they do, we don’t know where it is. But if we find it, then we know that person has Lynch syndrome, and this is the mistake that caused their Lynch syndrome. That’s like saying, ‘In the encyclopedia, on page 100, line four, word three is misspelled.’ For the rest of the family members, I don’t have to go through the whole encyclopedia, I can turn straight to page 100, line four, word three, and either they will have the mutation or not. It’s very reliable and very definitive.”

A full gene test might cost somewhere between $1,000 and $2,000 per gene, and some patients require two gene tests. However, once the mutation of that particular patient’s family is discovered, genetic testing costs about $200 to $400 for relatives.

Once a colorectal cancer patient is clearly identified as having Lynch syndrome, a genetic counselor invites him or her and as many at-risk family members as possible to a counseling session. Because offspring have a 50% chance of inheriting the syndrome, a patient’s children are usually part of that initial meeting.

“We’ll then counsel the children who are at risk and anyone over the age of 18 is then eligible, if they’d like, to be tested,” notes Hampel. “And they can decide on their own. They make an informed decision.”

She says most relatives choose to be tested once the benefits are fully explained. If a young relative tests negative, a colonoscopy is not necessary until age 50. If the result is positive, a patient is recommended to begin having colonoscopies at 25. Should genetic testing be declined, the safest route to take is to assume a patient is positive and recommend frequent colonoscopies, says Hampel.

“You explain to the relative that they don’t have to be tested, but if they don’t get tested, they need to act as if they’re positive,” she adds.

A patient’s siblings can be tested as well. Like offspring, siblings of a patient with Lynch syndrome will have a 50% chance of inheriting the syndrome. If that is indeed the case, then their children can be tested as well. If the siblings did not inherit the mutation, it is unnecessary to test their children.

“As a genetic counselor, the part I love the best is when I get to work with the patients and their family members once we know they do have Lynch syndrome to help them determine whether they inherited it and, if they did, know exactly what they need to do for cancer prevention. And if they didn’t [inherit it], that’s great news,” Hampel says.

She and her colleagues at Ohio State have received calls from hospitals across the country that are considering implementing screening programs for their colorectal cancer patients. “[The phone calls] used to be something that happened once every few months,” she says. “Now it happens twice a week because the ball is rolling. It’s an exciting time.”

— Carolyn Gutierrez is a freelance writer based in New York City.