Hand Me Down Genes

In 1994, at age 27, Keira Berman became acutely ill with what she thought was the flu. She also had blood in her stool, an issue she had dealt with since childhood and assumed to be a reaction to certain foods. Berman’s physician sent her to a gastroenterologist, who detected thousands of polyps in her colon via colonoscopy.

Neither her gastroenterologist nor his pathologist knew what the polyps were, so they sent slides to several universities, Berman recalls. Johns Hopkins University responded that, based on her age and the number of polyps in her colon, the New Jersey resident likely had a relatively rare hereditary syndrome known as familial adenomatous polyposis (FAP).

The impact of the diagnosis was dramatic. Informed that the polyps in her colon would likely become cancerous soon, Berman underwent a total colectomy and ileoanal anastomosis surgery to construct a J pouch for waste elimination. In the years that followed, FAP affected almost every aspect of her life, from the foods she could eat to her decision to have a family.

AN UNCOMMON CONDITION

Colorectal cancer is diagnosed in an estimated 135,000 Americans each year, and is responsible for more than 50,000 deaths, report the Centers for Disease Control and Prevention. Of that number, 5 to 10 percent of cases are the result of an inherited genetic mutation, most commonly Lynch syndrome and, less so, FAP.

While relatively uncommon, these inherited syndromes can pose significant health issues for individuals who carry the genetic mutations, and for their family members. Among the most concerning is a dramatically increased risk for colorectal cancer and other specific cancer types.

Other long-term health issues are created by treatment, which can include removal of all or most of the colon, either prophylactically or during surgery for colorectal cancer. In addition, some women with Lynch syndrome choose to have preventive hysterectomies with removal of their fallopian tubes and ovaries once they are done having children, as a means of reducing their heightened risk for gynecologic cancers. And the syndromes mean that regular screening will forever remain a part of patients’ lives.

THE SYNDROMES

Lynch syndrome, previously known as hereditary nonpolyposis colorectal cancer (HNPCC), affects approximately one in 2,000 people. It is responsible for a little more than 3 percent of colon cancers, notes Dennis J. Ahnen, professor of medicine at the University of Colorado Denver School of Medicine, and co-director of the school’s Hereditary Cancer Clinic.

“Colon cancer risk is enormous in this group,” Ahnen states. “It is estimated that between 30 and 55 percent of people who have a Lynch syndrome mutation will develop colon cancer, compared to a little less than 5 percent for the general population.” In addition to having a higher risk, individuals with Lynch syndrome typically develop colon cancer at a much younger age than those in the general population.

Colon cancer isn’t the only cancer that can occur among individuals with Lynch syndrome, Ahnen adds. Women with the condition have a much higher risk of endometrial and ovarian cancers, and both men and women face a higher risk of cancers of the small bowel, stomach and ureter.

Classic FAP, which has an incidence at birth of 1 in 8,300 people, differs from Lynch syndrome in that it predisposes individuals to develop hundreds to thousands of polyps, known as adenomas, in the colon. Only a small percentage of adenomas progress to cancer, explains Ahnen, but because there are so many, colon cancer is almost inevitable. Without intervention, those with FAP have a 90 percent chance of developing the disease by the age of 45. As a result, the most common treatment for classic FAP is removal of the entire colon.

Whereas mutations in any one of five different genes may cause Lynch syndrome, FAP is caused by mutations in the APC gene, reports Francis M. Giardiello, the John G. Rangos Sr. Professor of Medicine at The Johns Hopkins University School of Medicine, and director of the Johns Hopkins Colorectal Cancer Registry and Risk Assessment Clinic. “People who have FAP usually present by age 15 with multiple colon adenomatous polyps and, if nothing is done, will develop colon cancer by age 39, on average,” Giardiello says.

Most people with FAP receive the gene mutation from their parents. But others, such as Berman, spontaneously develop the mutation, making them the first in their families to develop the syndrome. Immediately after Berman was diagnosed with FAP, her parents and sister were tested and found to be free of the syndrome.

Lynch syndrome and FAP are the most common hereditary conditions that can lead to colorectal cancer, but there are others, including MUTYH-associated polyposis (MAP) and serrated polyposis syndrome (SPS), formerly known as hyperplastic polyposis syndrome.

MAP is similar to FAP, observes Ahnen, but results in scores to hundreds of adenomas in the colon rather than the thousands that can be seen in FAP. MAP is an autosomal recessive syndrome, whereas FAP is autosomal dominant. This means that an individual must inherit a mutant copy of the MUTYH gene from each parent to develop the disease. “If someone presents with lots and lots of polyps and their parents do not have colonic polyposis or colon cancer, MAP is one of the things we have to think about,” Ahnen says. “It’s really important, and we’re just learning more about the spectrum of cancers that can occur in MAP.” Left unattended, MAP can result in a 50 to 80 percent lifetime cancer risk.

Serrated polyposis syndrome is so named because, under a microscope, the associated polyps, which can number in the hundreds, appear serrated, like bread knives. “We know individuals with serrated polyposis have a high risk of developing colon cancer,” Ahnen says. “However, so far, no specific gene mutation has been linked to the syndrome, so whether it’s a truly genetically inherited syndrome or some sort of non-genetic predisposition is not clear.”

The symptoms associated with colorectal cancers that arise from hereditary conditions are similar to those seen in sporadic forms of the disease (those cases not associated with inherited risk), including rectal bleeding and abdominal pain, observes Giardiello. The biggest difference, he says, is the age of presentation. “The mean age of diagnosis for sporadic colon cancer is 64, so patients tend to present with colon cancer or related symptoms in their 50s and 60s,” he explains. “But in all of these hereditary conditions, the mean age of diagnosis is the mid-40s or younger.”

Hereditary colorectal cancer syndromes can affect anyone, notes Giardiello. Race and gender play no role, nor, for the most part, does ethnicity. The one exception is the Ashkenazi Jewish population, which is at higher risk of FAP as a result of a unique APC gene mutation. “That’s the only ethnic exception we know about,” Giardiello says. “Lynch syndrome and the other conditions are worldwide, with no ethnic variation.”

DIAGNOSIS

Accurate diagnosis is different for each of the hereditary syndromes that can lead to colorectal cancer. Lynch syndrome is most commonly identified through a multigenerational family history that puts the spotlight on clusters of cancer which present at a very young age. “We’re talking about colon and endometrial cancers for sure, but a clustering of ovarian cancer or some of the more rare cancers, such as small bowel or cancer of the ureter, might also be the first clue that there is a hereditary syndrome in the family, and that it might be Lynch syndrome,” says Ahnen.

Lynch syndrome also is identified by screening the actual tumors of individuals with colon cancers for the syndrome’s molecular signature, called microsatellite instability, which means that the body is failing to correct errors in DNA. “Essentially all Lynch colon cancers have microsatellite instability, so it makes a useful screening test, but approximately 15 percent of colon cancers (in people who don’t have Lynch syndrome) are also microsatellite unstable, so these have to be distinguished,” Ahnen explains.Once microsatellite instability is confirmed, additional testing can determine if any of the five Lynch syndrome genes are involved.

“Lynch syndrome is woefully underdiagnosed,” Ahnen notes. “It is estimated that the large majority, perhaps up to 95 percent, of all families with Lynch syndrome have not been diagnosed. But we’re getting better because we now have more tools to help identify these families.”

Adds Giardiello: “The one thing we have advocated is that everyone with colon cancer, no matter how old they are, receive a screening test for Lynch syndrome. If there is evidence of the syndrome, then we would send that person to a genetic counselor for follow-up.”

FAP also is typically diagnosed through a detailed family history that identifies individuals who had their colons removed due to an unusually large number of polyps. Sometimes a family member will undergo genetic testing, which confirms FAP within the bloodline. “FAP is easier to diagnose because you don’t see hundreds or thousands of polyps sporadically—it’s usually caused by a familial syndrome,” notes Ahnen. “Once FAP is identified, children and siblings within the bloodline should be tested.” That process should start when children are between the ages of 10 and 12, national guidelines suggest.

When Anne Fagan of Coyningham, Pa., was diagnosed with FAP at age 27, her daughters, Kate and Sarah, were 3 years and 18 months old, respectively. Fagan feared more for them than herself.

“Not being all that medically oriented, I was in shock and very upset at the thought that the girls could also carry the gene,” Fagan recalls. “I felt resentment, anger, tremendous sorrow and real terror about the future of my family.”

But ultimately, Fagan says, she came to value that knowledge, realizing it provided her with a way to protect her daughters from potential illness.

SCREENING OPTIONS

A variety of screening options are available for the detection of both colon cancer and precancerous polyps, some more effective than others. “Ideally, you don’t want to find colon cancer when screening—you want to find the precursor lesion and remove it before it becomes cancerous,” says Giardiello. “Some tests concentrate on screening for cancer, and some more directly look for the precancerous lesions. So colonoscopy is probably the best of these tests because it looks for the precursor lesion.”

Hemoccult stool tests, which look for blood in the stool, are an indirect test for lesions which are close to, if not actually at, the point of becoming cancerous. “They are effective in that they decrease the risk of death from colon cancer, but they are going to find the problem at a much later stage in the game,” Giardiello explains.

Flexible sigmoidoscopy is similar to colonoscopy but not as effective, according to Giardiello, because it can examine only a third of the colon. “It’s the third where most (sporadic) cancers occur, but it doesn’t pick up the right side of the colon at all (which is most often implicated in the inherited syndromes), so it can miss things,” Giardiello says. “It is my opinion that colonoscopy is the better test because it looks at the entire colon.”

A relatively new family of colorectal screening tests, which includes Cologuard, looks for blood and tumor DNA markers in stool samples. These tests can be effective at detecting colon cancer, notes Giardello, but may not be effective at finding precancerous polyps because, at that stage, the polyps don’t bleed and may not carry some of the abnormalities in DNA that are carried in cancer cells. Because it is intended for patients age 50 and older, Cologuard is specifically not recommended for patients diagnosed with a hereditary cancer syndrome, according to the test’s literature.

LIFESTYLE: RISKS AND RAMIFICATIONS

Hereditary forms of colorectal cancer are typically gene-driven, but lifestyle factors may increase one’s risk of developing the disease. Obesity and lack of physical activity are risk factors for colon cancer. Diet can be a causative factor, so doctors emphasize a diet high in fruits and vegetables and low in fat, processed meats and red meat, especially meat cooked over high heat, such as on a grill. Alcohol and tobacco use may also increase one’s risk of developing colon cancer.

The diagnosis of a hereditary syndrome can be emotionally devastating for a family, says genetic counselor Ellen T. Matloff, founder and former director of the Yale Cancer Genetic Counseling Program and founder of My Gene Counsel. “Genetic counseling and testing really taps into a great number of emotional responses,” she explains. “They can range from fear to anger to guilt over the fact that perhaps they passed the genetic mutation on to their children. A depth of emotion can be observed, which is why genetic counseling is so important. Counselors can address those emotions and help the patient deal with them.”

Fagan can relate. Soon after her own diagnosis of FAP, she learned that both of her daughters also carried the gene. Fagan became an advocate for FAP patients, and once received a call from a woman with the gene who made the conscious decision not to inform her children because she didn’t want to frighten them. “It ended tragically,” Fagan says. “Her son was diagnosed with FAP while in the Army, and he was extremely angry that his mother hadn’t told him and allowed him to go through his life, marry and have a child. Then, unfortunately, he developed cancer and died.”

Fagan and her husband, Peter, took the opposite track. They kept Kate and Sarah in the loop, and started having them examined regularly before the girls reached puberty. Kate and Sarah had their colons removed prophylactically in their teens, and went on to marry and have two children each. Three of the four children have undergone genetic testing, and one, now 6, has FAP, Fagan says. The fourth child will receive genetic testing by the time he’s 2.

“We’re very big proponents of putting the issue on the table and talking about it,” says Fagan, who had her colon removed and underwent a tubal ligation following her diagnosis. “Get all your facts together and try to understand what’s happening. Everybody in your family should be on the same page, because you’re going to need that support.”